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1

The Broadly Neutralizing Anti-Human Immunodeficiency Virus Type 1 4E10 Monoclonal Antibody Is Better Adapted to Membrane-Bound Epitope Recognition and Blocking than 2F5? †  

PubMed Central

The broadly neutralizing 2F5 and 4E10 monoclonal antibodies (MAbs) recognize epitopes within the membrane-proximal external region (MPER) that connects the human immunodeficiency virus type 1 (HIV-1) envelope gp41 ectodomain with the transmembrane anchor. By adopting different conformations that stably insert into the virion external membrane interface, such as helical structures, a conserved aromatic-rich sequence within the MPER is thought to participate in HIV-1-cell fusion. Recent experimental evidence suggests that the neutralizing activity of 2F5 and 4E10 might correlate with the MAbs' capacity to recognize epitopes inserted into the viral membrane, thereby impairing MPER fusogenic activity. To gain new insights into the molecular mechanism underlying viral neutralization by these antibodies, we have compared the capacities of 2F5 and 4E10 to block the membrane-disorganizing activity of MPER peptides inserted into the surface bilayer of solution-diffusing unilamellar vesicles. Both MAbs inhibited leakage of vesicular aqueous contents (membrane permeabilization) and intervesicular lipid mixing (membrane fusion) promoted by MPER-derived peptides. Thus, our data support the idea that antibody binding to a membrane-inserted epitope may interfere with the function of the MPER during gp41-induced fusion. Antibody insertion into a cholesterol-containing, uncharged virion-like membrane is mediated by specific epitope recognition, and moreover, partitioning-coupled folding into a helix reduces the efficiency of 2F5 MAb binding to its epitope in the membrane. We conclude that the capacity to interfere with the membrane activity of conserved MPER sequences is best correlated with the broad neutralization of the 4E10 MAb.

Huarte, Nerea; Lorizate, Maier; Maeso, Ruben; Kunert, Renate; Arranz, Rocio; Valpuesta, Jose M.; Nieva, Jose L.

2008-01-01

2

Naphthalene sulfonate polymers with CD4-blocking and anti-human immunodeficiency virus type 1 activities.  

PubMed Central

PIC 024-4 and PRO 2000 are naphthalene sulfonate polymers that bind to CD4 with nanomolar affinity and block binding of gp120. Both have activity against human immunodeficiency virus type 1 in H9 cells, peripheral blood mononuclear cells, and primary monocyte/macrophages, are synergistic with zidovudine, and do not inhibit tetanus toxoid-stimulated T-cell proliferation at anti-human immunodeficiency virus type 1 concentrations.

Rusconi, S; Moonis, M; Merrill, D P; Pallai, P V; Neidhardt, E A; Singh, S K; Willis, K J; Osburne, M S; Profy, A T; Jenson, J C; Hirsch, M S

1996-01-01

3

Structure-activity correlationship and strain specificity of polyoxometalates in anti-human immunodeficiency virus activity.  

PubMed

The anti-human immunodeficiency virus (HIV) activity of polyoxometalates of representative structural families, such as Keggin, lacunary Keggin, trivacant Keggin, Keggin sandwich, Wells-Dawson and Wells-Dawson sandwich, was determined using two strains of HIV type 1 (HIV-1HTLV-IIIB and HIV-1SF-2H). The compounds were preferably selected to cover both polyoxotungstates and polyoxomolybdates in each structural family. In general, polyoxotungstates of Keggin, lacunary Keggin, trivacant Keggin, Keggin sandwich, Wells-Dawson and Wells-Dawson sandwich structures showed anti-HIV-1HTLVIIIB activity, whereas most compounds not included in these structural categories were inactive. Among the compounds with a potent anti-HIV-1HTLV-IIIB activity, those of Keggin and its closely related structural families (lacunary Keggin, trivacant Keggin and Keggin sandwich) inhibited the cytopathogenicity and syncytium formation caused by HIV-1SF-2 to a much higher extent compared with HIV-1HTLV-IIIB-related ones. The difference between the spectra of anti-HIV-1HTLV-IIIB activity and the specificity for HIV-1SF-2H might result from differential structural requirements in these functions. PMID:7581257

Inouye, Y; Fujimoto, Y; Sugiyama, M; Yoshida, T; Yamase, T

1995-07-01

4

Candidate Sulfonated and Sulfated Topical Microbicides: Comparison of Anti-Human Immunodeficiency Virus Activities and Mechanisms of Action  

Microsoft Academic Search

Poly(styrene 4-sulfonate), cellulose sulfate, polymethylenehydroquinone, and PRO 2000 are sulfated or sulfonated polymers (SPs) under development as topical microbicides. They are presumed to work through similar mechanisms of action, although to date there has been no extensive comparison of their anti-human immunodeficiency virus activities. To determine whether any of these candidate microbicides offers a potential advantage, their in vitro activities,

Irini A. Scordi-Bello; Arevik Mosoian; Cejiang He; Yiban Chen; Yang Cheng; Gary A. Jarvis; Marla J. Keller; Kathleen Hogarty; Donald P. Waller; Albert T. Profy; Betsy C. Herold; Mary E. Klotman

2005-01-01

5

Essential regions for antiviral activities of actinohivin, a sugar-binding anti-human immunodeficiency virus protein from an actinomycete  

Microsoft Academic Search

Actinohivin (AH) is a potent anti-human immunodeficiency virus (HIV) protein that consists of highly conserved three-tandem repeats (segments 1, 2, and 3). The molecular target of AH in its anti-HIV activity is high-mannose-type saccharide chains of HIV gp120. This article deals with sequence requirements for the anti-HIV activity of AH. The deleted or substituted DNAs encoding AH or His-AH were

Atsushi Takahashi; Junji Inokoshi; Harumi Chiba; Satoshi Omura; Haruo Tanaka

2005-01-01

6

Broad-Spectrum Anti-Human Immunodeficiency Virus (HIV) Potential of a Peptide HIV Type 1 Entry Inhibitor?  

PubMed Central

The AIDS epidemic continues to spread at an alarming rate worldwide, especially in developing countries. One approach to solving this problem is the generation of anti-human immunodeficiency virus (HIV) compounds with inhibition spectra broad enough to include globally prevailing forms of the virus. We have examined the HIV type 1 (HIV-1) envelope specificity of a recently identified entry inhibitor candidate, HNG-105, using surface plasmon resonance spectroscopy and pseudovirus inhibition assays. The combined results suggest that the HNG-105 molecule may be effective across the HIV-1 subtypes, and they highlight its potential as a lead for developing therapeutic and microbicidal agents to help combat the spread of AIDS.

Cocklin, Simon; Gopi, Hosahudya; Querido, Bianca; Nimmagadda, Manideepthi; Kuriakose, Syna; Cicala, Claudia; Ajith, Sandya; Baxter, Sabine; Arthos, James; Martin-Garcia, Julio; Chaiken, Irwin M.

2007-01-01

7

Induction of Murine Mucosal CCR5-Reactive Antibodies as an Anti-Human Immunodeficiency Virus Strategy  

PubMed Central

The genital mucosa is the main site of initial human immunodeficiency virus type 1 (HIV-1) contact with its host. In spite of repeated sexual exposure, some individuals remain seronegative, and a small fraction of them produce immunoglobulin G (IgG) and IgA autoantibodies directed against CCR5, which is probably the cause of the CCR5-minus phenotype observed in the peripheral blood mononuclear cells of these subjects. These antibodies recognize the 89-to-102 extracellular loop of CCR5 in its native conformation. The aim of this study was to induce infection-preventing mucosal anti-CCR5 autoantibodies in individuals at high risk of HIV infection. Thus, we generated chimeric immunogens containing the relevant CCR5 peptide in the context of the capsid protein of Flock House virus, a presentation system in which it is possible to engineer conformationally constrained peptide in a highly immunogenic form. Administered in mice via the systemic or mucosal route, the immunogens elicited anti-CCR5 IgG and IgA (in sera and vaginal fluids). Analogous to exposed seronegative individuals, mice producing anti-CCR5 autoantibodies express significantly reduced levels of CCR5 on the surfaces of CD4+ cells from peripheral blood and vaginal washes. In vitro studies have shown that murine IgG and IgA (i) specifically bind human and mouse CD4+ lymphocytes and the CCR5-transfected U87 cell line, (ii) down-regulate CCR5 expression of CD4+ cells from both humans and untreated mice, (iii) inhibit Mip-1? chemotaxis of CD4+ CCR5+ lymphocytes, and (iv) neutralize HIV R5 strains. These data suggest that immune strategies aimed at generating anti-CCR5 antibodies at the level of the genital mucosa might be feasible and represent a strategy to induce mucosal HIV-protective immunity.

Barassi, C.; Soprana, E.; Pastori, C.; Longhi, R.; Buratti, E.; Lillo, F.; Marenzi, C.; Lazzarin, A.; Siccardi, A. G.; Lopalco, L.

2005-01-01

8

Sophorolipids, Microbial Glycolipids with Anti-Human Immunodeficiency Virus and Sperm-Immobilizing Activities  

Microsoft Academic Search

The increased incidence of human immunodeficiency virus (HIV)\\/AIDS disease in women aged 15 to 49 years has identified the urgent need for a female-controlled, efficacious, and safe vaginal topical microbicide. To meet this challenge, sophorolipid (SL) produced by Candida bombicola and its structural analogs have been studied in this report for their spermicidal, anti-HIV, and cytotoxic activities. The sophorolipid diacetate

Vishal Shah; Gustavo F. Doncel; Theodoros Seyoum; Kristin M. Eaton; Irina Zalenskaya; Rena Hagver; Abul Azim; Richard Gross

2005-01-01

9

Sophorolipids, microbial glycolipids with anti-human immunodeficiency virus and sperm-immobilizing activities.  

PubMed

The increased incidence of human immunodeficiency virus (HIV)/AIDS disease in women aged 15 to 49 years has identified the urgent need for a female-controlled, efficacious, and safe vaginal topical microbicide. To meet this challenge, sophorolipid (SL) produced by Candida bombicola and its structural analogs have been studied in this report for their spermicidal, anti-HIV, and cytotoxic activities. The sophorolipid diacetate ethyl ester derivative is the most potent spermicidal and virucidal agent of the series of SLs studied. Its virucidal activity against HIV and sperm-immobilizing activity against human semen are similar to those of nonoxynol-9. However, it also induced enough vaginal cell toxicity to raise concerns about its applicability for long-term microbicidal contraception. Its structure-activity relationship has been established for creating new analogs with less cytotoxicity and higher activity. PMID:16189085

Shah, Vishal; Doncel, Gustavo F; Seyoum, Theodoros; Eaton, Kristin M; Zalenskaya, Irina; Hagver, Rena; Azim, Abul; Gross, Richard

2005-10-01

10

Sophorolipids, Microbial Glycolipids with Anti-Human Immunodeficiency Virus and Sperm-Immobilizing Activities  

PubMed Central

The increased incidence of human immunodeficiency virus (HIV)/AIDS disease in women aged 15 to 49 years has identified the urgent need for a female-controlled, efficacious, and safe vaginal topical microbicide. To meet this challenge, sophorolipid (SL) produced by Candida bombicola and its structural analogs have been studied in this report for their spermicidal, anti-HIV, and cytotoxic activities. The sophorolipid diacetate ethyl ester derivative is the most potent spermicidal and virucidal agent of the series of SLs studied. Its virucidal activity against HIV and sperm-immobilizing activity against human semen are similar to those of nonoxynol-9. However, it also induced enough vaginal cell toxicity to raise concerns about its applicability for long-term microbicidal contraception. Its structure-activity relationship has been established for creating new analogs with less cytotoxicity and higher activity.

Shah, Vishal; Doncel, Gustavo F.; Seyoum, Theodoros; Eaton, Kristin M.; Zalenskaya, Irina; Hagver, Rena; Azim, Abul; Gross, Richard

2005-01-01

11

Studies on anti-human immunodeficiency virus oligonucleotides that have alternating methylphosphonate/phosphodiester linkages.  

PubMed

Preliminary investigations of the physical properties of oligonucleotide analogs that contain alternating methylphosphonate/phosphodiester linkages are described. An alternating oligo-2'-O-methylribonucleoside methylphosphonate, oligomer 1676, whose sequence is complementary to the upper hairpin region of human immunodeficiency virus TAR RNA, has been synthesized. This 15-mer forms a very stable duplex with its complementary RNA target, whose melting temperature is 71 degrees C. Introduction of two mismatched bases reduces the melting temperature by 16 degrees C. Similar results were obtained with the all-phosphodiester version of oligomer 1676, which demonstrates that introduction of the methylphosphonate linkages does not significantly perturb the ability of the oligo-2'-O-methylribonucleoside methylphosphonate to bind to RNA. Unlike the phosphodiester oligomer, however, oligomer 1676 is completely resistant to hydrolysis by the 3'-exonuclease activity found in mammalian serum. The interactions between nuclease-resistant, 5'-psoralen-derivatized, alternating oligo-2'-deoxypyrimidine methylphosphonates and double-stranded DNA were also studied. A 15-mer that contains thymine, 5-methylcytosine, and 5-propynyl-uracil forms a triplex with a polypurine tract found in the env gene of human immunodeficiency virus proviral DNA with an apparent dissociation constant of 400 nM at 22 degrees C. Maximal triplex formation by these oligomers is observed at approximately 2.5 mM magnesium, whereas maximal triplex formation by the corresponding all-phosphodiester oligomers occurs between 10 and 20 mM magnesium. This reduced magnesium dependence most likely results from reduced charge repulsion between the backbones of the methylphosphonate oligomer and purine strand of the target. The nuclease stability and ability of the methylphosphonate oligomers to form stable complexes with their target nucleic acids suggest that these oligomers are potential candidates for use as antisense or antigene agents in cell culture. PMID:10739870

Miller, P S; Cassidy, R A; Hamma, T; Kondo, N S

2000-03-01

12

ACTG 260: a Randomized, Phase I-II, Dose-Ranging Trial of the Anti-Human Immunodeficiency Virus Activity of Delavirdine Monotherapy  

Microsoft Academic Search

ACTG 260 was an open-label, four-arm trial designed to study the safety and anti-human immunodeficiency virus (anti-HIV) activity of delavirdine monotherapy at three ranges of concentrations in plasma compared to those of control therapy with zidovudine or didanosine. Delavirdine doses were adjusted weekly until subjects were within their target trough concentration range (3 to 10, 11 to 30, or 31

MICHAEL F. PARA; PATRICIA MEEHAN; JEANNE HOLDEN-WILTSE; MARGARET FISCHL; GENE MORSE; ROBERT SHAFER; LISA M. DEMETER; KENNETH WOOD; TOM NEVIN; WILLIAM W. FREIMUTH

1999-01-01

13

Ontogeny of anti-human immunodeficiency virus (HIV) antibody production in HIV-1-infected infants.  

PubMed Central

The early serologic response of infants to infection with human immunodeficiency virus type 1 (HIV-1) is normally obscured by the presence of transplacentally acquired maternal HIV antibody. By measuring HIV antibody produced in vitro by lymphocytes isolated from peripheral blood of infants and children of HIV-1-infected mothers, we have been able to study the natural acquisition of humoral immunity to perinatal HIV-1 infection. One hundred ninety-seven infants of HIV-1-infected women were studied prospectively and longitudinally from birth. In the neonatal period, infected infants produced only small amounts of HIV-specific IgG antibodies to a restricted number of antigens. The amount of immunoglobulin to HIV-1 and the number of HIV-1 antigens recognized increased with age. After 6 months of life 85% of infected infants made detectable antibody to two or more viral proteins. Antibody to gp160 appeared first and was the most frequently found at all ages, followed by antibody to the envelope proteins gp120 and gp41. The amount of HIV antibody produced correlated positively with the percentage of CD4+ T lymphocytes in peripheral blood. This assay provides a method of studying the immunogenicity of vaccines against HIV-1 in HIV-1-infected infants and of assessing the effect of early therapeutic interventions on the humoral response to HIV-1.

Pollack, H; Zhan, M X; Ilmet-Moore, T; Ajuang-Simbiri, K; Krasinski, K; Borkowsky, W

1993-01-01

14

Anti-(human immunodeficiency virus) activity of polyoxotungstates and their inhibition of human immunodeficiency virus reverse transcriptase.  

PubMed Central

Heteropolyoxotungstates of the Keggin class containing different heteroatoms were tested for inhibition of two strains of human immunodeficiency virus 1 (HIV-1); they exhibited varying antiviral activity. Compounds containing boron were inactive, only one of those containing phosphorus showed selective anti-viral activity, whereas all silicon-containing compounds exhibited significant anti-viral activity in C8166 cells infected with the IIIB strain. Their effectiveness was some 10-fold higher in JM cells with selectivity indices of about 2000. The silicotungstates were effective inhibitors of HIV reverse transcriptase, showing greater inhibition with RNA/DNA template primers than with DNA/DNA template.primer. Kinetic analysis demonstrated that they inhibit the enzyme by different mechanisms, as, of the four compounds examined, two competed with template.primer and two competed with deoxynucleoside triphosphate. Inhibition of DNA polymerase activity by these compounds was compared using polymerases from different sources, including human; although not necessarily most specific for HIV-1 reverse transcriptase, they did not inhibit all DNA polymerases to a similar degree.

Moore, P S; Jones, C J; Mahmood, N; Evans, I G; Goff, M; Cooper, R; Hay, A J

1995-01-01

15

Trappin-2/Elafin: a novel innate anti-human immunodeficiency virus-1 molecule of the human female reproductive tract.  

PubMed

Trappin-2/Elafin is a serine protease inhibitor that plays a major role as an anti-inflammatory mediator at mucosal surfaces. In addition, Trappin-2/Elafin has antibacterial activity against Gram-positive and Gram-negative bacterial and fungal pathogens. In this study we examined the production of Trappin-2/Elafin by epithelial cells from the human upper and lower female reproductive tract as well as its activity as an anti-human immunodeficiency virus (HIV)-1 molecule. We found that primary uterine, Fallopian tube, cervical and ectocervical epithelial cells produce Trappin-2/Elafin constitutively and that production of Trappin-2/Elafin is enhanced following stimulation with Poly(I:C), especially by the uterine cells. Given the presence of Trappin-2/Elafin in the reproductive tract, we tested the ability of recombinant Trappin-2/Elafin to inhibit HIV-1, an important sexually transmitted pathogen. We found that recombinant Trappin-2/Elafin was able to inhibit both T-cell-tropic X4/IIIB and macrophage-tropic R5/BaL HIV-1 in a dose-dependent manner. The inhibitory activity was observed when virus was incubated with Trappin-2/Elafin but not when Trappin-2/Elafin was added to cells either before infection or after infection. This suggests that the mechanism of inhibition is likely to be a direct interaction between HIV-1 and Trappin-2/Elafin. Additionally, we measured the levels of secreted Trappin-2/Elafin in cervico-vaginal lavages (CVL) from both HIV-positive and HIV-negative women and found that average levels of secreted Trappin-2/Elafin were higher in the CVL from HIV-negative women, although the values did not reach statistical significance. We also found that women at the secretory phase of the menstrual cycle produced more Trappin-2/Elafin in CVL relative to women at the proliferative phase of the menstrual cycle. Our data suggest that Trappin-2/Elafin might be an important endogenous microbicide of the female reproductive tract that is protective against HIV-1. PMID:19824918

Ghosh, Mimi; Shen, Zheng; Fahey, John V; Cu-Uvin, Susan; Mayer, Kenneth; Wira, Charles R

2009-07-18

16

Characterization of a novel anti-human TNF-alpha murine monoclonal antibody with high binding affinity and neutralizing activity.  

PubMed

In order to develop an anti-human TNF-alpha mAb, mice were immunized with recombinant human TNF-alpha. A murine mAb, TSK114, which showed the highest binding activity for human TNF-alpha was selected and characterized. TSK114 specifically bound to human TNF-alpha without cross-reactivity with the homologous murine TNF-alpha and human TNF-beta. TSK114 was found to be of IgG1 isotype with kappa light chain. The nucleotide sequences of the variable regions of TSK114 heavy and light chains were determined and analyzed for the usage of gene families for the variable (V), diversity (D), and joining (J) segments. Kinetic analysis of TSK114 binding to human TNF-alpha by surface plasmon resonance technique revealed a binding affinity (K(D)) of approximately 5.3 pM, which is about 1,000- and 100-fold higher than those of clinically relevant infliximab (Remicade) and adalimumab (Humira) mAbs, respectively. TSK114 neutralized human TNF-alpha-mediated cytotoxicity in proportion to the concentration, exhibiting about 4-fold greater efficiency than those of infliximab and adalimumab in WEHI 164 cells used as an in vitro model system. These results suggest that TSK114 has the potential to be developed into a therapeutic TNF-alpha-neutralizing antibody with picomolar affinity. PMID:18305396

Song, Moo Young; Park, Sang Koo; Kim, Chang Seok; Yoo, Tae Hyoung; Kim, Bongtae; Kim, Min Soo; Kim, Yong Sung; Kwag, Won Jae; Lee, Byung Kyu; Baek, Kwanghee

2008-02-29

17

Anti-human immunodeficiency virus (anti-HIV) natural products with special emphasis on HIV reverse transcriptase inhibitors  

Microsoft Academic Search

This review article aims at summarizing research findings concerning natural products which are endowed with the ability to inhibit human immunodeficiency virus (HIV). An emphasis is placed on HIV reverse transcriptase inhibitors because the bulk of the literature is focused on these compounds. It was found that a spectacular diversity of chemical structures encompassing proteins, terpenoids, coumarins, xanthones, alkaloids, flavonoids,

T. B Ng; B Huang; W. P Fong; H. W Yeung

1997-01-01

18

Pharmacokinetics of the Anti-Human Immunodeficiency Virus Agent 1-( -D-Dioxolane)Thymine in Rhesus Monkeys  

Microsoft Academic Search

-D-Dioxolane-thymine (D-DOT) has potent and selective in vitro activity against several clinically impor- tant resistant human immunodeficiency virus (HIV) mutants and is in advanced preclinical development. Therefore, the single-dose intravenous and oral pharmacokinetics of D-DOT were studied with three rhesus monkeys. The pharmacokinetic profiles of D-DOT in serum and urine were adequately described by a two-compartment open pharmacokinetic model. D-DOT

Ghazia Asif; Selwyn J. Hurwitz; Aleksandr Obikhod; David Delinsky; Janarthanan Narayanasamy; Chung K. Chu; Harold M. McClure; Raymond F. Schinazi

2007-01-01

19

Anti-Human Immunodeficiency Virus Type 1 Antibody Complexes on Platelets of Seropositive Thrombocytopenic Homosexuals and Narcotic Addicts  

Microsoft Academic Search

Patients with human immunodeficiency virus type 1 (HIV-1) infection develop an immunologic thrombocytopenic purpura associated with markedly elevated platelet IgG, IgM, and C3C4 as well as serum immune complexes determined by the polyethylene glycol (PEG) method. Analysis of their serum PEG-precipitable immune complexes as well as platelet acid eluates revealed the presence of anti-HIV-1 antibody existing as a complex that

S. Karpatkin; M. Nardi; E. T. Lennette; B. Byrne; B. Poiesz

1988-01-01

20

In vitro anti-human immunodeficiency virus (HIV) activity of the chromanone derivative, 12-oxocalanolide A, a novel NNRTI.  

PubMed

The three chromanone derivatives, (+)-, (-)-, and (+/-)-12-oxocalanolide A (2), were evaluated for in vitro antiviral activities against HIV and simian immunodeficiency virus (SIV). The compounds were determined to be inhibitors of HIV-1 reverse transcriptase (RT) and exhibited activity against a variety of viruses selected for resistance to other HIV-1 nonnucleoside RT inhibitors. They are the first reported calanolide analogues capable of inhibiting SIV. PMID:9873509

Xu, Z Q; Buckheit, R W; Stup, T L; Flavin, M T; Khilevich, A; Rizzo, J D; Lin, L; Zembower, D E

1998-08-18

21

Evaluation of CD4-CD4i Antibody Architectures Yields Potent, Broadly Cross-Reactive Anti-Human Immunodeficiency Virus Reagents? †  

PubMed Central

The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) has several adaptations that allow the virus to evade antibody neutralization. Nevertheless, a few broadly cross-reactive neutralizing antibodies as well as reagents containing portions of CD4, the HIV receptor, have demonstrated partial efficacy in suppressing viral replication. One type of reagent designed for improved HIV neutralization fuses the CD4 D1-D2 domains to the variable regions of an antibody recognizing the CD4-induced (CD4i) coreceptor binding site on the gp120 portion of the HIV envelope spike. We designed, expressed, purified, and tested the neutralization potencies of CD4-CD4i antibody reagents with different architectures, antibody combining sites, and linkers. We found that fusing CD4 to the heavy chain of the CD4i antibody E51 yields a bivalent reagent including an antibody Fc region that expresses well, is expected to have a long serum half-life, and has comparable or greater neutralization activity than well-known broadly neutralizing anti-HIV antibodies. A CD4 fusion with the anti-HIV carbohydrate antibody 2G12 also results in a potent neutralizing reagent with more broadly neutralizing activity than 2G12 alone.

West, Anthony P.; Galimidi, Rachel P.; Foglesong, Christopher P.; Gnanapragasam, Priyanthi N. P.; Klein, Joshua S.; Bjorkman, Pamela J.

2010-01-01

22

Human immunodeficiency virus neutralizing antibodies recognize several conserved domains on the envelope glycoproteins.  

PubMed Central

Serum neutralizing antibodies against the human immunodeficiency virus were frequently detected in infected individuals, and low or absent serum neutralizing titers correlated with poor prognosis. Multiple diverse human immunodeficiency virus isolates were found to exhibit similar susceptibility to neutralization by a panel of human seropositive sera, suggesting that neutralizing antibodies are largely directed against conserved viral domains. Furthermore, utilizing antisera raised against a library of synthetic env peptides, four regions which are important in the neutralization process have been identified within both human immunodeficiency virus envelope glycoproteins (gp41 and gp120). Three of these are in conserved domains and should be considered for inclusion in a candidate vaccine. Images

Ho, D D; Sarngadharan, M G; Hirsch, M S; Schooley, R T; Rota, T R; Kennedy, R C; Chanh, T C; Sato, V L

1987-01-01

23

Induction of broad and potent anti-human immunodeficiency virus immune responses in rhesus macaques by priming with a DNA vaccine and boosting with protein-adsorbed polylactide coglycolide microparticles.  

PubMed

Several vaccine technologies were evaluated for their abilities to induce anti-human immunodeficiency virus Gag immune responses in rhesus macaques. While no vaccine alone was able to induce broad and strong immune responses, these were achieved by priming with Gag DNA and boosting with Gag protein adsorbed to polylactide coglycolide microparticles. This regimen elicited strong antibodies, helper T cells, and cytotoxic T lymphocytes and thus holds promise as an effective vaccination scheme. PMID:12719603

Otten, Gillis; Schaefer, Mary; Greer, Catherine; Calderon-Cacia, Maria; Coit, Doris; Kazzaz, Jina; Medina-Selby, Angelica; Selby, Mark; Singh, Manmohan; Ugozzoli, Mildred; zur Megede, Jan; Barnett, Susan W; O'Hagan, Derek; Donnelly, John; Ulmer, Jeffrey

2003-05-01

24

Pharmacokinetics of the Anti-Human Immunodeficiency Virus Agent 1-(?-d-Dioxolane)Thymine in Rhesus Monkeys? †  

PubMed Central

?-d-Dioxolane-thymine (D-DOT) has potent and selective in vitro activity against several clinically important resistant human immunodeficiency virus (HIV) mutants and is in advanced preclinical development. Therefore, the single-dose intravenous and oral pharmacokinetics of D-DOT were studied with three rhesus monkeys. The pharmacokinetic profiles of D-DOT in serum and urine were adequately described by a two-compartment open pharmacokinetic model. D-DOT was rapidly and almost completely absorbed (absorption rate constant = 2.7 h?1; fraction of oral dose absorbed = 0.82 to 1.06). The average serum beta half-life was 2.16 h. The average central and steady-state volumes of distributions were 0.52 and 1.02 liter/kg of body weight, respectively, and the average systemic and renal clearance values were 0.36 liter/h/kg and 0.18 liter/h/kg. Four or eight percent of administered D-DOT was eliminated in the urine as glucuronide within 8 h after intravenous or oral administration, respectively. D-DOT reached levels in the cerebrospinal fluid in excess of 10 to 20 times the median effective concentration for wild-type HIV and resistant mutants. The potent antiretroviral activity of D-DOT against a lamivudine- and zidovudine-resistant HIV-1 mutant, together with an excellent pharmacokinetic profile for rhesus monkeys, suggest that further development is warranted.

Asif, Ghazia; Hurwitz, Selwyn J.; Obikhod, Aleksandr; Delinsky, David; Narayanasamy, Janarthanan; Chu, Chung K.; McClure, Harold M.; Schinazi, Raymond F.

2007-01-01

25

Mechanism of Anti-Human Immunodeficiency Virus Activity of ?-d-6-Cyclopropylamino-2?,3?-Didehydro-2?,3?-Dideoxyguanosine  

PubMed Central

To better understand the importance of the oxygen in the ribose ring of planar unsaturated nucleoside analogs that target human immunodeficiency virus (HIV), a 6-cyclopropyl-substituted prodrug of 2?,3?-didehydro-2?,3?-dideoxyguanosine (cyclo-d4G) was synthesized, and its cellular metabolism, antiviral activity, and pharmacokinetic behavior were studied. Cyclo-d4G had selective anti-HIV activity in primary blood mononuclear cells (PBMCs), effectively inhibiting the LAI strain of HIV-1 by 50% at 1.1 ± 0.1 ?M while showing 50% inhibition of cell viability at 84.5 ?M. The antiviral activity in PBMCs was not markedly affected by mutations of methionine to valine at position 184 or by thymidine-associated mutations in the viral reverse transcriptase. Mutations of leucine 74 to valine and of lysine 65 to arginine had mild to moderate resistance (as high as fivefold). Studies to delineate the mechanism of cellular metabolism and activation of cyclo-d4G showed reduced potency in inhibiting viral replication in the presence of the adenosine/adenylate deaminase inhibitor 2?-deoxycoformycin, implying that the antiviral activity is due to its metabolism to the 2?-dGTP analog d4GTP. Intracellular formation of sugar catabolites illustrates the chemical and potentially enzymatic instability of the glycosidic linkage in d4G. Further studies suggest that cyclo-d4G has a novel intracellular phosphorylation pathway. Cyclo-d4G had a lower potential to cause mitochondrial toxicity than 2?,3?-dideoxycytidine and 2?,3?-didehydro-3?-deoxythymidine in neuronal cells. Also, cyclo-d4G had advantageous synergism with many currently used anti-HIV drugs. Poor oral bioavailability observed in rhesus monkeys may be due to the labile glycosidic bond, and special formulation may be necessary for oral delivery.

Ray, Adrian S.; Hernandez-Santiago, Brenda I.; Mathew, Judy S.; Murakami, Eisuke; Bozeman, Carey; Xie, Meng-Yu; Dutschman, Ginger E.; Gullen, Elizabeth; Yang, Zhenjun; Hurwitz, Selwyn; Cheng, Yung-Chi; Chu, Chung K.; McClure, Harold; Schinazi, Raymond F.; Anderson, Karen S.

2005-01-01

26

Anti-human immunodeficiency virus type 1 activity of an oligocationic compound mediated via gp120 V3 interactions.  

PubMed Central

An oligocationic peptide compound (ALX40-4C) was developed for consideration in the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This compound was designed to mimic the basic domain of the HIV-1 transactivation protein, Tat, and will competitively inhibit Tat binding to its specific RNA hairpin target (TAR [transactivation region]), found at the 5' end of all HIV-1 transcripts. Blocking Tat-TAR interactions can abrogate HIV-1 replication. ALX40-4C was shown to inhibit replication of HIV-1NL4-3 in a range of cell types, including primary cells and transformed cell lines, by as much as 10(4)-fold. In some experiments, virus rescue was not possible even after removal of ALX40-4C from the cultures. Strain-dependent resistance has been demonstrated for all antiretroviral agents tested; therefore, we tested for variable sensitivity to ALX40-4C. The cloned primary strains, HIV-JR-CSF and HIV-JR-FL, were less sensitive to ALX40-4C inhibition. Unexpectedly, determinants for efficient ALX40-4C inhibition were mapped by using recombinant virus strains to the V3 region of gpl20 and were shown to act at early events in viral replication, which include viral entry. If entry and reverse transcription are bypassed by transfection, a more modest, virus strain-independent inhibition is shown; this inhibition is likely due to blocking of Tat-TAR interaction. Thus, the highly basic oligocationic Tat inhibitor ALX40-4C appears to interfere with initial virus-target cell interactions which involve HIV-1 gp120 V3 determinants, most efficiently for T-cell line-adapted strains.

O'Brien, W A; Sumner-Smith, M; Mao, S H; Sadeghi, S; Zhao, J Q; Chen, I S

1996-01-01

27

Long-Lasting Enfuvirtide Carrier Pentasaccharide Conjugates with Potent Anti-Human Immunodeficiency Virus Type 1 Activity ?  

PubMed Central

Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is an antiretroviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells. This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections. Although enfuvirtide is an efficient anti-HIV-1 drug, its clinical use is limited by a short plasma half-life, i.e., approximately 2 h, which requires twice-daily subcutaneous injections, often resulting in skin sensitivity reaction side effects at the injection sites. Ultimately, 80% of patients stop enfuvirtide treatment within 6 months because of these side effects. We report on the development of long-lasting enfuvirtide conjugates by the use of the site-specific conjugation of enfuvirtide to an antithrombin-binding carrier pentasaccharide (CP) through polyethylene glycol (PEG) linkers of various lengths. These conjugates showed consistent and broad anti-HIV-1 activity in the nanomolar range. The coupling of the CP to enfuvirtide only moderately affected the in vitro anti-HIV-1 activity in the presence of antithrombin. Most importantly, one of these conjugates, enfuvirtide-PEG12-CP (EP40111), exhibited a prolonged elimination half-life of more than 10 h in rat plasma compared to the half-life of native enfuvirtide, which was 2.8 h. On the basis of the pharmacokinetic properties of antithrombin-binding pentasaccharides, the anticipated half-life of EP40111 in humans would putatively be about 120 h, which would allow subcutaneous injection once a week instead of twice daily. In conclusion, EP40111 is a promising compound with strong potency as a novel long-lasting anti-HIV-1 drug.

Huet, Thierry; Kerbarh, Olivier; Schols, Dominique; Clayette, Pascal; Gauchet, Cecile; Dubreucq, Guy; Vincent, Loic; Bompais, Heidi; Mazinghien, Romain; Querolle, Olivier; Salvador, Arnaud; Lemoine, Jerome; Lucidi, Bruno; Balzarini, Jan; Petitou, Maurice

2010-01-01

28

Characteristics of a group of nonnucleoside reverse transcriptase inhibitors with structural diversity and potent anti-human immunodeficiency virus activity.  

PubMed

Current thrust in controlling the Acquired Immune Deficiency Syndrome (AIDS) focuses on antiviral drug development targeting the infection and replication of the human immunodeficiency virus (HIV), the causative agent of AIDS. To date, treatment of AIDS has relied on nucleoside reverse transcriptase inhibitors such as AZT, ddI, and ddC, which eventually become ineffective upon the emergence of resistant mutants bearing specific nucleotide substitutions. The Anti-AIDS Drug Screening Program of the NCI conducts and coordinates a high-capacity semi-robotic in vitro screening of synthetic or natural compounds submitted by academic, research and pharmaceutical institutions world-wide. About 10,000 synthetic compounds are screened annually for anti-HIV activity. Confirmed active agents are subjected to in-depth studies on range and mechanism of action. Emerging from this intense screening activity were a number of potentially promising categories of nonnucleoside reverse transcriptase inhibitors (NNRTI) with structural diversity but strong and reproducible anti-HIV activity. Over 2500 active compounds were evaluated for their inhibitory activity against a panel of both laboratory and clinical virus isolates in the appropriate established cell line or fresh human peripheral blood leukocyte and macrophage preparations. Out of these, 40 agents could be placed structurally in nine categories with an additional 16 unique compounds that share the characteristics of NNRTI. These NNRTIs were shown to inhibit reverse transcriptase enzymatically using homopolymeric or ribosomal RNA as templates. NNRTIs demonstrated similarity in their inhibitory pattern against the HIV-1 laboratory strains IIIB and RF, and an AZT-resistant strain; all were inactive against HIV-2. These compounds were further tested against NNRTI-resistant HIV-1 isolates. NNRTI-resistant HIV-1 isolates were selected and characterized with respect to the change(s) in the viral reverse transcriptase nucleotide sequence. Also, differential cross-resistance or sensitivity patterns to NNRTIs were studied in detail among NNRTI-resistant mutants. When tested in combination with AZT, all of the NNRTI's uniformly exhibited synergistic inhibition of HIV-1, suggesting that combination antiviral therapy of NNRTIs with AZT may be therapeutically promising for AIDS treatment. PMID:7475321

Yang, S S; Fliakas-Boltz, V; Bader, J P; Buckheit, R W

1995-10-01

29

Unique Anti-Human Immunodeficiency Virus Activities of the Nonnucleoside Reverse Transcriptase Inhibitors Calanolide A, Costatolide, and Dihydrocostatolide  

PubMed Central

(+)-Calanolide A (NSC 650886) has previously been reported to be a unique and specific nonnucleoside inhibitor of the reverse transcriptase (RT) of human immunodeficiency virus (HIV) type 1 (HIV-1) (M. J. Currens et al., J. Pharmacol. Exp. Ther., 279:645–651, 1996). Two isomers of calanolide A, (?)-calanolide B (NSC 661122; costatolide) and (?)-dihydrocalanolide B (NSC 661123; dihydrocostatolide), possess antiviral properties similar to those of calanolide A. Each of these three compounds possesses the phenotypic properties ascribed to the pharmacologic class of nonnucleoside RT inhibitors (NNRTIs). The calanolide analogs, however, exhibit 10-fold enhanced antiviral activity against drug-resistant viruses that bear the most prevalent NNRTI resistance that is engendered by amino acid change Y181C in the RT. Further enhancement of activity is observed with RTs that possess the Y181C change together with mutations that yield resistance to AZT. In addition, enzymatic inhibition assays have demonstrated that the compounds inhibit RT through a mechanism that affects both the Km for dTTP and the Vmax, i.e., mixed-type inhibition. In fresh human cells, costatolide and dihydrocostatolide are highly effective inhibitors of low-passage clinical virus strains, including those representative of the various HIV-1 clade strains, syncytium-inducing and non-syncytium-inducing isolates, and T-tropic and monocyte-tropic isolates. Similar to calanolide A, decreased activities of the two isomers were observed against viruses and RTs with amino acid changes at residues L100, K103, T139, and Y188 in the RT, although costatolide exhibited a smaller loss of activity against many of these NNRTI-resistant isolates. Comparison of cross-resistance data obtained with a panel of NNRTI-resistant virus strains suggests that each of the three stereoisomers may interact differently with the RT, despite their high degree of structural similarity. Selection of viruses resistant to each of the three compounds in a variety of cell lines yielded viruses with T139I, L100I, Y188H, or L187F amino acid changes in the RT. Similarly, a variety of resistant virus strains with different amino acid changes were selected in cell culture when the calanolide analogs were used in combination with other active anti-HIV agents, including nucleoside and nonnucleoside RT and protease inhibitors. In assays with combinations of anti-HIV agents, costatolide exhibited synergy with these anti-HIV agents. The calanolide isomers represent a novel and distinct subgroup of the NNRTI family, and these data suggest that a compound of the calanolide A series, such as costatolide, should be evaluated further for therapeutic use in combination with other anti-HIV agents.

Buckheit, Robert W.; White, E. Lucile; Fliakas-Boltz, Valerie; Russell, Julie; Stup, Tracy L.; Kinjerski, Tracy L.; Osterling, Mark C.; Weigand, Ann; Bader, John P.

1999-01-01

30

Post-Infection Immunodeficiency Virus Control by Neutralizing Antibodies  

PubMed Central

Background Unlike most acute viral infections controlled with the appearance of virus-specific neutralizing antibodies (NAbs), primary HIV infections are not met with such potent and early antibody responses. This brings into question if or how the presence of potent antibodies can contribute to primary HIV control, but protective efficacies of antiviral antibodies in primary HIV infections have remained elusive; and, it has been speculated that even NAb induction could have only a limited suppressive effect on primary HIV replication once infection is established. Here, in an attempt to answer this question, we examined the effect of passive NAb immunization post-infection on primary viral replication in a macaque AIDS model. Methods and Findings The inoculums for passive immunization with simian immunodeficiency virus mac239 (SIVmac239)-specific neutralizing activity were prepared by purifying polyclonal immunoglobulin G from pooled plasma of six SIVmac239-infected rhesus macaques with NAb induction in the chronic phase. Passive immunization of rhesus macaques with the NAbs at day 7 after SIVmac239 challenge resulted in significant reduction of set-point plasma viral loads and preservation of central memory CD4 T lymphocyte counts, despite the limited detection period of the administered NAb responses. Peripheral lymph node dendritic cell (DC)-associated viral RNA loads showed a remarkable peak with the NAb administration, and DCs stimulated in vitro with NAb-preincubated SIV activated virus-specific CD4 T lymphocytes in an Fc-dependent manner, implying antibody-mediated virion uptake by DCs and enhanced T cell priming. Conclusions Our results present evidence indicating that potent antibody induction post-infection can result in primary immunodeficiency virus control and suggest direct and indirect contribution of its absence to initial control failure in HIV infections. Although difficulty in achieving requisite neutralizing titers for sterile HIV protection by prophylactic vaccination has been suggested, this study points out a possibility of non-sterile HIV control by prophylactic vaccine-induced, sub-sterile titers of NAbs post-infection, providing a rationale of vaccine-based NAb induction for primary HIV control.

Yamamoto, Hiroyuki; Kawada, Miki; Takeda, Akiko; Igarashi, Hiroko; Matano, Tetsuro

2007-01-01

31

Characterization of a human immunodeficiency virus neutralizing monoclonal antibody and mapping of the neutralizing epitope.  

PubMed Central

A monoclonal antibody was produced to the exterior envelope glycoprotein (gp120) of the human T-cell lymphotropic virus (HTLV)-IIIB isolate of the human immunodeficiency virus (HIV). This antibody binds to gp120 of HTLV-IIIB and lymphadenopathy-associated virus type 1 (LAV-1) and to the surface of HTLV-IIIB- and LAV-1-infected cells, neutralizes infection by cell-free virus, and prevents fusion of virus-infected cells. In contrast, it does not bind, or weakly binds, the envelope of four heterologous HIV isolates and does not neutralize heterologous isolates HTLV-IIIRF and HTLV-IIIMN. The antibody-binding site was mapped to a 24-amino-acid segment, using recombinant and synthetic segments of HTLV-IIIB gp120. This site is within a segment of amino acid variability known to contain the major neutralizing epitopes (S. D. Putney, T. J. Matthews, W. G. Robey, D. L. Lynn, M. Robert-Guroff, W. T. Mueller, A. J. Langlois, J. Ghrayeb, S. R. Petteway, K. J. Weinhold, P. J. Fischinger, F. Wong-Staal, R. C. Gallo, and D. P. Bolognesi, Science 234:1392-1395, 1986). These results localize an epitope of HIV type-specific neutralization and suggest that neutralizing antibodies may be effective in controlling cell-associated, as well as cell-free, virus infection. Images

Matsushita, S; Robert-Guroff, M; Rusche, J; Koito, A; Hattori, T; Hoshino, H; Javaherian, K; Takatsuki, K; Putney, S

1988-01-01

32

Principal Neutralizing Domain of the Human Immunodeficiency Virus Type 1 Envelope Protein  

Microsoft Academic Search

The principal neutralizing determinant of human immunodeficiency virus type 1 (HIV-1) is located in the external envelope protein, gp120, and has previously been mapped to a 24-amino acid-long sequence (denoted RP135). We show here that deletion of this sequence renders the envelope unable to elicit neutralizing antibodies. In addition, using synthetic peptide fragments of RP135, we have mapped the neutralizing

Kashi Javaherian; Alphonse J. Langlois; Charlene McDanal; Karen L. Ross; Lawrence I. Eckler; Cindy L. Jellis; Albert T. Profy; James R. Rusche; Dani P. Bolognesi; Scott D. Putney; Thomas J. Matthews

1989-01-01

33

In Vivo Efficacy of Human Immunodeficiency Virus Neutralizing Antibodies: Estimates for Protective Titers  

Microsoft Academic Search

The definition of plasma neutralizing antibody titers capable of controlling human immunodeficiency virus (HIV) infection in vivo is considered a critical step in vaccine development. Here we provide estimates for effective neutralization titers by assessing samples from a recent passive immunization trial with the neutral- izing monoclonal antibodies (MAbs) 2G12, 2F5, and 4E10 using an analytic strategy that dissects the

Alexandra Trkola; Herbert Kuster; Peter Rusert; Viktor von Wyl; Christine Leemann; Rainer Weber; Gabriela Stiegler; Hermann Katinger; Beda Joos; H. F. Gunthard

2008-01-01

34

Studies of the conformation-dependent neutralizing epitopes of simian immunodeficiency virus envelope protein.  

PubMed Central

It has been shown previously that the major neutralizing epitopes in simian immunodeficiency virus (SIV) are discontinuous and conformation dependent and that the V3 loop, in contrast to that of human immunodeficiency virus (HIV) type 1, does not by itself elicit neutralizing antibodies (K. Javaherian et al., Proc. Natl. Acad. Sci. USA 89:1418-1422, 1992). We now present data showing that on the basis of fractionation of infected macaque sera, protease digestion of the envelope, and binding properties of two neutralizing monoclonal antibodies to SIV and SIV-HIV chimeric envelope proteins, changes in V3 can disrupt the conformation-dependent neutralization region. The chimeric protein did not produce significant neutralizing antibodies against either SIV or HIV. We also report that neutralizing antibodies elicited by recombinant SIV envelope proteins of mac251 and B670 isolates cross-neutralize. Finally, we show that deglycosylation of the SIV envelope results in a molecule which binds neither soluble CD4 nor the neutralizing monoclonal antibodies being investigated here and does not elicit sera with a significant neutralizing titer. Images

Javaherian, K; Langlois, A J; Montefiori, D C; Kent, K A; Ryan, K A; Wyman, P D; Stott, J; Bolognesi, D P; Murphey-Corb, M; Larosa, G J

1994-01-01

35

Neutralizing Antibodies in Sera from Macaques Immunized with Attenuated Simian Immunodeficiency Virus  

Microsoft Academic Search

Infection with attenuated simian immunodeficiency virus (SIV) in rhesus macaques has been shown to raise antibodies capable of neutralizing an animal challenge stock of primary SIVmac251 in CEMx174 cells that cor- relate with resistance to infection after experimental challenge with this virulent virus (M. S. Wyand, K. H. Man- son, M. Garcia-Moll, D. C. Montefiori, and R. C. Desrosiers, J.

ALPHONSE J. LANGLOIS; RONALD C. DESROSIERS; MARK G. LEWIS; VINEET N. KEWALRAMANI; DAN R. LITTMAN; JI YING ZHOU; KELLEDY MANSON; MICHAEL S. WYAND; DANI P. BOLOGNESI; DAVID C. MONTEFIORI

1998-01-01

36

Chimpanzees Immunized with Recombinant Soluble CD4 Develop Anti-Self CD4 Antibody Responses with Anti-Human Immunodeficiency Virus Activity  

NASA Astrophysics Data System (ADS)

In view of the efficiency with which human immunodeficiency virus replication can be blocked in vitro with anti-CD4 antibodies, the elicitation of an anti-CD4 antibody response through active immunization might represent a useful therapeutic strategy for AIDS. Here we demonstrate that immunization of chimpanzees with recombinant soluble human CD4 elicited an anti-CD4 antibody response. The elicited antibody bound self CD4 on digitonin-treated but not freshly isolated lymphocytes. Nevertheless, this antibody blocked human immunodeficiency virus replication in chimpanzee and human lymphocytes. These observations suggest that immunization with recombinant soluble CD4 from human immunodeficiency virus-infected humans may be feasible and therapeutically beneficial.

Watanabe, Mamoru; Boyson, Jonathan E.; Lord, Carol I.; Letvin, Norman L.

1992-06-01

37

How Accurate is Serologic Testing of Plasma Pools for Hepatitis B Virus Surface Antigen, anti-Human Immunodeficiency Virus 1 and 2, and anti-Hepatitis C Virus?  

Microsoft Academic Search

SummaryObjective: The European pharmacopeia prescribes that, during the manufacture of blood derivates, the first homogeneous pool of plasma (for example, after removal of cryoprecipitate) must be tested for hepatitis B virus surface antigen (HBsAg), for hepatitis C virus (HCV) antibodies and for human immunodeficiency virus (HIV) antibodies using test methods of suitable sensitivity and specificity, in order to reduce the

H. Rabenau; R. Schütz; A. Berger; H. W. Doerr; B. Weber

1996-01-01

38

Anti-Human Immunodeficiency Virus Type 1 Microbicide Cellulose Acetate 1,2-Benzenedicarboxylate in a Human In Vitro Model of Vaginal Inflammation  

Microsoft Academic Search

The sexual transmission of human immunodeficiency virus type 1 (HIV-1) is facilitated by inflammation and related epithelial barrier perturbation. Microbicides for vaginal applications are currently being developed to reduce the risk of HIV-1 transmission. However, little is known about their interference with epithelial immune function. In recent clinical trials, nonoxynol-9 (N-9), a virucide with a long history of intravaginal use

R. N. Fichorova; F. Zhou; V. Ratnam; V. Atanassova; S. Jiang; N. Strick; A. R. Neurath

2005-01-01

39

Anti-Human Immunodeficiency Virus Interactions of SCH-C (SCH 351125), a CCR5 Antagonist, with Other Antiretroviral Agents In Vitro  

Microsoft Academic Search

SCH-C (SCH 351125) is a small-molecule antagonist of the human immunodeficiency virus type 1(HIV-1) coreceptor CCR5. It has in vitro activity against R5 viruses with 50% inhibitory concentrations ranging from 1.0 to 30.9 nM. We have studied anti-HIV-1 interactions of SCH-C with other antiretroviral agents in vitro. Synergistic interactions were seen with nucleoside reverse transcriptase inhibitors (zidovudine and lamivu- dine),

Cécile L. Tremblay; Françoise Giguel; Christopher Kollmann; Yongbiao Guan; Ting-Chao Chou; Bahige M. Baroudy; Martin S. Hirsch

2002-01-01

40

Murine leukemia virus-based Tat-inducible long terminal repeat replacement vectors: a new system for anti-human immunodeficiency virus gene therapy.  

PubMed Central

We have constructed new murine leukemia virus (MLV)-based vectors (TIN vectors) which, following integration, contain human immunodeficiency virus (HIV) type 1 U3 and R sequences in place of the MLV U3 and R regions. This provides, for the first time, single transcriptional unit retroviral vectors under the control of Tat. TIN vectors have several advantages for anti-HIV gene therapy applications.

Cannon, P M; Kim, N; Kingsman, S M; Kingsman, A J

1996-01-01

41

Wild type and H43Y variant of human TRIM5? show similar anti-human immunodeficiency virus type 1 activity both in vivo and in vitro  

Microsoft Academic Search

Polymorphisms in human genes have been shown to affect the rate of disease progression to acquired immune deficiency syndrome\\u000a in human immunodeficiency virus type 1 (HIV-1)-infected individuals. Recently, tripartite motif 5? (TRIM5?) was identified\\u000a as a factor that confers resistance to HIV-1 infection in Old World monkey cells. Subsequently, Sawyer et al. (Curr Biol 16:95–100,\\u000a 2006) reported a single nucleotide

Emi E. Nakayama; Wassila Carpentier; Dominique Costagliola; Tatsuo Shioda; Aikichi Iwamoto; Patrice Debre; Kazuhisa Yoshimura; Brigitte Autran; Shuzo Matsushita; Ioannis Theodorou

2007-01-01

42

Evaluation of anti-human immunodeficiency virus effect of recombinant CD4-immunoglobulin in vitro: a good candidate for AIDS treatment  

Microsoft Academic Search

CD4 molecule, a surface marker of helper T lymphocytes, interacts with gp 120 of human immunodeficiency virus (HIV) with a high affinity and, hence, serves as a virus receptor. Soluble chimeric CD4-immunoglobulin (Ig) possesses anti-HIV activity due to its binding activity to gp 120. Furthermore, this recombinant molecule has unique Ig-like properties representing Fc receptor-binding activity and a long half-life

Iqbal Hossain Chowdhury; Yoshio Koyanagi; Keita Takamatsu; Osamu Yoshida; Susumu Kobayashi; Naoki Yamamoto

1991-01-01

43

Antibody-mediated in vitro neutralization of human immunodeficiency virus type 1 abolishes infectivity for chimpanzees.  

PubMed Central

This study was undertaken to establish whether antibody directed against the human immunodeficiency virus type 1 (HIV-1) principal gp120 type-specific neutralization determinant can abolish the infectivity of HIV-1 in chimpanzees. Challenge inocula of the IIIb virus isolate were mixed in vitro with either immunoglobulin G (IgG) from an uninfected chimpanzee, nonneutralizing IgG from an HIV-seropositive human, a virus-neutralizing murine monoclonal antibody directed against the HIV-1 IIIb isolate, or virus-neutralizing IgG from a chimpanzee infected with the IIIb isolate. Both neutralizing antibodies were directed against the principal neutralization determinant of the challenge isolate. Establishment of infection following inoculation of each virus-antibody mixture into chimpanzees was assessed by virus-specific antibody development and by virus isolation. No protective effect was noted either with the control IgG or with the nonneutralizing anti-HIV IgG. By contrast, the polyclonal chimpanzee virus-neutralizing IgG prevented HIV-1 in vivo infection, while the neutralizing monoclonal antibody notably decreased the infectivity of the challenge virus. Hence, antibody to the gp120 principal neutralization determinant is able both to prevent HIV-1 infection in vitro and to inhibit infection in vivo.

Emini, E A; Nara, P L; Schleif, W A; Lewis, J A; Davide, J P; Lee, D R; Kessler, J; Conley, S; Matsushita, S; Putney, S D

1990-01-01

44

Molecular characterization of five human anti-human immunodeficiency virus type 1 antibody heavy chains reveals extensive somatic mutation typical of an antigen-driven immune response.  

PubMed Central

We report the heavy chain variable region sequences from the cDNAs of five previously described monoclonal cell lines producing human antibodies specific for the human immunodeficiency virus type 1 and detail the molecular characteristics, germ-line origins, and extent of somatic mutation among these antibodies. Three of the five heavy chain variable regions derive from the VHIV gene family, but each has arisen from a different heavy chain variable region (VH) gene segment within the VHIV family. In addition, one is derived from a VHI gene segment, and one is derived from a VHV gene segment. Since four of the five antibodies arise from known germ-line VH elements, a precise determination of the extent of somatic variation is possible. The amount of variation from the closest germ-line sequence ranges from 4.5% to 14.8% among these antibodies, most of which is concentrated in the complementarity-determining regions. In general, the diversity (D) segments are long, characteristic of D-D fusions and/or extensive terminal deoxynucleotidyltransferase activity; however, definitive homologies cannot be found with the known germ-line D segments. Joining (JH) gene segment utilization appears random. The use of five different germ-line VH gene segments and extensive somatic mutation provides evidence that a polyclonal, antigen-driven immune response occurs during the natural infection with human immunodeficiency virus.

Andris, J S; Johnson, S; Zolla-Pazner, S; Capra, J D

1991-01-01

45

Resistance to the Anti-Human Immunodeficiency Virus Type 1 Compound l-Chicoric Acid Results from a Single Mutation at Amino Acid 140 of Integrase  

PubMed Central

l-Chicoric acid is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase in vitro and of HIV-1 replication in tissue culture. Following 3 months of selection in the presence of increasing concentrations of l-chicoric acid, HIV-1 was completely resistant to the compound. Introduction of the mutant integrase containing a single glycine-to-serine amino acid change at position 140 into the native, l-chicoric acid-sensitive virus demonstrated that this change was sufficient to confer resistance to l-chicoric acid. These results confirm through natural selection previous biochemical studies showing that l-chicoric acid inhibits integrase and that the drug is likely to interact at residues near the catalytic triad in the integrase active site.

King, Peter J.; Robinson, W. Edward

1998-01-01

46

Quinqueginsin, a Novel Protein with Anti-Human Immunodeficiency Virus, Antifungal, Ribonuclease and Cell-Free Translation-Inhibitory Activities from American Ginseng Roots  

Microsoft Academic Search

A homodimeric protein designated quinqueginsin, with a molecular weight of 53 kDa, has been isolated from the roots of American ginseng Panax quinquefolium. It was unadsorbed on DEAE cellulose in low ionic strength and neutral pH, and adsorbed on Affigel blue gel and SP-Sepharose under similar conditions. Its N-terminal sequence bore similarity to those of plant ribosome inactivating proteins and

H. X. Wang; T. B. Ng

2000-01-01

47

Anti-human immunodeficiency virus 1 (HIV-1) activities of 3-deazaadenosine analogs: increased potency against 3'-azido-3'-deoxythymidine-resistant HIV-1 strains.  

PubMed

3-Deazaadenosine (DZA), 3-deaza-(+/-)-aristeromycin (DZAri), and 3-deazaneplanocin A (DZNep) are powerful modulators of cellular processes. When tested against H9 cells infected acutely with two different strains of human immunodeficiency virus 1 (HIV-1) and in the chronically infected monocytoid cell lines U1 and THP-1, the 3-deazanucleosides caused a marked reduction in p24 antigen production. Similar reductions in p24 antigen were seen in phytohemagglutinin-stimulated peripheral blood mononuclear cells infected with clinical HIV-1 isolates. Strikingly, in comparing the therapeutic indices between the paired pre- and post-3'-azido-3'-deoxythymidine (AZT) treatment HIV-1 isolates, DZNep and neplanocin A showed an increase of 3- to 18-fold in their potency against AZT-resistant HIV-1 isolates. In H9 cells treated with DZNep and DZAri, the formation of triphosphate nucleotides of DZNep and DZAri was observed. The mode of action of DZNep and DZAri appears complex, at least in part, at the level of infectivity as shown by decreases in syncytia formation in HIV-1-infected H9 cells and at the level of transcription as both drugs inhibited the expression of basal or tat-induced HIV-1 long terminal repeat chloramphenicol acetyltransferase activity in stably transfected cell lines. Since DZNep induced in H9 cells a rapid expression of nuclear binding factors that recognize the AP-1 transcription site, the anti-HIV-1 activity of the DZA analogs could partly be the induction of critical factors in the host cells. Thus, the 3-deazanucleoside drugs belong to an unusual class of anti-HIV-1 drugs, which may have therapeutic potential, in particular against AZT-resistant strains. PMID:7816820

Mayers, D L; Mikovits, J A; Joshi, B; Hewlett, I K; Estrada, J S; Wolfe, A D; Garcia, G E; Doctor, B P; Burke, D S; Gordon, R K

1995-01-01

48

Anti-human immunodeficiency virus (HIV) activities of halogenated gomisin J derivatives, new nonnucleoside inhibitors of HIV type 1 reverse transcriptase.  

PubMed Central

Halogenated gomisin J (a derivative of lignan compound), represented by the bromine derivative 1506 [(6R, 7S, S-biar)-4,9-dibromo-3,10-dihydroxy-1,2,11,12-tetramethoxy-6, 7-dimethyl-5,6,7,8- tetrahydrodibenzo[a,c]cyclo-octene], was found to be a potent inhibitor of the cytopathic effects of human immunodeficiency virus type 1 (HIV-1) on MT-4 human T cells (50% effective dose, 0.1 to 0.5 microM). Gomisin J derivatives were active in preventing p24 production from acutely HIV-1-infected H9 cells. The selective indices (toxic dose/effective dose) of these compounds were as high as > 300 in some systems. 1506 was active against 3'-azido-3'-deoxythymidine-resistant HIV-1 and acted synergistically with AZT and 2',3'-ddC. 1506 inhibited HIV-1 reverse transcriptase (RT) in vitro but not HIV-1 protease. From the time-of-addition experiment, 1506 was found to inhibit the early phase of the HIV life cycle. A 1506-resistant HIV mutant was selected and shown to possess a mutation within the RT-coding region (at position 188 [Tyr to Leu]). The mutant RT expressed in Escherichia coli was resistant to 1506 in the in vitro RT assay. Some of the HIV strains resistant to other nonnucleoside HIV-1 RT inhibitors were also resistant to 1506. Comparison of various gomisin J derivatives with gomisin J showed that iodine, bromine, and chlorine in the fourth and ninth positions increased RT inhibitory activity as well as cytoprotective activity.

Fujihashi, T; Hara, H; Sakata, T; Mori, K; Higuchi, H; Tanaka, A; Kaji, H; Kaji, A

1995-01-01

49

In vitro effect of anti-human immunodeficiency virus CCR5 antagonist maraviroc on chemotactic activity of monocytes, macrophages and dendritic cells.  

PubMed

Compounds targeting the chemokine receptor CCR5 have recently been approved for treatment of human immunodeficiency virus (HIV) infection. Given the central role of CCR5 in inflammation and recruitment of antigen-presenting cells (APC), it is important to investigate the immunological consequences of pharmacological inhibition of CCR5. We evaluated the in vitro effect of different concentrations of CCR5 antagonist maraviroc (MVC) on cell migration of monocytes, macrophages (MO) and monocyte-derived dendritic cells (MDC) towards peptide formyl-methionyl-leucyl-phenylalanine (fMLP) and chemokines regulated upon activation normal T cell expressed and secreted (RANTES) and CCL4/macrophage inflammatory protein-1 (MIP-1?) and CCL2/monocyte chemotactic protein-1 (MCP-1). Results of flow cytometric analysis showed that monocytes treated in vitro with MVC exhibited a significant dose-dependent reduction of chemotaxis towards MIP-1? and MCP-1. fMLP-induced chemotactic activity decreased only at higher concentration (1 µM and 10 µM of MVC). In addition, all concentrations of MVC (0·1, 1 and 10 µM) induced in vitro a significant inhibition of chemotaxis of MO and MDC in response to all tested chemoattractants. No change in phenotype (CD1a and CD14) and CCR1, CCR4, CCR5 and formyl peptide receptor (FPR) expression was seen after in vitro treatment with MVC. These findings suggest that CCR5 antagonist MVC may have the in vitro ability of inhibiting the migration of innate immune cells by mechanism which could be independent from the pure anti-HIV effect. The drug might have a potential role in the down-regulation of HIV-associated chronic inflammation by blocking the recirculation and trafficking of MO and MDC. PMID:21985364

Rossi, R; Lichtner, M; De Rosa, A; Sauzullo, I; Mengoni, F; Massetti, A P; Mastroianni, C M; Vullo, V

2011-11-01

50

Neutralizing antibodies in sera from macaques immunized with attenuated simian immunodeficiency virus.  

PubMed

Infection with attenuated simian immunodeficiency virus (SIV) in rhesus macaques has been shown to raise antibodies capable of neutralizing an animal challenge stock of primary SIVmac251 in CEMx174 cells that correlate with resistance to infection after experimental challenge with this virulent virus (M. S. Wyand, K. H. Manson, M. Garcia-Moll, D. C. Montefiori, and R. C. Desrosiers, J. Virol. 70:3724-3733, 1996). Here we show that these neutralizing antibodies are not detected in human and rhesus peripheral blood mononuclear cells (PBMC). In addition, neutralization of primary SIVmac251 in human and rhesus PBMC was rarely detected with plasma samples from a similar group of animals that had been infected either with SIVmac239Deltanef for 1.5 years or with SIVmac239Delta3 for 3.2 years, although low-level neutralization was detected in CEMx174 cells. Potent neutralization was detected in CEMx174 cells when the latter plasma samples were assessed with laboratory-adapted SIVmac251. In contrast to primary SIVmac251, laboratory-adapted SIVmac251 did not replicate in human and rhesus PBMC despite its ability to utilize CCR5, Bonzo/STRL33, and BOB/gpr15 as coreceptors for virus entry. These results illustrate the importance of virus passage history and the choice of indicator cells for making assessments of neutralizing antibodies to lentiviruses such as SIV. They also demonstrate that primary SIVmac251 is less sensitive to neutralization in human and rhesus PBMC than it is in established cell lines. Results obtained in PBMC did not support a role for neutralizing antibodies as a mechanism of protection in animals immunized with attenuated SIV and challenged with primary SIVmac251. PMID:9658152

Langlois, A J; Desrosiers, R C; Lewis, M G; KewalRamani, V N; Littman, D R; Zhou, J Y; Manson, K; Wyand, M S; Bolognesi, D P; Montefiori, D C

1998-08-01

51

Role of Human Immunodeficiency Virus Type 1 Envelope Structure in the Induction of Broadly Neutralizing Antibodies  

PubMed Central

Very soon after the discovery of neutralizing antibodies (NAbs) toward human immunodeficiency virus type 1 (HIV-1) infection, it became apparent that characterization of these NAbs would be an important step in finding a cure for or a vaccine to eradicate HIV-1. Since the initial description of broadly cross-clade NAbs naturally produced in HIV-1 patients, numerous studies have described new viral targets for these antibodies. More recently, studies concerning new groups of patients able to control their viremia, such as long-term nonprogressors (LTNPs) or elite controllers, have described the generation of numerous envelope-targeted NAbs. Recent studies have marked a new stage in research on NAbs with the description of antibodies obtained from a worldwide screening of HIV-positive patients. These studies have permitted the discovery of NAb families with great potential for both neutralization and neutralization breadth, such as PG, PGT, CH, and highly active agonistic anti-CD4 binding site antibodies (HAADs), of which VRC01 and its variants are members. These antibodies are able to neutralize more than 80% of circulating strains without any autoreactivity and can be rapidly integrated into clinical trials in order to test their protective potential. In this review, we will focus on new insights into HIV-1 envelope structure and their implications for the generation of potent NAbs.

Benjelloun, F.; Lawrence, P.; Verrier, B.; Genin, C.

2012-01-01

52

Passive Immunotherapy in Simian Immunodeficiency Virus-Infected Macaques Accelerates the Development of Neutralizing Antibodies  

PubMed Central

Passively transferred neutralizing antibodies can block lentivirus infection, but their role in postexposure prophylaxis is poorly understood. In this nonhuman-primate study, the effects of short-term antibody therapy on 5-year disease progression, virus load, and host immunity were explored. We reported previously that postinfection passive treatment with polyclonal immune globulin with high neutralizing titers against SIVsmE660 (SIVIG) significantly improved the 67-week health of SIVsmE660-infected Macaca mulatta macaques. Four of six treated macaques maintained low or undetectable levels of virus in plasma, compared with one of ten controls, while two rapid progressors controlled viremia only as long as the SIVIG was present. SIVIG treatment delayed the de novo production of envelope (Env)-specific antibodies by 8 weeks (13). We show here that differences in disease progression were also significant at 5 years postinfection, excluding rapid progressors (P = 0.05). Macaques that maintained ?103 virus particles per ml of plasma and ?30 infectious virus particles per 106 mononuclear cells from peripheral blood and lymph nodes had delayed disease onset. All macaques that survived beyond 18 months had measurable Gag-specific CD8+ cytotoxic T cells, regardless of treatment. Humoral immunity in survivors beyond 20 weeks was strikingly different in the SIVIG and control groups. Despite a delay in Env-specific binding antibodies, de novo production of neutralizing antibodies was significantly accelerated in SIVIG-treated macaques. Titers of de novo neutralizing antibodies at week 12 were comparable to levels achieved in controls only by week 32 or later. Acceleration of de novo simian immunodeficiency virus immunity in the presence of passively transferred neutralizing antibodies is a novel finding with implications for postexposure prophylaxis and vaccines.

Haigwood, Nancy L.; Montefiori, David C.; Sutton, William F.; McClure, Janela; Watson, Andrew J.; Voss, Gerald; Hirsch, Vanessa M.; Richardson, Barbra A.; Letvin, Norman L.; Hu, Shiu-Lok; Johnson, Philip R.

2004-01-01

53

Stoichiometry of Monoclonal Antibody Neutralization of T-Cell Line-Adapted Human Immunodeficiency Virus Type 1  

Microsoft Academic Search

In order to study the stoichiometry of monoclonal antibody (MAb) neutralization of T-cell line-adapted human immunodeficiency virus type 1 (HIV-1) in antibody excess and under equilibrium conditions, we exploited the ability of HIV-1 to generate mixed oligomers when different env genes are coexpressed. By the coexpression of Env glycoproteins that either can or cannot bind a neutralizing MAb in an

KRISTIAN SCHØNNING; OLE LUND; JOHN-ERIK STIG HANSEN

1999-01-01

54

Neutralizing antibody in Celebes black macaques recovering from infection with simian acquired immunodeficiency syndrome retrovirus type 2.  

PubMed

Neutralizing antibodies that block the ability of simian acquired immunodeficiency syndrome (SAIDS) retrovirus type 2 (SRV-2) to induce syncytium formation in cultures of Raji cells have been found in the serum of nonviremic Celebes black macaques (Macaca nigra). Serum from Celebes macaques that are viremic have little or no neutralizing activity. The neutralizing antibodies were shown to block viral infectivity. The group of monkeys with neutralizing antibodies in their serum exhibited a dramatic improvement in their health from 1982 to 1984. The correlation of neutralizing antibodies with clinical improvement suggests that neutralizing antibodies may play a critical role in limiting the pathogenic effects of SAIDS retrovirus infection and in helping eliminate the infection. PMID:3013474

Shiigi, S M; Wilson, B J; Chandler, R A; Malley, A; Olson, L C; McNulty, W P; Marx, P A

1986-08-01

55

Human immunodeficiency virus type 1 is trapped by acidic but not by neutralized human cervicovaginal mucus.  

PubMed

To reliably infect a primate model for human immunodeficiency virus (HIV), approximately 10,000-fold more virus must be delivered vaginally than intravenously. However, the vaginal mechanisms that help protect against HIV are poorly understood. Here, we report that human cervicovaginal mucus (CVM), obtained from donors with normal lactobacillus-dominated vaginal flora, efficiently traps HIV, causing it to diffuse more than 1,000-fold more slowly than it does in water. Lactobacilli acidify CVM to pH approximately 4 by continuously producing lactic acid. At this acidic pH, we found that lactic acid, but not HCl, abolished the negative surface charge on HIV without lysing the virus membrane. In contrast, in CVM neutralized to pH 6 to 7, as occurs when semen temporarily neutralizes the vagina, HIV maintained its native surface charge and diffused only 15-fold more slowly than it would in water. Thus, methods that can maintain both a high lactic acid content and acidity for CVM during coitus may contribute to both vaginal and penile protection by trapping HIV before it can reach target cells. Our results reveal that CVM likely plays an important but currently unappreciated role in decreasing the rate of HIV sexual transmission. PMID:19692470

Lai, Samuel K; Hida, Kaoru; Shukair, Shetha; Wang, Ying-Ying; Figueiredo, Anna; Cone, Richard; Hope, Thomas J; Hanes, Justin

2009-08-19

56

Immunodeficiency \\  

Microsoft Academic Search

For the last 50 years immune deficiency disorders were thought to be rare occurring in one out of thousands of infants. Indeed in the last 10 years with the development of new genetic techniques more than 100 mutations in various genes were found to be associated with pri- mary immunodeficiencies entities. It should be noted that in some diseases several

Amos Etzioni

57

Evaluation of Human and Simian Immunodeficiency Virus Plaque and Neutralization Assays  

Microsoft Academic Search

SUMMARY A number of CD4 ÷ T cell lines were compared for their ability to act as target cells for human immunodeficiency virus (HIV) infection in syncytium- and plaque-forming assays. MT-4 and C8166 cells were the most sensitive indicator cells for HIV- and simian immunodeficiency virus (SIV)-induced cytopathic effects, and gave rise to macroscopic (MT-4) and microscopic (C8166) plaques. The

J. A. McKeating; A. McKnight; K. McIntosh; P. R. Clapham; C. Mulder; R. A. Weiss

1989-01-01

58

Access of Antibody Molecules to the Conserved Coreceptor Binding Site on Glycoprotein gp120 Is Sterically Restricted on Primary Human Immunodeficiency Virus Type 1  

Microsoft Academic Search

Anti-human immunodeficiency virus type 1 (HIV-1) antibodies whose binding to gp120 is enhanced by CD4 binding (CD4i antibodies) are generally considered nonneutralizing for primary HIV-1 isolates. However, a novel CD4i-specific Fab fragment, X5, has recently been found to neutralize a wide range of primary isolates. To investigate the precise nature of the extraordinary neutralizing ability of Fab X5, we evaluated

Aran F. Labrijn; Pascal Poignard; Aarti Raja; Michael B. Zwick; Karla Delgado; Michael Franti; James Binley; Veronique Vivona; Christoph Grundner; Chih-Chin Huang; Miro Venturi; Christos J. Petropoulos; Terri Wrin; Dimiter S. Dimitrov; James Robinson; Peter D. Kwong; Richard T. Wyatt; Joseph Sodroski; Dennis R. Burton

2003-01-01

59

Protective Effects of Broadly Neutralizing Immunoglobulin against Homologous and Heterologous Equine Infectious Anemia Virus Infection in Horses with Severe Combined Immunodeficiency?  

PubMed Central

Using the equine infectious anemia virus (EIAV) lentivirus model system, we previously demonstrated protective effects of broadly neutralizing immune plasma in young horses (foals) with severe combined immunodeficiency (SCID). However, in vivo selection of a neutralization-resistant envelope variant occurred. Here, we determined the protective effects of purified immunoglobulin with more potent broadly neutralizing activity. Overall, protection correlated with the breadth and potency of neutralizing activity in vitro. Four of five SCID foals were completely protected against homologous challenge, while partial protection occurred following heterologous challenge. These results support the inclusion of broadly neutralizing antibodies in lentivirus control strategies.

Taylor, Sandra D.; Leib, Steven R.; Wu, Wuwei; Nelson, Robert; Carpenter, Susan; Mealey, Robert H.

2011-01-01

60

Identification of gp120 Regions Targeted by a Highly Potent Neutralizing Antiserum Elicited in a Chimpanzee Inoculated with a Primary Human Immunodeficiency Virus Type 1 Isolate  

Microsoft Academic Search

We have previously reported that a chimpanzee infected with a primary human immunodeficiency virus type 1 (HIV-1) isolate (HIV-1DH12) developed an extremely potent virus-neutralizing antibody. Immunoglobulin G purified from this animal conferred sterilizing immunity following passive transfer to macaques which were subsequently challenged with simian immunodeficiency virus\\/HIV-1 chimeric virus strain DH12. In addition to being highly strain specific, the chimpanzee

MICHAEL W. CHO; MYUNG K. LEE; CHIN H. CHEN; TOM MATTHEWS; MALCOLM A. MARTIN

2000-01-01

61

Human Immunodeficiency Virus Type 1 Elite Neutralizers: Individuals with Broad and Potent Neutralizing Activity Identified by Using a High-Throughput Neutralization Assay together with an Analytical Selection Algorithm? †  

PubMed Central

The development of a rapid and efficient system to identify human immunodeficiency virus type 1 (HIV-1)-infected individuals with broad and potent HIV-1-specific neutralizing antibody responses is an important step toward the discovery of critical neutralization targets for rational AIDS vaccine design. In this study, samples from HIV-1-infected volunteers from diverse epidemiological regions were screened for neutralization responses using pseudovirus panels composed of clades A, B, C, and D and circulating recombinant forms (CRFs). Initially, 463 serum and plasma samples from Australia, Rwanda, Uganda, the United Kingdom, and Zambia were screened to explore neutralization patterns and selection ranking algorithms. Samples were identified that neutralized representative isolates from at least four clade/CRF groups with titers above prespecified thresholds and ranked based on a weighted average of their log-transformed neutralization titers. Linear regression methods selected a five-pseudovirus subset, representing clades A, B, and C and one CRF01_AE, that could identify top-ranking samples with 50% inhibitory concentration (IC50) neutralization titers of ?100 to multiple isolates within at least four clade groups. This reduced panel was then used to screen 1,234 new samples from the Ivory Coast, Kenya, South Africa, Thailand, and the United States, and 1% were identified as elite neutralizers. Elite activity is defined as the ability to neutralize, on average, more than one pseudovirus at an IC50 titer of 300 within a clade group and across at least four clade groups. These elite neutralizers provide promising starting material for the isolation of broadly neutralizing monoclonal antibodies to assist in HIV-1 vaccine design.

Simek, Melissa D.; Rida, Wasima; Priddy, Frances H.; Pung, Pham; Carrow, Emily; Laufer, Dagna S.; Lehrman, Jennifer K.; Boaz, Mark; Tarragona-Fiol, Tony; Miiro, George; Birungi, Josephine; Pozniak, Anton; McPhee, Dale A.; Manigart, Olivier; Karita, Etienne; Inwoley, Andre; Jaoko, Walter; DeHovitz, Jack; Bekker, Linda-Gail; Pitisuttithum, Punnee; Paris, Robert; Walker, Laura M.; Poignard, Pascal; Wrin, Terri; Fast, Patricia E.; Burton, Dennis R.; Koff, Wayne C.

2009-01-01

62

Reconstitution of Spontaneous Neutralizing Antibody Response against Autologous Human Immunodeficiency Virus during Highly Active Antiretroviral Therapy  

Microsoft Academic Search

Longitudinal changes in neutralizing antibody responses against autologous human immuno- deficiency virus (HIV) type 1 were investigated in 19 chronically infected patients who were undergoing highly active antiretroviral therapy (HAART). Reconstitution of or increase in neutralization activity was observed in 4 of 19 patients during HAART, but neutralization activity was more or less unchanged in most patients. Three of 4

Tetsuya Kimura; Kazuhisa Yoshimura; Kumiko Nishihara; Yosuke Maeda; Shintaro Matsumi; Atsushi Koito; Shuzo Matsushita

2002-01-01

63

Heterogeneity in Neutralization Sensitivities of Viruses Comprising the Simian Immunodeficiency Virus SIVsmE660 Isolate and Vaccine Challenge Stock  

PubMed Central

The sooty mangabey-derived simian immunodeficiency virus (SIV) strain E660 (SIVsmE660) is a genetically heterogeneous, pathogenic isolate that is commonly used as a vaccine challenge strain in the nonhuman primate (NHP) model of human immunodeficiency virus type 1 (HIV-1) infection. Though it is often employed to assess antibody-based vaccine strategies, its sensitivity to antibody-mediated neutralization has not been well characterized. Here, we utilize single-genome sequencing and infectivity assays to analyze the neutralization sensitivity of the uncloned SIVsmE660 isolate, individual viruses comprising the isolate, and transmitted/founder (T/F) viruses arising from low-dose mucosal inoculation of macaques with the isolate. We found that the SIVsmE660 isolate overall was highly sensitive to neutralization by SIV-infected macaque plasma samples (50% inhibitory concentration [IC50] < 10?5) and monoclonal antibodies targeting V3 (IC50 < 0.01 ?g/ml), CD4-induced (IC50 < 0.1 ?g/ml), CD4 binding site (IC50 ? 1 ?g/ml), and V4 (IC50, ?5 ?g/ml) epitopes. In comparison, SIVmac251 and SIVmac239 were highly resistant to neutralization by these same antibodies. Differences in neutralization sensitivity between SIVsmE660 and SIVmac251/239 were not dependent on the cell type in which virus was produced or tested. These findings indicate that in comparison to SIVmac251/239 and primary HIV-1 viruses, SIVsmE660 generally exhibits substantially less masking of antigenically conserved Env epitopes. Interestingly, we identified a minor population of viruses (?10%) in both the SIVsmE660 isolate and T/F viruses arising from it that were substantially more resistant (>1,000-fold) to antibody neutralization and another fraction (?20%) that was intermediate in neutralization resistance. These findings may explain the variable natural history and variable protection afforded by heterologous Env-based vaccines in rhesus macaques challenged by high-dose versus low-dose SIVsmE660 inoculation regimens.

Lopker, Michael; Easlick, Juliet; Sterrett, Sarah; Decker, Julie M.; Barbian, Hannah; Learn, Gerald; Keele, Brandon F.; Robinson, James E.; Li, Hui; Hahn, Beatrice H.; Shaw, George M.

2013-01-01

64

Broad, Intense Anti-Human Immunodeficiency Virus (HIV) Ex Vivo CD8 1 Responses in HIV Type 1Infected Patients: Comparison with Anti-Epstein-Barr Virus Responses and Changes during Antiretroviral Therapy  

Microsoft Academic Search

The ex vivo antiviral CD8 1 repertoires of 34 human immunodeficiency virus (HIV)-seropositive patients with various CD4 1 T-cell counts and virus loads were analyzed by gamma interferon enzyme-linked immunospot assay, using peptides derived from HIV type 1 and Epstein-Barr virus (EBV). Most patients recognized many HIV peptides, with markedly high frequencies, in association with all the HLA class I

MARC DALOD; MARION DUPUIS; JEAN-CHRISTOPHE DESCHEMIN; DIDIER SICARD; DOMINIQUE SALMON; JEAN-FRANCOIS DELFRAISSY; ALAIN VENET; MARTINE SINET; JEAN-GERARD GUILLET

1999-01-01

65

Human Immunodeficiency Virus Type 1 env Clones from Acute and Early Subtype B Infections for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies  

Microsoft Academic Search

Induction of broadly cross-reactive neutralizing antibodies is a high priority for AIDS vaccine development but one that has proven difficult to be achieved. While most immunogens generate antibodies that neutralize a subset of T-cell-line-adapted strains of human immunodeficiency virus type 1 (HIV-1), none so far have generated a potent, broadly cross-reactive response against primary isolates of the virus. Even small

Ming Li; Feng Gao; John R. Mascola; Leonidas Stamatatos; Victoria R. Polonis; Marguerite Koutsoukos; Gerald Voss; Paul Goepfert; Peter Gilbert; Kelli M. Greene; Miroslawa Bilska; Denise L. Kothe; Jesus F. Salazar-Gonzalez; Xiping Wei; Julie M. Decker; Beatrice H. Hahn; David C. Montefiori

2005-01-01

66

Neutralization of primary and T-cell line adapted isolates of human immunodeficiency virus type 1: role of V3-specific antibodies  

Microsoft Academic Search

The role of the third variable domain (V3) of gp120 in the neutralization of primary and T-cell line adapted (TCLA) strains of human immunodeficiency virus type 1 (HIV-1) by serum from HIV-1-infected individuals was investigated. A primary virus iso- late, M2424\\/4, when adapted to H9 cells, was more sensitive to neutralization on MT2 cells than the same stock passaged in

Simon Beddows; Suda Louisirirotchanakul; Rachanee Cheingsong-Popov; Philippa J. Easterbrook; Peter Simmonds; Jonathan Weber

67

Neutralizing IgG at the Portal of Infection Mediates Protection against Vaginal Simian/Human Immunodeficiency Virus Challenge.  

PubMed

Neutralizing antibodies may have critical importance in immunity against human immunodeficiency virus type 1 (HIV-1) infection. However, the amount of protective antibody needed at mucosal surfaces has not been fully established. Here, we evaluated systemic and mucosal pharmacokinetics (PK) and pharmacodynamics (PD) of 2F5 IgG and 2F5 Fab fragments with respect to protection against vaginal challenge with simian-human immunodeficiency virus-BaL in macaques. Antibody assessment demonstrated that 2F5 IgG was more potent than polymeric forms (IgM and IgA) across a range of cellular and tissue models. Vaginal challenge studies demonstrated a dose-dependent protection for 2F5 IgG and no protection with 2F5 Fab despite higher vaginal Fab levels at the time of challenge. Animals receiving 50 or 25 mg/kg of body weight 2F5 IgG were completely protected, while 3/5 animals receiving 5 mg/kg were protected. In the control animals, infection was established by a minimum of 1 to 4 transmitted/founder (T/F) variants, similar to natural human infection by this mucosal route; in the two infected animals that had received 5 mg 2F5 IgG, infection was established by a single T/F variant. Serum levels of 2F5 IgG were more predictive of sterilizing protection than measured vaginal levels. Fc-mediated antiviral activity did not appear to influence infection of primary target cells in cervical explants. However, PK studies highlighted the importance of the Fc portion in tissue biodistribution. Data presented in this study may be important in modeling serum levels of neutralizing antibodies that need to be achieved by either vaccination or passive infusion to prevent mucosal acquisition of HIV-1 infection in humans. PMID:23966410

Klein, Katja; Veazey, Ronald S; Warrier, Ranjit; Hraber, Peter; Doyle-Meyers, Lara A; Buffa, Viviana; Liao, Hua-Xin; Haynes, Barton F; Shaw, George M; Shattock, Robin J

2013-08-21

68

Identification and Characterization of a New Cross-Reactive Human Immunodeficiency Virus Type 1-Neutralizing Human Monoclonal Antibody  

PubMed Central

The identification and characterization of new human monoclonal antibodies (hMAbs) able to neutralize primary human immunodeficiency virus type 1 (HIV-1) isolates from different subtypes may help in our understanding of the mechanisms of virus entry and neutralization and in the development of entry inhibitors and vaccines. For enhanced selection of broadly cross-reactive antibodies, soluble HIV-1 envelope glycoproteins (Envs proteins) from two isolates complexed with two-domain soluble CD4 (sCD4) were alternated during panning of a phage-displayed human antibody library; these two Env proteins (89.6 and IIIB gp140s), and one additional Env (JR-FL gp120) alone and complexed with sCD4 were used for screening. An antibody with relatively long HCDR3 (17 residues), designated m14, was identified that bound to all antigens and neutralized heterologous HIV-1 isolates in multiple assay formats. Fab m14 potently neutralized selected well-characterized subtype B isolates, including JRCSF, 89.6, IIIB, and Yu2. Immunoglobulin G1 (IgG1) m14 was more potent than Fab m14 and neutralized 7 of 10 other clade B isolates; notably, although the potency was on average significantly lower than that of IgG1 b12, IgG1 m14 neutralized two of the isolates with significantly lower 50% inhibitory concentrations than did IgG1 b12. IgG1 m14 neutralized four of four selected clade C isolates with potency higher than that of IgG1 b12. It also neutralized 7 of 17 clade C isolates from southern Africa that were difficult to neutralize with other hMAbs and sCD4. IgG1 m14 neutralized four of seven primary HIV-1 isolates from other clades (A, D, E, and F) much more efficiently than did IgG1 b12; for the other three isolates, IgG b12 was much more potent. Fab m14 bound with high (nanomolar range) affinity to gp120 and gp140 from various isolates; its binding was reduced by soluble CD4 and antibodies recognizing the CD4 binding site (CD4bs) on gp120, and its footprint as defined by alanine-scanning mutagenesis overlaps that of b12. These results suggest that m14 is a novel CD4bs cross-reactive HIV-1-neutralizing antibody that exhibits a different inhibitory profile compared to the only known potent broadly neutralizing CD4bs human antibody, b12, and may have implications for our understanding of the mechanisms of immune evasion and for the development of inhibitors and vaccines.

Zhang, Mei-Yun; Xiao, Xiaodong; Sidorov, Igor A.; Choudhry, Vidita; Cham, Fatim; Zhang, Peng Fei; Bouma, Peter; Zwick, Michael; Choudhary, Anil; Montefiori, David C.; Broder, Christopher C.; Burton, Dennis R.; Quinnan, Gerald V.; Dimitrov, Dimiter S.

2004-01-01

69

Potent Neutralizing Serum Immunoglobulin A (IgA) in Human Immunodeficiency Virus Type 2-Exposed IgG-Seronegative Individuals  

PubMed Central

The mechanisms behind the resistance to human immunodeficiency virus type 2 (HIV-2) infection are still not fully understood. In the present study, we explored the HIV-2-specific humoral serum immunoglobulin A (IgA) immune response in HIV-2-exposed IgG-seronegative (EGSN) individuals. Serum samples from heterosexual EGSN individuals and their known HIV-2-infected partners, as well as controls originating from Guinea-Bissau in Africa, were studied. Antibody reactivity to native and recombinant envelope glycoproteins was investigated, and the capacity of purified serum IgA to neutralize HIV-2SBL6669 was tested. Our results showed that 16 of 25 EGSN samples exhibited reactivity against whole HIV-2 antigen, 6 of 25 samples reacted with recombinant gp36 (rgp36), and 3 of 25 samples were positive against HIV-2 rgp105; no reactivity to native HIV-2 gp125 was detected. Purified serum IgA antibodies from both EGSN and HIV-2-positive individuals, but not that from the negative controls, exhibited neutralization of HIV-2SBL6669. The most potent neutralization activity was exhibited by IgA purified from EGSN compared to infected individuals' IgA. The antigenic pattern of the HIV-2-positive partners showed that all serum IgA samples were reactive to whole HIV-2 antigen, and 14 of 15 reacted with rgp36. For rgp105 and gp125, 5 of 15 and 4 of 15 samples exhibited binding, respectively. The serum of the EGSN group had a higher mean IgA concentration than that of the negative controls (P < 0.05). Thus, we describe HIV-2-specific serum IgA antigen reactivity and show a more potent serum IgA-mediated HIV-2-neutralizing activity in EGSN individuals than in HIV-2-infected patients.

Lizeng, Qin; Nilsson, Charlotta; Sourial, Samer; Andersson, Soren; Larsen, Olav; Aaby, Peter; Ehnlund, Mariethe; Bjorling, Ewa

2004-01-01

70

Variable epitope libraries: new vaccine immunogens capable of inducing broad human immunodeficiency virus type 1-neutralizing antibody response.  

PubMed

The extreme antigenic variability of human immunodeficiency virus (HIV) leads to immune escape of the virus, representing a major challenge in the design of effective vaccine. We have developed a novel concept for immunogen construction based on introduction of massive mutations within the epitopes targeting antigenically variable pathogens and diseases. Previously, we showed that these immunogens carrying large combinatorial libraries of mutated epitope variants, termed as variable epitope libraries (VELs), induce potent, broad and long lasting CD8+IFN-?+ T-cell response. Moreover, we demonstrated that these T cells recognize more than 50% of heavily mutated variants (5 out of 10 amino acid positions were mutated in each epitope variant) of HIV-1 gp120 V3 loop-derived cytotoxic T lymphocyte epitope (RGPGRAFVTI) in mice. The constructed VELs had complexities of 10000 and 12500 individual members, generated as plasmid DNA or as M13 phage display combinatorial libraries, respectively, and with structural composition RGPGXAXXXX or XGXGXAXVXI, where X is any of 20 natural amino acids. Here, we demonstrated that sera from mice immunized with these VELs are capable of neutralizing 5 out of 10 viral isolates from Tier 2 reference panel of subtype B envelope clones, including HIV-1 isolates which are known to be resistant to neutralization by several potent monoclonal antibodies, described previously. These data indicate the feasibility of the application of immunogens based on VEL concept as an alternative approach for the development of molecular vaccines against antigenically variable pathogens. PMID:21600948

Charles-Niño, Claudia; Pedroza-Roldan, Cesar; Viveros, Monica; Gevorkian, Goar; Manoutcharian, Karen

2011-05-19

71

Serum neutralization of feline immunodeficiency virus is markedly dependent on passage history of the virus and host system.  

PubMed Central

Sera from feline immunodeficiency virus (FIV)-infected cats exhibited extremely low levels of neutralizing antibodies against virus passaged a few times in vitro (low passage), when residual infectivity was assayed in the CD3+ CD4- CD8- MBM lymphoid cell line or mitogen-activated peripheral blood mononuclear cells. By sharp contrast, elevated titers of highly efficient neutralizing activity against FIV were measured, by use of high-passage virus, in assays on either the fibroblastoid CrFK or MBM cell line. However, high-passage virus behaved the same as low-passage virus after one in vivo passage in a specific-pathogen-free cat and reisolation. Subneutralizing concentrations of infected cat sera enhanced the production of low-passage virus by MBM cells, an effect not seen with high-passage virus in CrFK cells. These qualitative and quantitative discrepancies could not be attributed to differences in the amount of immunoreactive viral material, to the amount of infectious virus present in the viral stocks, or to the presence of anti-cell antibodies. The observed effects were most likely due to the different passage history of the viral preparations used. The observation that neutralizing antibodies detected with high-passage virus were broadly cross-reactive in assays with CrFK cells but isolate specific in MBM cells suggests also that the cell substrate can influence the result of FIV neutralization assays. This possibility could not be tested directly because FIV adapted to grow in CrFK cells had little infectivity for lymphoid cells and vice versa. In vitro exposure to infected cat sera had little or no effect on the ability of in vivo-passaged FIV to infect cats. These data reveal no obvious relationship between titers against high-passage virus and ability to block infectivity of FIV in cats and suggest caution in the use of such assays to measure vaccine efficacy. In conclusion, by contrast with what has been previously reported for the use of CrFK cells and high-passage virus, both natural and experimental infections of cats with FIV generate poor neutralizing antibody responses with regard to in vivo protection.

Baldinotti, F; Matteucci, D; Mazzetti, P; Giannelli, C; Bandecchi, P; Tozzini, F; Bendinelli, M

1994-01-01

72

Studies on Antiretroviral Drug Concentrations in Breast Milk: Validation of a Liquid Chromatography-Tandem Mass Spectrometric Method for the Determination of 7 Anti-Human Immunodeficiency Virus Medications  

PubMed Central

Studying the pharmacokinetics of antiretroviral drugs in breast milk has important implications for the health of both the mother and the infant, particularly in resource-poor countries. Breast milk is a highly complex biological matrix, yet it is necessary to develop and validate methods in this matrix, which simultaneously measure multiple analytes, as women may be taking any number of drug combinations to combat human immunodeficiency virus infection. Here, we report a novel extraction method coupled to high-performance liquid chromatography and tandem mass spectrometry for the accurate, precise, and specific measurement of 7 antiretroviral drugs currently prescribed to infected mothers. Using 200 µL of human breast milk, simultaneous quantification of lamivudine (3TC), stavudine (d4T), zidovudine (ZDV), nevirapine (NVP), nelfinavir (NFV), ritonavir, and lopinavir was validated over the range of 10–10,000 ng/mL. Intraday accuracy and precision for all analytes were 99.3% and 5.0 %, respectively. Interday accuracy and precision were 99.4 % and 7.8%, respectively. Cross-assay validation with UV detection was performed using clinical breast milk samples, and the results of the 2 assays were in good agreement (P = 0.0001, r = 0.97). Breast milk to plasma concentration ratios for the different antiretroviral drugs were determined as follows: 3TC = 2.96, d4T = 1.73, ZDV = 1.17, NVP = 0.82, and NFV = 0.21.

Rezk, Naser L.; White, Nicole; Bridges, Arlene S.; Abdel-Megeed, Mohamed F.; Mohamed, Tarek M.; Moselhy, Said S.; Kashuba, Angela D. M.

2010-01-01

73

Human monoclonal antibody that recognizes the V3 region of human immunodeficiency virus gp120 and neutralizes the human T-lymphotropic virus type IIIMN strain.  

PubMed Central

We describe a human IgG1 monoclonal antibody (N701.9b) derived by Epstein-Barr virus transformation of B cells from a human immunodeficiency virus-seropositive asymptomatic donor. This antibody was shown to recognize the principal neutralizing domain contained within the V3 region of gp120 of the MN strain of human immunodeficiency virus and MN-like strains, as determined by binding to the PB-1 fragment of MN gp120 and to synthetic peptides corresponding to the V3 region of MN and related virus strains. The epitope identified by monoclonal antibody N701.9b was mapped to a segment of V3 containing at least 7 amino acids (amino acids 316-322), which is located in the "tip" and "right" side of the V3 loop of the MN strain. Furthermore, this antibody manifested potent type-specific fusion-inhibitory activity against the MN strain but not against the IIIB or RF virus strains. This antibody also neutralized four virus isolates that had MN-like V3 region sequences and failed to neutralize three other strains containing unrelated V3 region sequences. Our findings confirm that the V3 region stimulates type-specific neutralizing antibody during natural human immunodeficiency virus infection in humans. The potential clinical use of this antibody is discussed.

Scott, C F; Silver, S; Profy, A T; Putney, S D; Langlois, A; Weinhold, K; Robinson, J E

1990-01-01

74

Use of Seroconversion Panels To Estimate Delay in Detection of Anti-Human Immunodeficiency Virus Antibodies by Enzyme-Linked Immunosorbent Assay of Pooled Compared to Singleton Serum Samples  

PubMed Central

The transfusion of unsafe blood worldwide accounts for 5 to 15% of new human immunodeficiency virus (HIV) infections, most of which occur in sub-Saharan Africa. While developed countries now apply PCR testing of pooled samples, some developing countries still do not have universal screening policies. More efficient low-cost procedures for the screening of pooled samples have the potential to encourage mass screening efforts in resource-poor settings. The aim of this study was to estimate the delay in the detection of HIV antibodies in pooled serum samples compared to that in singleton serum samples by enzyme-linked immunosorbent assay (ELISA) and to evaluate the risk of transfusion-transmitted HIV infection during the window period. Serial blood samples obtained from five HIV seroconversion panels were mixed with HIV-seronegative blood samples to create pools of 6, 12, 16, 24, 32, and 48 samples. The delay in detection of the first anti-HIV antibody-positive sample in tests with pooled samples was calculated for each pool size and compared to that obtained by testing of singleton samples and statistically evaluated by a robust log-linear regression analysis. The risk of a false-negative (FN) result caused by dilution was estimated by use of the incidence risk/window period model. The additional risk of transmission related to ELISA screening of pooled samples for HIV did not exceed 9% of the current risk of an FN result (estimated to be 1/1,067,000). The countries with virus prevalence rates in donors of less than 15% are expected to save up to 30% in the number of tests. ELISA screening of pooled samples could be considered in settings where the testing of blood supplies for HIV is not routinely done.

Novack, Lena; Galai, Noya; Yaari, Arieh; Orgel, Mordechai; Shinar, Eilat; Sarov, Batia

2006-01-01

75

Evidence for non-V3-specific neutralizing antibodies that interfere with gp120/CD4 binding in human immunodeficiency virus 1-infected humans.  

PubMed Central

Total anti-gp120 antibodies (total anti-gp120 Abs) were purified from a pool of four human immunodeficiency virus-positive (HIV+) sera by affinity chromatography on a gp120SF2-Sepharose column and exhibited both type- and group-specific neutralizing activities. To dissect the epitope specificity of the group-specific neutralizing antibodies, CD4 attachment site-specific antibodies (CD4-site Abs) were isolated from total anti-gp120 Abs by using a CD4-blocked gp120SF2-Sepharose column. The CD4-site Abs exhibited group-specific neutralizing activities. Another approach to dissecting type- and group-specific neutralizing activities of total anti-gp120 Abs was to separate the third variable region (V3)-specific antibodies (V3-region Abs) from non-V3-region-specific antibodies (non-V3 Abs). The results indicated that V3-region Abs exhibited type-specific neutralizing activities, whereas non-V3 Abs exhibited group-specific neutralizing activities. By comparing the neutralizing activities of V3-region Abs to those of non-V3 Abs, we concluded that V3-region Abs are more effective than non-V3 Abs in neutralizing a specific HIV isolate. Collectively, this study indicates that group-specific neutralizing anti-gp120 antibodies are specific for the CD4 attachment site.

Kang, C Y; Nara, P; Chamat, S; Caralli, V; Ryskamp, T; Haigwood, N; Newman, R; Kohler, H

1991-01-01

76

A Cell Line-Based Neutralization Assay for Primary Human Immunodeficiency Virus Type 1 Isolates That Use either the CCR5 or the CXCR4 Coreceptor  

Microsoft Academic Search

We describe here a cell line-based assay for the evaluation of human immunodeficiency virus type 1 (HIV-1) neutralization. The assay is based on CEM.NKR cells, transfected to express the HIV-1 coreceptor CCR5 to supplement the endogenous expression of CD4 and the CXCR4 coreceptor. The resulting CEM.NKR-CCR5 cells efficiently replicate primary HIV-1 isolates of both R5 and X4 phenotypes. A comparison

ALEXANDRA TRKOLA; JAMIE MATTHEWS; CYNTHIA GORDON; TOM KETAS; JOHN P. MOORE

1999-01-01

77

A predominant group-specific neutralizing epitope of human immunodeficiency virus type 1 maps to residues 342 to 511 of the envelope glycoprotein gp120.  

PubMed Central

Recombinant native human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins gp160 and gp120 (residues 1 to 511) expressed in insect cells quantitatively adsorbed the group-specific neutralizing antibodies found in human sera. However, these antibodies were not adsorbed by envelope fragment 1 to 471 or 472 to 857 or by both fragments sequentially, even though together they add up to the full-length gp160 sequence. A hybrid envelope glycoprotein was constructed with residues 342 to 511 of the HIV-1 sequence and residues 1 to 399 of the simian immunodeficiency virus type 1 sequence to vary the HIV-1 sequence while preserving its conformation. This hybrid glycoprotein quantitatively adsorbed human neutralizing antibodies, while native simian immunodeficiency virus type 1 envelope glycoprotein did not. These results identify a new neutralizing epitope that depends on conformation and maps to residues 342 to 511 of gp120. It overlaps the extended CD4-binding site but is distinct from the V3 loop described previously (K. Javaherian et al., Proc. Natl. Acad. Sci. USA 86:6768-6772, 1989; J. R. Rusche et al., Proc. Natl. Acad. Sci. USA 85:3198-3202). Since it is conserved among diverse HIV-1 isolates, this new epitope may be a suitable target for future vaccine development. Images

Berkower, I; Murphy, D; Smith, C C; Smith, G E

1991-01-01

78

Sequential Immunization with V3 Peptides from Primary Human Immunodeficiency Virus Type 1 Produces Cross-Neutralizing Antibodies against Primary Isolates with a Matching Narrow-Neutralization Sequence Motif  

Microsoft Academic Search

An antibody response capable of neutralizing not only homologous but also heterologous forms of the CXCR4-tropic human immunodeficiency virus type 1 (HIV-1) MNp and CCR5-tropic primary isolate HIV-1 JR-CSF was achieved through sequential immunization with a combination of synthetic peptides representing HIV-1 Env V3 sequences from field and laboratory HIV-1 clade B isolates. In contrast, repeated immunization with a single

Yasuyuki Eda; Mari Takizawa; Toshio Murakami; Hiroaki Maeda; Kazuhiko Kimachi; Hiroshi Yonemura; Satoshi Koyanagi; Kouichi Shiosaki; Hirofumi Higuchi; Keiichi Makizumi; Toshihiro Nakashima; Kiyoshi Osatomi; Sachio Tokiyoshi; Shuzo Matsushita; Naoki Yamamoto; Mitsuo Honda

2006-01-01

79

Chimeric gag-V3 virus-like particles of human immunodeficiency virus induce virus-neutralizing antibodies.  

PubMed Central

A 41-kDa unprocessed human immunodeficiency virus 2 (HIV-2) gag precursor protein that has a deletion of a portion of the viral protease assembles as virus-like particles by budding through the cytoplasmic membrane of recombinant baculovirus-infected insect cells. We have constructed six different combinations of chimeric genes by coupling the truncated HIV-2 gag gene to the neutralizing domain (V3) or the neutralizing and the CD4 binding domains (V3+CD4BD) of gp120 env gene sequences from HIV-1 or HIV-2. The env gene sequences were inserted either into the middle of the gag gene or at the 3' terminus of the gag gene. Virus-like particles were formed by chimeric gene products only when the env gene sequences were linked to the 3' terminus of the gag gene. Insertion of env gene sequence in the middle of the gag gene resulted in high-level chimeric gene expression but without the formation of virus-like particles. Three different chimeric genes [gag gene with HIV-1 V3 (1V3), gag gene with HIV-2 V3 (2V3), and gag gene with HIV-2 V3+CD4BD (2V3+CD4BD)] formed virus-like particles that were secreted into the cell culture medium. In contrast, the HIV-1 V3+CD4BD/HIV-2 gag construct did not form virus-like particles. The chimeric gag-env particles had spherical morphology and the size was slightly larger than that of the gag particles, but the chimeric particles were similar to the mature HIV particles. Western blot analysis showed that the gag-env chimeric proteins were recognized by antibodies in HIV-positive human serum and rabbit anti-gp120 serum. Rabbit anti-gag 1V3 and anti-gag 2V3 sera reacted with authentic gp120 of HIV-1 and HIV-2, respectively, and neutralized homologous HIV infectivity. Our results show that precursor gag protein has potential as a carrier for the presentation of foreign epitopes in good immunological context. The gag protein is highly immunogenic and has the ability to carry large foreign inserts; as such, it offers an attractive approach for HIV vaccine development. Images

Luo, L; Li, Y; Cannon, P M; Kim, S; Kang, C Y

1992-01-01

80

Immunogenicity and ability of variable loop-deleted human immunodeficiency virus type 1 envelope glycoproteins to elicit neutralizing antibodies.  

PubMed

It has been extremely difficult to elicit broadly cross-reactive neutralizing antibodies (Nabs) against human immunodeficiency virus type 1 (HIV-1). In this study, we compared the immunogenic properties of the wild-type and variable loop-deleted HIV-1 envelope glycoproteins. Mice were immunized with recombinant vaccinia viruses expressing either the wild-type or the variable loop-deleted (V1-2, V3, V4, and V1-3) HIV-1(DH12) gp160s. The animals were subsequently boosted with respective recombinant gp120s. All envelope constructs elicited similar levels of gp120-binding antibodies when analyzed by enzyme-linked immunosorbent assay (ELISA). However, the highest neutralizing activity was observed in sera from animals immunized with the wild-type envelope protein, followed by those immunized with DeltaV4 and DeltaV1-2. No neutralizing activity was detected in sera from animals immunized with DeltaV3 or DeltaV1-3. To identify immunogenic epitopes, ELISA was performed with overlapping 15-mer peptides that cover the entire length of gp120. For the wild-type gp120, the immunogenic epitopes mapped primarily to the variable loops V1-2 and to the conserved regions C1 and C5. When they were plotted onto known coordinates of gp120 core crystal structure, the epitopes in the conserved regions mapped predominantly to the inner domain of the protein. By immunizing with variable loop-deleted envelopes, the immune responses could be redirected to other regions of the protein. However, the newly targeted epitopes were neither on the exposed surface of the protein nor on the receptor binding regions. Interestingly, the removal of the V3 loop resulted in loss of immunoreactivity for both V3 and V1/V2 loops, suggesting structural interaction between the two regions. Our results suggest that obtaining broadly reactive Nabs may not be achieved simply by deleting the variable loops of gp120. However, the observation that the immune responses could be redirected by altering the protein composition might allow us to explore alternative strategies for modifying the antigenic properties of HIV-1 envelope glycoprotein. PMID:12504547

Kim, Young B; Han, Dong P; Cao, Carlos; Cho, Michael W

2003-01-01

81

Protection of Rhesus Monkeys against Infection with Minimally Pathogenic Simian-Human Immunodeficiency Virus: Correlations with Neutralizing Antibodies and Cytotoxic T Cells  

PubMed Central

We studied the capacity of active immunization of rhesus monkeys with HIV-1 envelope protein (Env) to induce primary virus cross-reactive neutralizing antibodies to prevent infection following intravenous challenge with simian-human immunodeficiency virus (SHIV). Monkeys were immunized with the human immunodeficiency type 1 (HIV-1) strain R2 Env. Initially, the Env was expressed in vivo by an alphavirus replicon particle system, and then it was administered as soluble oligomeric gp140. Concurrently, groups of monkeys received expression vectors that encoded either simian immunodeficiency virus (SIV) gag/pol genes or no SIV genes in vivo to test the additional protective benefit of concurrent induction of virus-specific cell-mediated immune (CMI) responses. Groups of control monkeys received either the gag/pol regimen or sham immunizations. The antibodies induced by the Env immunization regimen neutralized diverse primary HIV-1 strains. Similarly, potent CMI responses were induced by the gag/pol regimen, as measured by gamma interferon enzyme-linked immunospot assays. Differences in the responses among groups of monkeys strongly suggested that there was interference between the Env and gag/pol immunization regimens. Complete protection of some of the monkeys against infection after intravenous challenge with the partially pathogenic SHIVDH12R (Clone 7) was associated independently with both neutralizing antibody and CMI responses. Protection was associated with SHIVDH12 (Clone 7) serum neutralizing antibody titers of ?1:80 or with cellular immune responses corresponding to >2,000 spot forming cells per 106 peripheral blood mononuclear cells. Immunization was also associated with a reduction in the magnitude and duration of virus load. Induction of cross-reactive, primary HIV-1-neutralizing antibodies is feasible and, when potent, may result in complete protection against infection with a heterologous challenge virus strain.

Quinnan, Gerald V.; Yu, Xiao-Fang; Lewis, Mark G.; Zhang, Peng Fei; Sutter, Gerd; Silvera, Peter; Dong, Ming; Choudhary, Anil; Sarkis, Phuong T. N.; Bouma, Peter; Zhang, Zhiqiang; Montefiori, David C.; VanCott, Thomas C.; Broder, Christopher C.

2005-01-01

82

Protection of rhesus monkeys against infection with minimally pathogenic simian-human immunodeficiency virus: correlations with neutralizing antibodies and cytotoxic T cells.  

PubMed

We studied the capacity of active immunization of rhesus monkeys with HIV-1 envelope protein (Env) to induce primary virus cross-reactive neutralizing antibodies to prevent infection following intravenous challenge with simian-human immunodeficiency virus (SHIV). Monkeys were immunized with the human immunodeficiency type 1 (HIV-1) strain R2 Env. Initially, the Env was expressed in vivo by an alphavirus replicon particle system, and then it was administered as soluble oligomeric gp140. Concurrently, groups of monkeys received expression vectors that encoded either simian immunodeficiency virus (SIV) gag/pol genes or no SIV genes in vivo to test the additional protective benefit of concurrent induction of virus-specific cell-mediated immune (CMI) responses. Groups of control monkeys received either the gag/pol regimen or sham immunizations. The antibodies induced by the Env immunization regimen neutralized diverse primary HIV-1 strains. Similarly, potent CMI responses were induced by the gag/pol regimen, as measured by gamma interferon enzyme-linked immunospot assays. Differences in the responses among groups of monkeys strongly suggested that there was interference between the Env and gag/pol immunization regimens. Complete protection of some of the monkeys against infection after intravenous challenge with the partially pathogenic SHIV(DH12R (Clone 7)) was associated independently with both neutralizing antibody and CMI responses. Protection was associated with SHIV(DH12 (Clone 7)) serum neutralizing antibody titers of > or =1:80 or with cellular immune responses corresponding to >2,000 spot forming cells per 10(6) peripheral blood mononuclear cells. Immunization was also associated with a reduction in the magnitude and duration of virus load. Induction of cross-reactive, primary HIV-1-neutralizing antibodies is feasible and, when potent, may result in complete protection against infection with a heterologous challenge virus strain. PMID:15731230

Quinnan, Gerald V; Yu, Xiao-Fang; Lewis, Mark G; Zhang, Peng Fei; Sutter, Gerd; Silvera, Peter; Dong, Ming; Choudhary, Anil; Sarkis, Phuong T N; Bouma, Peter; Zhang, Zhiqiang; Montefiori, David C; Vancott, Thomas C; Broder, Christopher C

2005-03-01

83

Identification of gp120 regions targeted by a highly potent neutralizing antiserum elicited in a chimpanzee inoculated with a primary human immunodeficiency virus type 1 isolate.  

PubMed

We have previously reported that a chimpanzee infected with a primary human immunodeficiency virus type 1 (HIV-1) isolate (HIV-1(DH12)) developed an extremely potent virus-neutralizing antibody. Immunoglobulin G purified from this animal conferred sterilizing immunity following passive transfer to macaques which were subsequently challenged with simian immunodeficiency virus/HIV-1 chimeric virus strain DH12. In addition to being highly strain specific, the chimpanzee antiserum did not bind to the V3 loop peptide of HIV-1(DH12), nor did it block the interaction of gp120 with the CD4 receptor. When neutralization was examined in the context of virus particles carrying chimeric envelope glycoproteins, the presence of all five hypervariable regions (V1 to V5) was required for optimal neutralization. Virions bearing chimeric gp120 containing the V1-V2 and V4 regions of HIV-1(DH12) could also be neutralized, but larger quantities of the chimpanzee antiserum were needed to block infection. These results indicate that the HIV-1 gp120 epitope(s) targeted by the chimpanzee antiserum is highly conformational, involving surface elements contributed by all of the hypervariable domains of the envelope glycoprotein. PMID:11000249

Cho, M W; Lee, M K; Chen, C H; Matthews, T; Martin, M A

2000-10-01

84

Identification of gp120 Regions Targeted by a Highly Potent Neutralizing Antiserum Elicited in a Chimpanzee Inoculated with a Primary Human Immunodeficiency Virus Type 1 Isolate  

PubMed Central

We have previously reported that a chimpanzee infected with a primary human immunodeficiency virus type 1 (HIV-1) isolate (HIV-1DH12) developed an extremely potent virus-neutralizing antibody. Immunoglobulin G purified from this animal conferred sterilizing immunity following passive transfer to macaques which were subsequently challenged with simian immunodeficiency virus/HIV-1 chimeric virus strain DH12. In addition to being highly strain specific, the chimpanzee antiserum did not bind to the V3 loop peptide of HIV-1DH12, nor did it block the interaction of gp120 with the CD4 receptor. When neutralization was examined in the context of virus particles carrying chimeric envelope glycoproteins, the presence of all five hypervariable regions (V1 to V5) was required for optimal neutralization. Virions bearing chimeric gp120 containing the V1–V2 and V4 regions of HIV-1DH12 could also be neutralized, but larger quantities of the chimpanzee antiserum were needed to block infection. These results indicate that the HIV-1 gp120 epitope(s) targeted by the chimpanzee antiserum is highly conformational, involving surface elements contributed by all of the hypervariable domains of the envelope glycoprotein.

Cho, Michael W.; Lee, Myung K.; Chen, Chin H.; Matthews, Tom; Martin, Malcolm A.

2000-01-01

85

Human Immunodeficiency Virus Type 1 Neutralization Epitope with Conserved Architecture Elicits Early Type-Specific Antibodies in Experimentally Infected Chimpanzees  

Microsoft Academic Search

Chimpanzees are susceptible to infection by divergent strains of human immunodeficiency virus type 1 (HIV-1), none of which cause clinical or immunological abnormalities. Chimpanzees were inoculated with one of four strains of HIV-1: human T-lymphotropic virus (HTLV) type IIIB, lymphadenopathy virus (LAV) type 1, HTLV type IIIRF, or an isolate from the brain of a patient with acquired immunodeficiency syndrome.

Jaap Goudsmit; Christine Debouck; Rob H. Meloen; Lia Smit; Margreet Bakker; David M. Asher; Axel V. Wolff; Clarence J. Gibbs; D. Carleton Gajdusek

1988-01-01

86

In Vivo gp41 Antibodies Targeting the 2F5 Monoclonal Antibody Epitope Mediate Human Immunodeficiency Virus Type 1 Neutralization Breadth ?  

PubMed Central

The broadly neutralizing human monoclonal antibodies (MAbs) 2F5 and 4E10, both targeting the highly conserved human immunodeficiency virus type 1 (HIV-1) envelope membrane proximal external region (MPER), are among the MAbs with the broadest heterologous neutralizing activity and are of considerable interest for HIV-1 vaccine development. We have identified serum antibodies from an HIV-infected subject that both were broadly neutralizing and specifically targeted MPER epitopes that overlap the 2F5 epitope. These MPER-specific antibodies were made 15 to 20 months following transmission and concomitantly with the development of autoantibodies. Our findings suggest that multiple events (i.e., genetic predisposition and HIV-1 immune dysregulation) may be required for induction of broadly reactive gp41 MPER antibodies in natural infection.

Shen, Xiaoying; Parks, Robert J.; Montefiori, David C.; Kirchherr, Jennifer L.; Keele, Brandon F.; Decker, Julie M.; Blattner, William A.; Gao, Feng; Weinhold, Kent J.; Hicks, Charles B.; Greenberg, Michael L.; Hahn, Beatrice H.; Shaw, George M.; Haynes, Barton F.; Tomaras, Georgia D.

2009-01-01

87

Profiling the Specificity of Neutralizing Antibodies in a Large Panel of Plasmas from Patients Chronically Infected with Human Immunodeficiency Virus Type 1 Subtypes B and C? †  

PubMed Central

Identifying the viral epitopes targeted by broad neutralizing antibodies (NAbs) that sometimes develop in human immunodeficiency virus type 1 (HIV-1)-infected subjects should assist in the design of vaccines to elicit similar responses. Here, we investigated the activities of a panel of 24 broadly neutralizing plasmas from subtype B- and C-infected donors using a series of complementary mapping methods, focusing mostly on JR-FL as a prototype subtype B primary isolate. Adsorption with gp120 immobilized on beads revealed that an often large but variable fraction of plasma neutralization was directed to gp120 and that in some cases, neutralization was largely mediated by CD4 binding site (CD4bs) Abs. The results of a native polyacrylamide gel electrophoresis assay using JR-FL trimers further suggested that half of the subtype B and a smaller fraction of subtype C plasmas contained a significant proportion of NAbs directed to the CD4bs. Anti-gp41 neutralizing activity was detected in several plasmas of both subtypes, but in all but one case, constituted only a minor fraction of the overall neutralization activity. Assessment of the activities of the subtype B plasmas against chimeric HIV-2 viruses bearing various fragments of the membrane proximal external region (MPER) of HIV-1 gp41 revealed mixed patterns, implying that MPER neutralization was not dominated by any single specificity akin to known MPER-specific monoclonal Abs. V3 and 2G12-like NAbs appeared to make little or no contribution to JR-FL neutralization titers. Overall, we observed significant titers of anti-CD4bs NAbs in several plasmas, but approximately two-thirds of the neutralizing activity remained undefined, suggesting the existence of NAbs with specificities unlike any characterized to date.

Binley, James M.; Lybarger, Elizabeth A.; Crooks, Emma T.; Seaman, Michael S.; Gray, Elin; Davis, Katie L.; Decker, Julie M.; Wycuff, Diane; Harris, Linda; Hawkins, Natalie; Wood, Blake; Nathe, Cory; Richman, Douglas; Tomaras, Georgia D.; Bibollet-Ruche, Frederic; Robinson, James E.; Morris, Lynn; Shaw, George M.; Montefiori, David C.; Mascola, John R.

2008-01-01

88

Increased Sensitivity to CD4 Binding Site-Directed Neutralization following In Vitro Propagation on Primary Lymphocytes of a Neutralization-Resistant Human Immunodeficiency Virus IIIB Strain Isolated from an Accidentally Infected Laboratory Worker  

PubMed Central

We previously described the adaptation of the neutralization-sensitive human immunodeficiency virus type 1 (HIV-1) strain IIIB to a neutralization-resistant phenotype in an accidentally infected laboratory worker. During long-term propagation of this resistant isolate, designated FF3346, on primary peripheral blood leukocytes in vitro, an HIV-1 variant appeared that had regained sensitivity to neutralization by soluble CD4 (sCD4) and the broadly neutralizing monoclonal antibody b12. When an early passage of FF3346 was subjected to limiting-dilution culture in peripheral blood mononuclear cells, eight virus variants with various degrees of neutralization resistance were isolated. Two of them, the sCD4 neutralization-resistant variant LW_H8res and the sCD4 neutralization-sensitive variant LW_G9sens, were selected for further study. Interestingly, these two viruses were equally resistant to neutralization by agents that recognize domains other than the CD4 binding site. Site-directed mutagenesis revealed that the increased neutralization sensitivity of variant LW_G9sens resulted from only two changes, an Asn-to-Ser substitution at position 164 in the V2 loop and an Ala-to-Glu substitution at position 370 in the C3 domain of gp120. In agreement with this notion, the affinity of b12 for monomeric gp120 containing the N164S and A370E substitutions in the background of the molecular clone LW_H8res was higher than its affinity for the parental gp120. Surprisingly, no correlation was observed between CD4 binding affinity for monomeric gp120 and the level of neutralization resistance, suggesting that differences in sCD4 neutralization sensitivity between these viruses are only manifested in the context of the tertiary or quaternary structure of gp120 on the viral surface. The results obtained here indicate that the neutralization-sensitive strain IIIB can become neutralization resistant in vivo under selective pressure by neutralizing antibodies but that this resistance may be easily reversed in the absence of immunological pressure.

Beaumont, Tim; Quakkelaar, Esther; van Nuenen, Ad; Pantophlet, Ralph; Schuitemaker, Hanneke

2004-01-01

89

Importance of the V1\\/V2 Loop Region of Simian-Human Immunodeficiency Virus Envelope Glycoprotein gp120 in Determining the Strain Specificity of the Neutralizing Antibody Response  

Microsoft Academic Search

Plasma samples from individuals infected with human immunodeficiency virus type 1 (HIV-1) are known to be highly strain specific in their ability to neutralize HIV-1 infectivity. Such plasma samples exhibit significant neutralizing activity against autologous HIV-1 isolates but typically exhibit little or no activity against heter- ologous strains, although some cross-neutralizing activity can develop late in infection. Monkeys infected with

Melissa E. Laird; Tatsuhiko Igarashi; Malcolm A. Martin; Ronald C. Desrosiers

2008-01-01

90

The Membrane-Proximal External Region of the Human Immunodeficiency Virus Type 1 Envelope: Dominant Site of Antibody Neutralization and Target for Vaccine Design  

PubMed Central

Summary: Enormous efforts have been made to produce a protective vaccine against human immunodeficiency virus type 1; there has been little success. However, the identification of broadly neutralizing antibodies against epitopes on the highly conserved membrane-proximal external region (MPER) of the gp41 envelope protein has delineated this region as an attractive vaccine target. Furthermore, emerging structural information on the MPER has provided vaccine designers with new insights for building relevant immunogens. This review describes the current state of the field regarding (i) the structure and function of the gp41 MPER; (ii) the structure and binding mechanisms of the broadly neutralizing antibodies 2F5, 4E10, and Z13; and (iii) the development of an MPER-targeting vaccine. In addition, emerging approaches to vaccine design are presented.

Montero, Marinieve; van Houten, Nienke E.; Wang, Xin; Scott, Jamie K.

2008-01-01

91

Neutralizing Polyclonal IgG Present during Acute Infection Prevents Rapid Disease Onset in Simian-Human Immunodeficiency Virus SHIVSF162P3-Infected Infant Rhesus Macaques  

PubMed Central

Simian-human immunodeficiency virus (SHIV) models for human immunodeficiency virus (HIV) infection have been widely used in passive studies with HIV neutralizing antibodies (NAbs) to test for protection against infection. However, because SHIV-infected adult macaques often rapidly control plasma viremia and any resulting pathogenesis is minor, the model has been unsuitable for studying the impact of antibodies on pathogenesis in infected animals. We found that SHIVSF162P3 infection in 1-month-old rhesus macaques not only results in high persistent plasma viremia but also leads to very rapid disease progression within 12 to 16 weeks. In this model, passive transfer of high doses of neutralizing IgG (SHIVIG) prevents infection. Here, we show that at lower doses, SHIVIG reduces both plasma and peripheral blood mononuclear cell (PBMC)-associated viremia and mitigates pathogenesis in infected animals. Moreover, production of endogenous NAbs correlated with lower set-point viremia and 100% survival of infected animals. New SHIV models are needed to investigate whether passively transferred antibodies or antibodies elicited by vaccination that fall short of providing sterilizing immunity impact disease progression or influence immune responses. The 1-month-old rhesus macaque SHIV model of infection provides a new tool to investigate the effects of antibodies on viral replication and clearance, mechanisms of B cell maintenance, and the induction of adaptive immunity in disease progression.

Jaworski, J. Pablo; Kobie, James; Brower, Zachary; Malherbe, Delphine C.; Landucci, Gary; Sutton, William F.; Guo, Biwei; Reed, Jason S.; Leon, Enrique J.; Engelmann, Flora; Zheng, Bo; Legasse, Al; Park, Byung; Dickerson, Mary; Lewis, Anne D.; Colgin, Lois M. A.; Axthelm, Michael; Messaoudi, Ilhem; Sacha, Jonah B.; Burton, Dennis R.; Forthal, Donald N.; Hessell, Ann J.

2013-01-01

92

Infection of vaginal and colonic epithelial cells by the human immunodeficiency virus type 1 is neutralized by antibodies raised against conserved epitopes in the envelope glycoprotein gp120.  

PubMed Central

The rectal and genital tract mucosae are considered to be major sites of entry for the human immunodeficiency virus (HIV) during sexual contact. We now demonstrate that vaginal epithelial cells can be infected by HIV type 1 (HIV-1) via a mechanism similar to that described for neuroglial cells and, more recently, for colorectal epithelial cells, involving initial interaction of the HIV-1 envelope glycoprotein gp120 with a cell-surface glycosphingolipid (sulfated lactosylceramide). A hyperimmune serum against gp120 was able to neutralize HIV-1 infection of vaginal epithelial cells. Site-directed immunization was employed to identify sites on gp120 recognized by antibodies neutralizing HIV-1 infection of vaginal and colonic epithelial cells. Hyperimmune sera were raised in monkeys against a series of 40 overlapping synthetic peptides covering the entire sequence of HIV-1 (HTLV-IIIB) gp120. Antisera raised against five synthetic peptides, corresponding to three relatively conserved regions and to the hypervariable region (V3 loop), efficiently neutralized HIV-1 infection of human vaginal epithelial cells in vitro. Similar results were obtained with the colonic cells. Hyperimmune sera to all five peptides have been shown earlier to neutralize HIV-1 infectivity in CD4+ T cells. These results have obvious implications for the design of mucosal subunit vaccines against sexually transmitted HIV-1 infections. Images Fig. 1 Fig. 2 Fig. 3

Furuta, Y; Eriksson, K; Svennerholm, B; Fredman, P; Horal, P; Jeansson, S; Vahlne, A; Holmgren, J; Czerkinsky, C

1994-01-01

93

High-Mannose Glycan-Dependent Epitopes Are Frequently Targeted in Broad Neutralizing Antibody Responses during Human Immunodeficiency Virus Type 1 Infection  

PubMed Central

Broad and potent neutralizing antibody (BNAb) responses are rare in people infected by human immunodeficiency virus type 1 (HIV-1). Clearly defining the nature of BNAb epitopes on HIV-1 envelope glycoproteins (Envs) targeted in vivo is critical for future directions of anti-HIV-1 vaccine development. Conventional techniques are successful in defining neutralizing epitopes in a small number of individual subjects but fail in studying large groups of subjects. Two independent methods were employed to investigate the nature of NAb epitopes targeted in 9 subjects, identified by the NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI) 001 and 008 clinical teams, known to make a strong BNAb response. Neutralizing activity from 8/9 subjects was enhanced by enriching high-mannose N-linked glycan (HM-glycan) of HIV-1 glycoproteins on neutralization target viruses and was sensitive to specific glycan deletion mutations of HIV-1 glycoproteins, indicating that HM-glycan-dependent epitopes are targeted by BNAb responses in these subjects. This discovery adds to accumulating evidence supporting the hypothesis that glycans are important targets on HIV-1 glycoproteins for BNAb responses in vivo, providing an important lead for future directions in developing NAb-based anti-HIV-1 vaccines.

Lavine, Christy L.; Lao, Socheata; Montefiori, David C.; Haynes, Barton F.; Sodroski, Joseph G.

2012-01-01

94

Adaptation to persistent growth in the H9 cell line renders a primary isolate of human immunodeficiency virus type 1 sensitive to neutralization by vaccine sera.  

PubMed Central

Seven diverse primary isolates of human immunodeficiency virus type 1 (HIV-1) were examined and found to be refractory to neutralization by antisera to recombinant gp120 (rgp120) protein from HIV-1 MN. This stands in marked contrast to the sensitivity exhibited by certain laboratory-adapted viruses. To understand the difference between primary and laboratory-adapted viruses, we adapted the primary virus ACH 168.10 to growth in the FDA/H9 cell line. ACH 168.10 was chosen because the V3 region of gp120 closely matches that of MN. After 4 weeks, infection became evident. The virus (168A) replicated in FDA/H9 cells with extensive cytopathic effect but was unchanged in sensitivity to antibody-mediated neutralization. Thus, growth in cell lines is not sufficient to render primary virus sensitive to neutralization. The 168A virus was, however, partially sensitive to CD4 immunoadhesin (CD4-Ig). Adaptation was continued to produce a persistently infected FDA/H9 culture that displayed minimal cytopathic effect. The virus (168C) was now sensitive to neutralization by MN rgp120 vaccine sera and by MN-specific monoclonal antibodies and showed increased sensitivity to HIVIG and CD4-Ig. 168C encoded three amino acid changes in gp120, including one within the V3 loop (I-166-->R, I-282-->N, G-318-->R). MN-specific monoclonal antibodies bound equally to the surface of cells infected with either neutralization-resistant or -sensitive virus. The coincidence of changes in neutralization sensitivity with changes in cell tropism and cytopathic effect suggests a common underlying mechanism(s) acting through the whole of the envelope protein complex.

Wrin, T; Loh, T P; Vennari, J C; Schuitemaker, H; Nunberg, J H

1995-01-01

95

Induction of Neutralizing Antibodies to T-Cell Line-Adapted and Primary Human Immunodeficiency Virus Type 1 Isolates with a Prime-Boost Vaccine Regimen in Chimpanzees  

PubMed Central

Five chimpanzees were immunized by administration of one or more intranasal priming doses of one to three recombinant adenoviruses containing a gp160 insert from human immunodeficiency virus type 1 (HIV-1) MN (HIV-1MN) followed by one or more boosts of recombinant HIV-1SF2 gp120 delivered intramuscularly with MF59 adjuvant. This regimen resulted in humoral immune responses in three of five animals. Humoral responses included immunochemically active anti-HIV-1 antibodies (Abs) directed to recombinant gp120 and neutralizing Abs reactive with T-cell-line-adapted HIV-1MN and HIV-1SF2. In addition, neutralizing activity was detected to the two homologous primary isolates and to two of three heterologous primary isolates which, like the immunizing strains, can use CXCR4 as a coreceptor for infection. The three animals with detectable neutralizing Abs and a fourth exhibiting the best cytotoxic T-lymphocyte response were protected from a low-dose intravenous challenge with a cell-free HIV-1SF2 primary isolate administered 4 weeks after the last boost. Animals were rested for 46 weeks and then rechallenged, without a boost, with an eightfold-higher challenge dose of HIV-1SF2. The three animals with persistent neutralizing Abs were again protected. These data show that a strong, long-lived protective Ab response can be induced with a prime-boost regimen in chimpanzees. The data suggest that in chimpanzees, the presence of neutralizing Abs correlates with protection for animals challenged intravenously with a high dose of a homologous strain of HIV-1, and they demonstrate for the first time the induction of neutralizing Abs to homologous and heterologous primary isolates.

Zolla-Pazner, Susan; Lubeck, Michael; Xu, Serena; Burda, Sherri; Natuk, Robert J.; Sinangil, Faruk; Steimer, Kathelyn; Gallo, Robert C.; Eichberg, Jorg W.; Matthews, Thomas; Robert-Guroff, Marjorie

1998-01-01

96

Human immunodeficiency virus type 1 neutralizing antibodies accelerate clearance of cell–free virions from blood plasma  

Microsoft Academic Search

The concentration of human immunodeficiency virus type 1 (HIV–1) particles in blood plasma is very predictive of the subsequent disease course in an infected individual; its measurement has become one of the most important parameters for monitoring clinical status. Steady–state virus levels in plasma reflect a balance between the rates of virions entering and leaving the peripheral blood. We analyzed

Tatsuhiko Igarashi; Charles Brown; Ali Azadegan; Nancy Haigwood; Dimiter Dimitrov; Malcolm A. Martin; Riri Shibata

1999-01-01

97

Variant-specific monoclonal and group-specific polyclonal human immunodeficiency virus type 1 neutralizing antibodies raised with synthetic peptides from the gp120 third variable domain.  

PubMed Central

The third variable (V3) domain of the human immunodeficiency virus type 1 (HIV-1) external membrane glycoprotein gp120 is of crucial importance in eliciting neutralizing antibodies in infected persons. Polyclonal (PAb) and monoclonal (MAb) antibodies directed against selected epitopes in the V3 domain are valuable tools for analysis of the involvement of such sequences in neutralization and for definition of the relation between amino acid variability and immunological cross-reactions. The aim of this study was to obtain such site-specific antibodies. By using synthetic peptides derived from the V3 domain, a group-specific neutralizing PAb, two high-affinity HIV-1 IIIB neutralizing MAb, and two nonneutralizing MAb were raised. A 15-amino-acid peptide overlapping the tip of the V3 domain of HIV-1 MN was used to produce a rabbit PAb (W0/07). This PAb inhibited syncytium formation induced by HIV-1 IIIB and four field isolates. A similar IIIB-derived peptide was used to generate two murine immunoglobulin G1 (IgG1) MAb (IIIB-V3-13 and IIIB-V3-34). Pepscan analysis mapped the binding site of IIIB-V3-34 to the sequence IRIQRGPGR. The Kds of IIIB-V3-13 and IIIB-V3-34 for gp120 were 6.8 x 10(-11) and 1.6 x 10(-10) M, respectively. These MAb neutralized IIIB but not MN and inhibited syncytium formation induced by IIIB. They are applicable in enzyme-linked immunosorbent assays, immunocytochemistry, and flow cytometry. A peptide covering the left base of the V3 domain was used to generate two murine IgG1 MAb (IIIB-V3-21 and IIIB-V3-26). The binding site of IIIB-V3-21 was mapped to the sequence INCTRPN. These MAb did not neutralize HIV-1 and did not inhibit syncytium formation. This study supports the notion that HIV-1 neutralizing antibodies suitable for multiassay performance can be obtained with synthetic peptides and that high-affinity MAb can be generated. Such site-specific antibodies are useful reagents in the analysis of HIV-1 neutralization. In addition, the cross-neutralization of different viral strains by PAb generated through single-peptide immunization is directly relevant to vaccine development. Images

Laman, J D; Schellekens, M M; Abacioglu, Y H; Lewis, G K; Tersmette, M; Fouchier, R A; Langedijk, J P; Claassen, E; Boersma, W J

1992-01-01

98

Formaldehyde-Treated, Heat-Inactivated Virions with Increased Human Immunodeficiency Virus Type 1 Env Can Be Used To Induce High-Titer Neutralizing Antibody Responses  

PubMed Central

The lack of success of subunit human immunodeficiency virus (HIV) type 1 vaccines to date suggests that multiple components or a complex virion structure may be required. We hypothesized that the failure of current vaccine strategies to induce protective antibodies is linked to the inability of native envelope structures to readily elicit these types of antibodies. We have previously reported on the ability of a formaldehyde-treated, heat-inactivated vaccine to induce modest antibody responses in animal vaccine models. We investigated here whether immunization for HIV with an envelope-modified, formaldehyde-stabilized, heat-inactivated virion vaccine could produce higher-titer and/or broader neutralizing antibody responses. Thus, a clade B vaccine which contains a single point mutation in gp41 (Y706C) that results in increased incorporation of oligomeric Env into virions was constructed. This vaccine was capable of inducing high-titer antibodies that could neutralize heterologous viruses, including those of clades A and C. These results further support the development of HIV vaccines with modifications in native Env structures for the induction of neutralizing antibody responses.

Poon, B.; Hsu, J. F.; Gudeman, V.; Chen, I. S. Y.; Grovit-Ferbas, K.

2005-01-01

99

Novel Ring Structure in the gp41 Trimer of Human Immunodeficiency Virus Type 1 That Modulates Sensitivity and Resistance to Broadly Neutralizing Antibodies? †  

PubMed Central

The identification of the determinants of sensitivity and resistance to broadly neutralizing antibodies is a high priority for human immunodeficiency virus (HIV) research. An analysis of the swarm of closely related envelope protein variants in an HIV-infected individual revealed a mutation that markedly affected sensitivity to neutralization by antibodies and antiviral entry inhibitors targeting both gp41 and gp120. This mutation mapped to the C34 helix of gp41 and disrupted an unexplored structural feature consisting of a ring of hydrogen bonds in the gp41 trimer. This mutation appeared to affect the assembly of the six-helix bundle required for virus fusion and to alter the conformational equilibria so as to favor the prehairpin intermediate conformation required for the binding of the membrane proximal external region-specific neutralizing antibodies 2F5 and 4E10 and the antiviral drug enfuvirtide (Fuzeon). The “swarm analysis” method we describe furthers our understanding of the relationships among the structure, function, and antigenicity of the HIV envelope protein and represents a new approach to the identification of vaccine antigens.

O'Rourke, Sara M.; Schweighardt, Becky; Scott, William G.; Wrin, Terri; Fonseca, Dora P. A. J.; Sinangil, Faruk; Berman, Phillip W.

2009-01-01

100

The Ability of an Oligomeric Human Immunodeficiency Virus Type 1 (HIV1) Envelope Antigen To Elicit Neutralizing Antibodies against Primary HIV1 Isolates Is Improved following Partial Deletion of the Second Hypervariable Region  

Microsoft Academic Search

Partial deletion of the second hypervariable region from the envelope of the primary-like SF162 virus increases the exposure of certain neutralization epitopes and renders the virus, SF162DV2, highly susceptible to neutralization by clade B and non-clade B human immunodeficiency virus (HIV-positive) sera (L. Stama- tatos and C. Cheng-Mayer, J. Virol. 78:7840-7845, 1998). This observation led us to propose that the

S. W. Barnett; S. Lu; I. Srivastava; S. Cherpelis; A. Gettie; J. Blanchard; S. Wang; I. Mboudjeka; L. Leung; Y. Lian; A. Fong; C. Buckner; A. Ly; S. Hilt; J. Ulmer; C. T. Wild; J. R. Mascola; L. Stamatatos

2001-01-01

101

The role of amino acid changes in the human immunodeficiency virus type 1 transmembrane domain in antibody binding and neutralization  

PubMed Central

The detailed interactions between antibodies and the HIV-1 envelope protein that lead to neutralization are not well defined. Here, we show that several conservative substitutions in the envelope gp41 led to a ~ 100 fold increase in neutralization sensitivity to monoclonal antibodies (MAbs) that target gp41: 4E10 and 2F5. Substitution at position 675 alone did not impact neutralization susceptibility to MAbs that recognize more distal sites in gp120 (b12, VRC01, PG9). However, changes at position 675 in conjunction with Thr to Ala at position 569 increased the neutralization sensitivity to all gp41 and gp120 MAbs and plasma, in some cases by more than 1000-fold. Interestingly, the T569A change had a dramatic effect on b12 binding, but no effect on neutralization sensitivity. This finding suggests that antibody neutralization may occur through a multi-step pathway that includes distinct changes in envelope conformation that may affect binding but not neutralization susceptibility.

Lovelace, Erica; Xu, Hengyu; Blish, Catherine A.; Strong, Roland; Overbaugh, Julie

2011-01-01

102

Identification of a novel WxSLVK motif in the N terminus of human immunodeficiency virus and simian immunodeficiency virus Vif that is critical for APOBEC3G and APOBEC3F neutralization.  

PubMed

The function of lentiviral Vif proteins is to neutralize the host antiviral cytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F). Vif bridges a cullin 5-based E3 ubiquitin ligase with A3G and A3F and mediates their degradation by proteasomes. Recent studies have found that Vif uses different domains to bind to A3G and A3F. A (14)DRMR(17) domain binds to A3F, (40)YRHHY(44) binds to A3G, and (69)YxxL(72) binds to both A3G and A3F. Here, we report another functional domain of Vif. Previously, we demonstrated that human immunodeficiency virus type 1 (HIV-1) Vif failed to mediate A3G proteasomal degradation when all 16 lysines were mutated to arginines. Here, we show that K26, and to a lesser extent K22, is critical for A3G neutralization. K22 and K26 are part of a conserved (21)WxSLVK(26) (x represents N, K, or H) motif that is found in most primate lentiviruses and that shows species-specific variation. Both K22 and K26 in this motif regulated Vif specificity only for A3G, whereas the SLV residues regulated Vif specificity for both A3F and A3G. Interestingly, SLV and K26 in HIV-1 Vif did not directly mediate Vif interaction with either A3G or A3F. Previously, other groups have reported an important role for W21 in A3F and A3G neutralization. Thus, (21)WxSLVK(26) is a novel functional domain that regulates Vif activity toward both A3F and A3G and is a potential drug target to inhibit Vif activity and block HIV-1 replication. PMID:19535447

Dang, Ying; Wang, Xiaojun; Zhou, Tao; York, Ian A; Zheng, Yong-Hui

2009-06-17

103

Identification of a Novel WxSLVK Motif in the N Terminus of Human Immunodeficiency Virus and Simian Immunodeficiency Virus Vif That Is Critical for APOBEC3G and APOBEC3F Neutralization?  

PubMed Central

The function of lentiviral Vif proteins is to neutralize the host antiviral cytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F). Vif bridges a cullin 5-based E3 ubiquitin ligase with A3G and A3F and mediates their degradation by proteasomes. Recent studies have found that Vif uses different domains to bind to A3G and A3F. A 14DRMR17 domain binds to A3F, 40YRHHY44 binds to A3G, and 69YxxL72 binds to both A3G and A3F. Here, we report another functional domain of Vif. Previously, we demonstrated that human immunodeficiency virus type 1 (HIV-1) Vif failed to mediate A3G proteasomal degradation when all 16 lysines were mutated to arginines. Here, we show that K26, and to a lesser extent K22, is critical for A3G neutralization. K22 and K26 are part of a conserved 21WxSLVK26 (x represents N, K, or H) motif that is found in most primate lentiviruses and that shows species-specific variation. Both K22 and K26 in this motif regulated Vif specificity only for A3G, whereas the SLV residues regulated Vif specificity for both A3F and A3G. Interestingly, SLV and K26 in HIV-1 Vif did not directly mediate Vif interaction with either A3G or A3F. Previously, other groups have reported an important role for W21 in A3F and A3G neutralization. Thus, 21WxSLVK26 is a novel functional domain that regulates Vif activity toward both A3F and A3G and is a potential drug target to inhibit Vif activity and block HIV-1 replication.

Dang, Ying; Wang, Xiaojun; Zhou, Tao; York, Ian A.; Zheng, Yong-Hui

2009-01-01

104

The Neutralization Sensitivity of Viruses Representing Human Immunodeficiency Virus Type 1 Variants of Diverse Subtypes from Early in Infection is Dependent on Producer Cell, as well as Characteristics of the Specific Antibody and Envelope Variant  

PubMed Central

Neutralization properties of human immunodeficiency virus (HIV-1) are often defined using pseudoviruses grown in transformed cells, which are not biologically relevant HIV-1 producer cells. Little information exists on how these viruses compare to viruses produced in primary lymphocytes, particularly for globally relevant HIV-1 strains. Therefore, replication-competent chimeras encoding envelope variants from the dominant HIV-1 subtypes (A, C, and D) obtained early after infection were generated and the neutralization properties explored. Pseudoviruses generated in 293T cells were the most sensitive to antibody neutralization. Replicating viruses generated in primary lymphocytes were most resistant to neutralization by plasma antibodies and most monoclonal antibodies (b12, 4E10, 2F5, VRC01). These differences were not associated with differences in envelope content. Surprisingly, the virus source did not impact neutralization sensitivity of most viruses to PG9. These findings suggest that producer cell type has a major effect on neutralization sensitivity, but in an antibody dependent manner.

Provine, Nicholas M.; Cortez, Valerie; Chohan, Vrasha; Overbaugh, Julie

2012-01-01

105

Importance of the V1/V2 loop region of simian-human immunodeficiency virus envelope glycoprotein gp120 in determining the strain specificity of the neutralizing antibody response.  

PubMed

Plasma samples from individuals infected with human immunodeficiency virus type 1 (HIV-1) are known to be highly strain specific in their ability to neutralize HIV-1 infectivity. Such plasma samples exhibit significant neutralizing activity against autologous HIV-1 isolates but typically exhibit little or no activity against heterologous strains, although some cross-neutralizing activity can develop late in infection. Monkeys infected with the simian-human immunodeficiency virus (SHIV) clone DH12 generated antibodies that neutralized SHIV DH12, but not SHIV KB9. Conversely, antibodies from monkeys infected with the SHIV clone KB9 neutralized SHIV KB9, but not SHIV DH12. To investigate the role of the variable loops of the HIV-1 envelope glycoprotein gp120 in determining this strain specificity, variable loops 1 and 2 (V1/V2), V3, or V4 were exchanged individually or in combination between SHIV DH12 and SHIV KB9. Despite the fact that both parental viruses exhibited significant infectivity and good replication in the cell lines examined, 3 of the 10 variable-loop chimeras exhibited such poor infectivity that they could not be used further for neutralization assays. These results indicate that a variable loop that is functional in the context of one particular envelope background will not necessarily function within another. The remaining seven replication-competent chimeras allowed unambiguous assignment of the sequences principally responsible for the strain specificity of the neutralizing activity present in SHIV-positive plasma. Exchange of the V1/V2 loop sequences conferred a dominant loss of sensitivity to neutralization by autologous plasma and a gain of sensitivity to neutralization by heterologous plasma. Substitution of V3 or V4 had little or no effect on the sensitivity to neutralization. These data demonstrate that the V1/V2 region of HIV-1 gp120 is principally responsible for the strain specificity of the neutralizing antibody response in monkeys infected with these prototypic SHIVs. PMID:18768967

Laird, Melissa E; Igarashi, Tatsuhiko; Martin, Malcolm A; Desrosiers, Ronald C

2008-09-03

106

Importance of the V1/V2 Loop Region of Simian-Human Immunodeficiency Virus Envelope Glycoprotein gp120 in Determining the Strain Specificity of the Neutralizing Antibody Response?  

PubMed Central

Plasma samples from individuals infected with human immunodeficiency virus type 1 (HIV-1) are known to be highly strain specific in their ability to neutralize HIV-1 infectivity. Such plasma samples exhibit significant neutralizing activity against autologous HIV-1 isolates but typically exhibit little or no activity against heterologous strains, although some cross-neutralizing activity can develop late in infection. Monkeys infected with the simian-human immunodeficiency virus (SHIV) clone DH12 generated antibodies that neutralized SHIV DH12, but not SHIV KB9. Conversely, antibodies from monkeys infected with the SHIV clone KB9 neutralized SHIV KB9, but not SHIV DH12. To investigate the role of the variable loops of the HIV-1 envelope glycoprotein gp120 in determining this strain specificity, variable loops 1 and 2 (V1/V2), V3, or V4 were exchanged individually or in combination between SHIV DH12 and SHIV KB9. Despite the fact that both parental viruses exhibited significant infectivity and good replication in the cell lines examined, 3 of the 10 variable-loop chimeras exhibited such poor infectivity that they could not be used further for neutralization assays. These results indicate that a variable loop that is functional in the context of one particular envelope background will not necessarily function within another. The remaining seven replication-competent chimeras allowed unambiguous assignment of the sequences principally responsible for the strain specificity of the neutralizing activity present in SHIV-positive plasma. Exchange of the V1/V2 loop sequences conferred a dominant loss of sensitivity to neutralization by autologous plasma and a gain of sensitivity to neutralization by heterologous plasma. Substitution of V3 or V4 had little or no effect on the sensitivity to neutralization. These data demonstrate that the V1/V2 region of HIV-1 gp120 is principally responsible for the strain specificity of the neutralizing antibody response in monkeys infected with these prototypic SHIVs.

Laird, Melissa E.; Igarashi, Tatsuhiko; Martin, Malcolm A.; Desrosiers, Ronald C.

2008-01-01

107

Insertion of primary syncytium-inducing (SI) and non-SI envelope V3 loops in human immunodeficiency virus type 1 (HIV-1) LAI reduces neutralization sensitivity to autologous, but not heterologous, HIV-1 antibodies.  

PubMed Central

The aim of the study was to investigate the influence of V3 loops from naturally occurring viruses on the neutralization sensitivity of a molecularly cloned virus. A selection of well-defined syncytium-inducing (SI) and non-SI V3 loops of a single human immunodeficiency virus type 1-infected individual (H594) and the V3 regions of two SI laboratory strains were inserted in an infectious molecular clone of human immunodeficiency type 1 LAI. Neutralization was performed with a heterologous serum pool and autologous patient serum, using the virus reduction neutralization assay and peripheral blood lymphocytes as target cells. High sensitivity of the chimeric viruses containing the laboratory strain V3 regions to neutralization by H594 sequential sera as well as the heterologous serum pool was found. A statistically significant correlation between the sensitivities of these viruses was seen. In contrast, insertion of the primary isolate NSI and SI envelope V3 loops significantly reduced the neutralization by autologous serum but not by the heterologous serum pool. No correlation was found between the neutralization of the viruses with laboratory strain-derived V3 regions and the viruses with primary isolate V3 domains. We conclude that heterologous antibodies are able to neutralize infectious molecular clones with V3 loops of both SI and NSI viruses, regardless of whether they originated from laboratory strains or primary isolates. However, serum of patient H594 discriminated between the two types of viruses and showed reduced neutralization of the viruses with the autologous NSI and SI primary isolate V3 loops. These results indicated that the neutralization sensitivity of the viruses depended on the capacity of the V3 region to influence the conformation of the virus envelope. These V3-dependent conformational changes partially explain the neutralization sensitivity of laboratory strains and the relative neutralization resistance of primary isolates.

Hogervorst, E; de Jong, J; van Wijk, A; Bakker, M; Valk, M; Nara, P; Goudsmit, J

1995-01-01

108

Neutralizing Antibody Responses in Macaques Induced by Human Immunodeficiency Virus Type 1 Monovalent or Trivalent Envelope Glycoproteins  

PubMed Central

A major goal of efforts to develop a vaccine to prevent HIV-1 infection is induction of broadly cross-reactive neutralizing antibodies (bcnAb). In previous studies we have demonstrated induction of neutralizing antibodies that did cross-react among multiple primary and laboratory strains of HIV-1, but neutralized with limited potency. In the present study we tested the hypothesis that immunization with multiple HIV-1 envelope glycoproteins (Envs) would result in a more potent and cross-reactive neutralizing response. One Env, CM243(N610Q), was selected on the basis of studies of the effects of single and multiple mutations of the four gp41 glycosylation sites. The other two Envs included R2 (subtype B) and 14/00/4 (subtype F), both of which were obtained from donors with bcnAb. Rhesus monkeys were immunized using a prime boost regimen as in previous studies. Individual groups of monkeys were immunized with either one of the three Envs or all three. The single N610Q and N615Q mutations of CM243 Env did not disrupt protein secretion, processing into, or reactivity with mAbs, unlike other single or multiple deglycosylation mutations. In rabbit studies the N610Q mutation alone or in combination was associated with an enhanced neutralizing response against homologous and heterologous subtype E viruses. In the subsequent monkey study the response induced by the R2 Env regimen was equivalent to the trivalent regimen and superior to the other monovalent regimens against the virus panel used for testing. The 14/00/4 Env induced responses superior to CM243(N610Q). The results indicate that elimination of the glycosylation site near the gp41 loop results in enhanced immunogenicity, but that immunization of monkeys with these three distinct Envs was not more immunogenic than with one.

Quinnan, Gerald V.; Zhang, Pengfei; Dong, Ming; Chen, Hong; Feng, Yan-Ru; Lewis, Mark; Broder, Christopher C.

2013-01-01

109

Polyvalent Envelope Glycoprotein Vaccine Elicits a Broader Neutralizing Antibody Response but Is Unable To Provide Sterilizing Protection against Heterologous Simian/Human Immunodeficiency Virus Infection in Pigtailed Macaques  

PubMed Central

The great difficulty in eliciting broadly cross-reactive neutralizing antibodies (NAbs) against human immunodeficiency virus type 1 (HIV-1) isolates has been attributed to several intrinsic properties of their viral envelope glycoprotein, including its complex quaternary structure, extensive glycosylation, and marked genetic variability. Most previously evaluated vaccine candidates have utilized envelope glycoprotein from a single virus isolate. Here we compare the breadth of NAb and protective immune response following vaccination of pigtailed macaques with envelope protein(s) derived from either single or multiple viral isolates. Animals were challenged with Simian/human immunodeficiency virus strain DH12 (SHIVDH12) following priming with recombinant vaccinia virus(es) expressing gp160(s) and boosting with gp120 protein(s) from (i) LAI, RF, 89.6, AD8, and Bal (Polyvalent); (ii) LAI, RF, 89.6, AD8, Bal, and DH12 (Polyvalent-DH12); (iii) 89.6 (Monovalent-89.6); and (iv) DH12 (Monovalent-DH12). Animals in the two polyvalent vaccine groups developed NAbs against more HIV-1 isolates than those in the two monovalent vaccine groups (P = 0.0054). However, the increased breadth of response was directed almost entirely against the vaccine strains. Resistance to SHIVDH12 strongly correlated with the level of NAbs directed against the virus on the day of challenge (P = 0.0008). Accordingly, the animals in the Monovalent-DH12 and Polyvalent-DH12 vaccine groups were more resistant to the SHIVDH12 challenge than the macaques immunized with preparations lacking a DH12 component (viz. Polyvalent and Monovalent-89.6) (P = 0.039). Despite the absence of any detectable NAb, animals in the Polyvalent vaccine group, but not those immunized with Monovalent-89.6, exhibited markedly lower levels of plasma virus than those in the control group, suggesting a superior cell-mediated immune response induced by the polyvalent vaccine.

Cho, Michael W.; Kim, Young B.; Lee, Myung K.; Gupta, Kailash C.; Ross, Will; Plishka, Ron; Buckler-White, Alicia; Igarashi, Tatsuhiko; Theodore, Ted; Byrum, Russ; Kemp, Chris; Montefiori, David C.; Martin, Malcolm A.

2001-01-01

110

Polyvalent envelope glycoprotein vaccine elicits a broader neutralizing antibody response but is unable to provide sterilizing protection against heterologous Simian/human immunodeficiency virus infection in pigtailed macaques.  

PubMed

The great difficulty in eliciting broadly cross-reactive neutralizing antibodies (NAbs) against human immunodeficiency virus type 1 (HIV-1) isolates has been attributed to several intrinsic properties of their viral envelope glycoprotein, including its complex quaternary structure, extensive glycosylation, and marked genetic variability. Most previously evaluated vaccine candidates have utilized envelope glycoprotein from a single virus isolate. Here we compare the breadth of NAb and protective immune response following vaccination of pigtailed macaques with envelope protein(s) derived from either single or multiple viral isolates. Animals were challenged with Simian/human immunodeficiency virus strain DH12 (SHIV(DH12)) following priming with recombinant vaccinia virus(es) expressing gp160(s) and boosting with gp120 protein(s) from (i) LAI, RF, 89.6, AD8, and Bal (Polyvalent); (ii) LAI, RF, 89.6, AD8, Bal, and DH12 (Polyvalent-DH12); (iii) 89.6 (Monovalent-89.6); and (iv) DH12 (Monovalent-DH12). Animals in the two polyvalent vaccine groups developed NAbs against more HIV-1 isolates than those in the two monovalent vaccine groups (P = 0.0054). However, the increased breadth of response was directed almost entirely against the vaccine strains. Resistance to SHIV(DH12) strongly correlated with the level of NAbs directed against the virus on the day of challenge (P = 0.0008). Accordingly, the animals in the Monovalent-DH12 and Polyvalent-DH12 vaccine groups were more resistant to the SHIV(DH12) challenge than the macaques immunized with preparations lacking a DH12 component (viz. Polyvalent and Monovalent-89.6) (P = 0.039). Despite the absence of any detectable NAb, animals in the Polyvalent vaccine group, but not those immunized with Monovalent-89.6, exhibited markedly lower levels of plasma virus than those in the control group, suggesting a superior cell-mediated immune response induced by the polyvalent vaccine. PMID:11160726

Cho, M W; Kim, Y B; Lee, M K; Gupta, K C; Ross, W; Plishka, R; Buckler-White, A; Igarashi, T; Theodore, T; Byrum, R; Kemp, C; Montefiori, D C; Martin, M A

2001-03-01

111

Human Immunodeficiency Virus Type 1 Subtype B Ancestral Envelope Protein Is Functional and Elicits Neutralizing Antibodies in Rabbits Similar to Those Elicited by a Circulating Subtype B Envelope  

PubMed Central

Human immunodeficiency virus type 1 (HIV-1) is a difficult target for vaccine development, in part because of its ever-expanding genetic diversity and attendant capacity to escape immunologic recognition. Vaccine efficacy might be improved by maximizing immunogen antigenic similarity to viruses likely to be encountered by vaccinees. To this end, we designed a prototype HIV-1 envelope vaccine using a deduced ancestral state for the env gene. The ancestral state reconstruction method was shown to be >95% accurate by computer simulation and 99.8% accurate when estimating the known inoculum used in an experimental infection study in rhesus macaques. Furthermore, the deduced ancestor gene differed from the set of sequences used to derive the ancestor by an average of 12.3%, while these latter sequences were an average of 17.3% different from each other. A full-length ancestral subtype B HIV-1 env gene was constructed and shown to produce a glycoprotein of 160 kDa that bound and fused with cells expressing the HIV-1 coreceptor CCR5. This Env was also functional in a virus pseudotype assay. When either gp160- or gp140-expressing plasmids and recombinant gp120 were used to immunize rabbits in a DNA prime-protein boost regimen, the artificial gene induced immunoglobulin G antibodies capable of weakly neutralizing heterologous primary HIV-1 strains. The results were similar for rabbits immunized in parallel with a natural isolate, HIV-1 SF162. Further design efforts to better present conserved neutralization determinants are warranted.

Doria-Rose, N. A.; Learn, G. H.; Rodrigo, A. G.; Nickle, D. C.; Li, F.; Mahalanabis, M.; Hensel, M. T.; McLaughlin, S.; Edmonson, P. F.; Montefiori, D.; Barnett, S. W.; Haigwood, N. L.; Mullins, J. I.

2005-01-01

112

Induction of Systemic and Mucosal Cross-Clade Neutralizing Antibodies in BALB\\/c Mice Immunized with Human Immunodeficiency Virus Type 1 Clade A Virus-Like Particles Administered by Different Routes of Inoculation  

Microsoft Academic Search

We have recently developed a candidate human immunodeficiency virus type 1 (HIV-1) vaccine model, based on virus-like particles (VLPs) expressing gp120 from a Ugandan HIV-1 isolate of clade A (HIV-VLPAs), which shows the induction of neutralizing antibodies as well as cytotoxic T lymphocytes (CTL) in BALB\\/c mice by intraperitoneal (i.p.) administration. In the present study, immunization experiments based on a

L. Buonaguro; M. L. Visciano; M. L. Tornesello; M. Tagliamonte; B. Biryahwaho; F. M. Buonaguro

2005-01-01

113

Polymerase chain reaction evidence for human immunodeficiency virus 1 neutralization by passive immunization in patients with AIDS and AIDS-related complex.  

PubMed Central

We tried to assess the long-term safety and potential efficacy of passive immunization in AIDS-related-complex (ARC) and AIDS patients. We also wanted to establish whether hyperimmune plasma from healthy human immunodeficiency virus 1 (HIV-1)-infected individuals clears the cell-free virus from circulation. Using the polymerase chain reaction (PCR), we were able to provide conclusive evidence that hyperimmune plasma is effective and maintains long-term neutralization of viremia. Using the cell test, we found that in most patients the total antibody level was maintained; in one of the ARC patients, it actually increased 8-fold and has remained at that level for nearly 2 years. The CD4+ cell count decreased in the AIDS patients but was stable in the ARC patient. Clinically, there was an initial improvement in all patients, but five of six of the advanced/terminal AIDS patients had died by month 17. Our studies suggest that passive immunization may be safe in ARC and AIDS patients. It reduces HIV-1 viremia to levels undetectable even by PCR. To advanced/terminal patients, the benefit is of limited duration, while to ARC patients it may be long-term. Therefore, passive immunization should start early in the disease. Images

Karpas, A; Hewlett, I K; Hill, F; Gray, J; Byron, N; Gilgen, D; Bally, V; Oates, J K; Gazzard, B; Epstein, J E

1990-01-01

114

Neutralizing Antibodies against Autologous Human Immunodeficiency Virus Type 1 Isolates in Patients with Increasing CD4 Cell Counts despite Incomplete Virus Suppression during Antiretroviral Treatment  

PubMed Central

Antiretroviral-treated human immunodeficiency virus (HIV) type 1-seropositive individuals can remain clinically stable for a long period of time with an increasing CD4 cell count irrespective of incomplete viral suppression. We evaluated the role of neutralizing antibody (NtAb) activity in the etiopathogenesis of this viro-immunological disconnection (defined as an increasing CD4+-cell count despite a persistent, detectable viral load during antiretroviral therapy) in 33 patients failing therapy with two analogue nucleoside reverse transcriptase inhibitors. An HIV NtAb titer of ?1:25 was detected in specimens from 16 out of 33 (48%) patients. A significant correlation was found between NtAb titers and CD4+-cell counts (P = 0.001; r = 0.546) but not with HIV RNA levels in plasma. Five patients with a viro-immunological disconnection had an NtAb titer of >1:125, statistically higher than the NtAb titers for the remaining 28 patients with both virologic and immunologic failure (P < 0.0001). The HIV-specific humoral immune response could play a role during antiretroviral treatment to improve immunological function despite an incomplete suppression of viral load.

Sarmati, Loredana; d'Ettorre, Gabriella; Nicastri, Emanuele; Ercoli, Lucia; Uccella, Ilaria; Massetti, Paola; Parisi, Saverio Giuseppe; Vullo, Vincenzo; Andreoni, Massimo

2001-01-01

115

N-Linked Glycosylation of the V3 Loop and the Immunologically Silent Face of gp120 Protects Human Immunodeficiency Virus Type 1 SF162 from Neutralization by Anti-gp120 and Anti-gp41 Antibodies  

PubMed Central

We examined how asparagine-linked glycans within and adjacent to the V3 loop (C2 and C3 regions) and within the immunologically silent face (V4, C4, and V5 regions) of the human immunodeficiency virus (HIV) SF612 envelope affect the viral phenotype. Five of seven potential glycosylation sites are utilized when the virus is grown in human peripheral blood mononuclear cells, with the nonutilized sites lying within the V4 loop. Elimination of glycans within and adjacent to the V3 loop renders SF162 more susceptible to neutralization by polyclonal HIV+-positive and simian/human immunodeficiency virus-positive sera and by monoclonal antibodies (MAbs) recognizing the V3 loop, the CD4- and CCR5-binding sites, and the extracellular region of gp41. Importantly, our studies also indicate that glycans located within the immunologically silent face of gp120, specifically the C4 and V5 regions, also conferred on SF162 resistance to neutralization by anti-V3 loop, anti-CD4 binding site, and anti-gp41 MAbs but not by antibodies targeting the coreceptor binding site. We also observed that the amino acid composition of the V4 region contributes to the neutralization phenotype of SF162 by anti-V3 loop and anti-CD4 binding site MAbs. Collectively, our data support the proposal that the glycosylation and structure of the immunologically silent face of the HIV envelope plays an important role in defining the neutralization phenotype of HIV type 1.

McCaffrey, Ruth A.; Saunders, Cheryl; Hensel, Mike; Stamatatos, Leonidas

2004-01-01

116

Immunodeficiency disorders  

MedlinePLUS

... that affect T cells may cause repeated Candida (yeast) infections. Inherited combined immunodeficiency affects both T cells ... infections (including some forms of pneumonia or repeated yeast infections) Tests used to help diagnose an immunodeficiency ...

117

Formaldehyde-Treated, Heat-Inactivated Virions with Increased Human Immunodeficiency Virus Type 1 Env Can Be Used To Induce High-Titer Neutralizing Antibody Responses  

Microsoft Academic Search

Received 3 January 2005\\/Accepted 4 May 2005 The lack of success of subunit human immunodeficiency virus (HIV) type 1 vaccines to date suggests that multiple components or a complex virion structure may be required. We hypothesized that the failure of current vaccine strategies to induce protective antibodies is linked to the inability of native envelope structures to readily elicit these

B. Poon; J. F. Hsu; V. Gudeman; I. S. Y. Chen; K. Grovit-Ferbas

2005-01-01

118

Envelope Variants from Women Recently Infected with Clade A Human Immunodeficiency Virus Type 1 Confer Distinct Phenotypes That Are Discerned by Competition and Neutralization Experiments  

Microsoft Academic Search

Women infected with clade A human immunodeficiency virus type 1 harbor a virus population that is genetically diverse in the envelope gene, a fact that contrasts with the homogeneous virus population identified in newly infected men. It is not known whether viral genetic diversity at this early stage of infection is manifested as phenotypic diversity. This is a significant question

Sally L. Painter; Roman Biek; David C. Holley; Mary Poss

2003-01-01

119

Predominant Mode of Human Immunodeficiency Virus Transfer between T Cells Is Mediated by Sustained Env-Dependent Neutralization-Resistant Virological Synapses  

Microsoft Academic Search

Cell-free human immunodeficiency virus type 1 (HIV-1) can initiate infections, but contact between infected and uninfected T cells can enhance viral spread through intercellular structures called virological synapses (VS). The relative contribution of VS to cell-free viral transfer has not been carefully measured. Using an ultrasensitive, fluorescent virus transfer assay, we estimate that when VS between HIV-expressing Jurkat T cells

Ping Chen; Wolfgang Hubner; Matthew A. Spinelli; Benjamin K. Chen

2007-01-01

120

Induction of Neutralizing Antibodies to T-Cell Line-Adapted and Primary Human Immunodeficiency Virus Type 1 Isolates with a Prime-Boost Vaccine Regimen in Chimpanzees  

Microsoft Academic Search

Five chimpanzees were immunized by administration of one or more intranasal priming doses of one to three recombinant adenoviruses containing a gp160 insert from human immunodeficiency virus type 1 (HIV-1) MN (HIV-1MN) followed by one or more boosts of recombinant HIV-1SF2 gp120 delivered intramuscularly with MF59 adjuvant. This regimen resulted in humoral immune responses in three of five animals. Humoral

SUSAN ZOLLA-PAZNER; MICHAEL LUBECK; SERENA XU; SHERRI BURDA; ROBERT J. NATUK; FARUK SINANGIL; KATHELYN STEIMER; ROBERT C. GALLO; JORG W. EICHBERG; THOMAS MATTHEWS; MARJORIE ROBERT-GUROFF

121

Neutralization of Tier-2 Viruses and Epitope Profiling of Plasma Antibodies from Human Immunodeficiency Virus Type 1 Infected Donors from India  

PubMed Central

Broadly cross neutralizing antibodies (NAbs) are generated in a group of HIV-1 infected individuals during the natural infection, but little is known about their prevalence in patients infected with viral subtypes from different geographical regions. We tested here the neutralizing efficiency of plasma antibodies from 80 HIV-1 infected antiretroviral drug naive patients against a panel of subtype-B and C tier 2 viruses. We detected cross-neutralizing antibodies in approximately 19–27% of the plasma, however the subtype-C specific neutralization efficiency predominated (p?=?0.004). The neutralizing activity was shown to be exclusively mediated by the immunoglobulin G (IgG) fraction in the representative plasma samples. Epitope mapping of three, the most cross-neutralizing plasma (CNP) AIIMS206, AIIMS239 and AIIMS249 with consensus-C overlapping envelope peptides revealed ten different binding specificities with only V3 and IDR being common. The V3 and IDR were highly antigenic regions but no correlation between their reciprocal Max50 binding titers and neutralization was observed. In addition, the neutralizing activity of CNP was not substantially reduced by V3 and gp41 peptides except a modest contribution of MPER peptide. The MPER was rarely recognized by plasma antibodies though antibody depletion and competition experiments demonstrated MPER dependent neutralization in two out of three CNP. Interestingly, the binding specificity of one of the CNP (AIIMS206) overlapped with broadly neutralizing mAb 2F5 epitope. Overall, the data suggest that, despite the low immunogenicity of HIV-1 MPER, the antibodies directed to this region may serve as crucial reagents for HIV-1 vaccine design.

Andrabi, Raiees; Bala, Manju; Kumar, Rajesh; Wig, Naveet; Hazarika, Anjali; Luthra, Kalpana

2012-01-01

122

Impact of V2 Mutations on Escape from a Potent Neutralizing Anti-V3 Monoclonal Antibody during In Vitro Selection of a Primary Human Immunodeficiency Virus Type 1 Isolate?  

PubMed Central

KD-247, a humanized monoclonal antibody to an epitope of gp120-V3 tip, has potent cross-neutralizing activity against subtype B primary human immunodeficiency virus type 1 (HIV-1) isolates. To assess how KD-247 escape mutants can be generated, we induced escape variants by exposing bulked primary R5 virus, MOKW, to increasing concentrations of KD-247 in vitro. In the presence of relatively low concentrations of KD-247, viruses with two amino acid mutations (R166K/D167N) in V2 expanded, and under high KD-247 pressure, a V3 tip substitution (P313L) emerged in addition to the V2 mutations. However, a virus with a V2 175P mutation dominated during passaging in the absence of KD-247. Using domain swapping analysis, we demonstrated that the V2 mutations and the P313L mutation in V3 contribute to partial and complete resistance phenotypes against KD-247, respectively. To identify the V2 mutation responsible for the resistance to KD-247, we constructed pseudoviruses with single or double amino acid mutations in V2 and measured their sensitivity to neutralization. Interestingly, the neutralization phenotypes were switched, so that amino acid residue 175 (Pro or Leu) located in the center of V2 was exchanged, indicating that the amino acid at position 175 has a crucial role, dramatically changing the Env oligomeric state on the membrane surface and affecting the neutralization phenotype against not only anti-V3 antibody but also recombinant soluble CD4. These data suggested that HIV-1 can escape from anti-V3 antibody attack by changing the conformation of the functional envelope oligomer by acquiring mutations in the V2 region in environments with relatively low antibody concentrations.

Shibata, Junji; Yoshimura, Kazuhisa; Honda, Akiko; Koito, Atsushi; Murakami, Toshio; Matsushita, Shuzo

2007-01-01

123

HIV (Human Immunodeficiency Virus) Subunit Vaccine.  

National Technical Information Service (NTIS)

The invention provides immunogenic peptide sequences of the gp120 envelope protein of the human immunodeficiency virus (HIV). Epitopes from the conserved region which give rise to neutralizing antibodies are described.

K. Krohn A. Ranki

1988-01-01

124

Spontaneous reversion of human immunodeficiency virus type 1 neutralization-resistant variant HXB2thr582: in vitro selection against cytopathicity highlights gp120-gp41 interactive regions.  

PubMed Central

Spontaneous revertants of the immune-selected variant HXB2thr582, which resists neutralization by certain conformationally dependent antibodies specific for the CD4-binding site on gp120 (such as F105), appeared after long-term culture in the absence of immune-selecting serum. Molecular analysis showed some of the viruses in the revertant stock contained a simple back mutation, whereas others retained the Thr-582 codon but contained a substitution of serine for phenylalanine in gp41 at position 673. Neutralization sensitivity to the selecting serum and to F105 of infectious clones containing either the back mutation or the compensatory mutation, HXB2thr582ser673, was confirmed. HXB2thr582-infected cells have a greater propensity for syncytium formation and single cell killing than do either the parental HXB2 or the revertant HXB2thr582ser673. This suggests that the revertant arose by selection in vitro for a less cytopathic virus. Our results link three envelope regions shown to influence virus-cell fusion as well as neutralization by antibody: the CD4-binding region, the leucine zipper domain, and a region hidden to antipeptide antibodies upon envelope oligomerization. Taken together they illustrate the functional importance of the gp120-gp41 interaction and emphasize the impact of the interplay between envelope regions on overall conformation and function and on recognition by neutralizing antibodies.

Stern, T L; Reitz, M S; Robert-Guroff, M

1995-01-01

125

Replicative Function and Neutralization Sensitivity of Envelope Glycoproteins from Primary and T-Cell Line-Passaged Human Immunodeficiency Virus Type 1 Isolates  

Microsoft Academic Search

The structure, replicative properties, and sensitivity to neutralization by soluble CD4 and monoclonal antibodies were examined for molecularly cloned envelope glycoproteins derived from human immunodefi- ciency virus type 1 (HIV-1) viruses either isolated directly from patients or passaged in T-cell lines. Comple- mentation of virus entry into peripheral blood mononuclear cell targets by primary patient envelope glyco- proteins exhibited efficiencies

NANCY SULLIVAN; YING SUN; JOHN LI; WOLFGANG HOFMANN; ANDJOSEPH SODROSKI

1995-01-01

126

Cryptic Nature of a Conserved, CD4-Inducible V3 Loop Neutralization Epitope in the Native Envelope Glycoprotein Oligomer of CCR5-Restricted, but Not CXCR4-Using, Primary Human Immunodeficiency Virus Type 1 Strains  

PubMed Central

The external subunit of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env), gp120, contains conserved regions that mediate sequential interactions with two cellular receptor molecules, CD4 and a chemokine receptor, most commonly CCR5 or CXCR4. However, antibody accessibility to such regions is hindered by diverse protective mechanisms, including shielding by variable loops, conformational flexibility and extensive glycosylation. For the conserved neutralization epitopes hitherto described, antibody accessibility is reportedly unrelated to the viral coreceptor usage phenotype. Here, we characterize a novel, conserved gp120 neutralization epitope, recognized by a murine monoclonal antibody (MAb), D19, which is differentially accessible in the native HIV-1 Env according to its coreceptor specificity. The D19 epitope is contained within the third variable (V3) domain of gp120 and is distinct from those recognized by other V3-specific MAbs. To study the reactivity of MAb D19 with the native oligomeric Env, we generated a panel of PM1 cells persistently infected with diverse primary HIV-1 strains. The D19 epitope was conserved in the majority (23/29; 79.3%) of the subtype-B strains tested, as well as in selected strains from other genetic subtypes. Strikingly, in CCR5-restricted (R5) isolates, the D19 epitope was invariably cryptic, although it could be exposed by addition of soluble CD4 (sCD4); epitope masking was dependent on the native oligomeric structure of Env, since it was not observed with the corresponding monomeric gp120 molecules. By contrast, in CXCR4-using strains (X4 and R5X4), the epitope was constitutively accessible. In accordance with these results, R5 isolates were resistant to neutralization by MAb D19, becoming sensitive only upon addition of sCD4, whereas CXCR4-using isolates were neutralized regardless of the presence of sCD4. Other V3 epitopes examined did not display a similar divergence in accessibility based on coreceptor usage phenotype. These results provide the first evidence of a correlation between HIV-1 biological phenotype and neutralization sensitivity, raising the possibility that the in vivo evolution of HIV-1 coreceptor usage may be influenced by the selective pressure of specific host antibodies.

Lusso, Paolo; Earl, Patricia L.; Sironi, Francesca; Santoro, Fabio; Ripamonti, Chiara; Scarlatti, Gabriella; Longhi, Renato; Berger, Edward A.; Burastero, Samuele E.

2005-01-01

127

Differential Neutralization of Human Immunodeficiency Virus (HIV) Replication in Autologous CD4 T Cells by HIV-Specific Cytotoxic T Lymphocytes  

Microsoft Academic Search

Defining the antiviral efficacy of CD8 T cells is important for immunogen design, and yet most current assays do not measure the ability of responses to neutralize infectious virus. Here we show that human immunode- ficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) clones and cell lines derived from infected persons and targeting diverse epitopes differ by over 1,000-fold in their ability

Huabiao Chen; Alicja Piechocka-Trocha; Toshiyuki Miura; Mark A. Brockman; Boris D. Julg; Brett M. Baker; Alissa C. Rothchild; Brian L. Block; Arne Schneidewind; Tomohiko Koibuchi; Florencia Pereyra; Todd M. Allen; Bruce D. Walker

2009-01-01

128

Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (+/-)-calanolide A and its enantiomers.  

PubMed

The anti-HIV agent (+/-)-calanolide A (1) has been synthesized in a five-step approach starting with phloroglucinol [-->5-->6-->11-->18-->(+/-)-1], which includes Pechmann reaction, Friedel-Crafts acylation, chromenylation with 4,4-dimethoxy-2-methylbutan-2-ol, cyclization, and Luche reduction. Cyclization of chromene 11 to chromanone 18 was achieved by employing either acetaldehyde diethyl acetal or paraldehyde in the presence of trifluoroacetic acid and pyridine or PPTS. Luche reduction of chromanone 18 at lower temperature preferably yielded (+/-)-1. Reduction of chromone 12, synthesized by Kostanecki-Robinson reaction from chromene 11, failed to afford (+/-)-1. The synthetic (+/-)-1 has been chromatographically resolved into its optically active forms, (+)- and (-)-1. The anti-HIV activities for synthetic (+/-)-1, as well as resultant (+)- and (-)-1, have been determined. Only (+)-1 accounted for anti-HIV activity, which was similar to the data reported for the natural product, and (-)-1 was inactive. PMID:8632437

Flavin, M T; Rizzo, J D; Khilevich, A; Kucherenko, A; Sheinkman, A K; Vilaychack, V; Lin, L; Chen, W; Greenwood, E M; Pengsuparp, T; Pezzuto, J M; Hughes, S H; Flavin, T M; Cibulski, M; Boulanger, W A; Shone, R L; Xu, Z Q

1996-03-15

129

Neutralizing antibody titers conferring protection to macaques from a simian/human immunodeficiency virus challenge using the TZM-bl assay.  

PubMed

We previously reported that passive transfer of polyclonal neutralizing antibodies (NAbs) sufficient to generate a titer of 1:38 in the plasma would confer sterilizing protection to 99% of macaques challenged intravenously with 75 TCID(50) of SHIV(DH12). Neutralizing activity in that study was measured in an MT4 cell assay in which infection was completely blocked (EC(100)). In the current study, the TZM-bl system was used to measure EC(50) neutralizing titers in several of the same macaque plasma samples and the relationship between these titers and in vivo protection was determined. The antiviral EC(50) NAb titers measured in individual plasma samples were higher than those previously obtained in the MT4 system. Furthermore, the geometric mean EC(50) NAb titers against pseudotyped SHIV(DH12) were 33-fold greater than the EC(100) titers measured in the MT4 cell assay against the replication-competent SHIV(DH12) inoculated into animals. An augmented probit regression model was used to generate curves relating TZM-bl EC(50) NAb titers and protection from a virus challenge; estimated titers conferring various levels of protection were then determined. In TZM-bl assays using pseudotyped SHIV(DH12), representative percent in vivo protection/estimated EC(50) titers were 99%/1:4467, 90%/1:1175, 80%/1:676, 50%/1:234, and 33%/1:141. Because it is likely that contributions from other arms of the immune system will contribute to vaccine-induced control, the range of EC(50) NAb titers we have derived may be more informative for evaluating the protective value of NAb activity from TZM-bl assays. PMID:20059398

Willey, Ronald; Nason, Martha C; Nishimura, Yoshiaki; Follmann, Dean A; Martin, Malcolm A

2010-01-01

130

Inactivation of Human Immunodeficiency Virus Type 1 by Porphyrins  

Microsoft Academic Search

We have evaluated the anti-human immunodeficiency virus (HIV) activity of a series of natural and synthetic porphyrins to identify compounds that could potentially be used as microbicides to provide a defense against infection by sexually transmitted virus. For assays we used an epithelial HeLa-CD4 cell line with an integrated long terminal repeat--galactosidase gene. For structure-activity analysis, we divided the porphyrins

Andrei N. Vzorov; Dabney W. Dixon; Jenna S. Trommel; Luigi G. Marzilli; Richard W. Compans

2002-01-01

131

Primary immunodeficiency  

PubMed Central

Primary immunodeficiency disorder (PID) refers to a heterogeneous group of over 130 disorders that result from defects in immune system development and/or function. PIDs are broadly classified as disorders of adaptive immunity (i.e., T-cell, B-cell or combined immunodeficiencies) or of innate immunity (e.g., phagocyte and complement disorders). Although the clinical manifestations of PIDs are highly variable, most disorders involve at least an increased susceptibility to infection. Early diagnosis and treatment are imperative for preventing significant disease-associated morbidity and, therefore, consultation with a clinical immunologist is essential. PIDs should be suspected in patients with: recurrent sinus or ear infections or pneumonias within a 1 year period; failure to thrive; poor response to prolonged use of antibiotics; persistent thrush or skin abscesses; or a family history of PID. Patients with multiple autoimmune diseases should also be evaluated. Diagnostic testing often involves lymphocyte proliferation assays, flow cytometry, measurement of serum immunoglobulin (Ig) levels, assessment of serum specific antibody titers in response to vaccine antigens, neutrophil function assays, stimulation assays for cytokine responses, and complement studies. The treatment of PIDs is complex and generally requires both supportive and definitive strategies. Ig replacement therapy is the mainstay of therapy for B-cell disorders, and is also an important supportive treatment for many patients with combined immunodeficiency disorders. The heterogeneous group of disorders involving the T-cell arm of the adaptive system, such as severe combined immunodeficiency (SCID), require immune reconstitution as soon as possible. The treatment of innate immunodeficiency disorders varies depending on the type of defect, but may involve antifungal and antibiotic prophylaxis, cytokine replacement, vaccinations and bone marrow transplantation. This article provides a detailed overview of the major categories of PIDs and strategies for the appropriate diagnosis and management of these rare disorders.

2011-01-01

132

Emergence of a highly pathogenic simian/human immunodeficiency virus in a rhesus macaque treated with anti-CD8 mAb during a primary infection with a nonpathogenic virus  

PubMed Central

Although simian/human immunodeficiency virus (SHIV) strain DH12 replicates to high titers and causes immunodeficiency in pig-tailed macaques, virus loads measured in SHIVDH12-infected rhesus monkeys are consistently 100-fold lower and none of 22 inoculated animals have developed disease. We previously reported that the administration of anti-human CD8 mAb to rhesus macaques at the time of primary SHIVDH12 infection resulted in marked elevations of virus loads. One of the treated animals experienced rapid and profound depletions of circulating CD4+ T lymphocytes. Although the CD4+ T cell number partially recovered, this monkey subsequently suffered significant weight loss and was euthanized. A tissue culture virus stock derived from this animal, designated SHIVDH12R, induced marked and rapid CD4+ cell loss after i.v. inoculation of rhesus monkeys. Retrospective analyses of clinical specimens, collected during the emergence of SHIVDH12R indicated: (i) the input cloned SHIV remained the predominant virus during the first 5–7 months of infection; (ii) variants bearing only a few of the SHIVDH12R consensus changes first appeared 7 months after the administration of anti-CD8 mAb; (iii) high titers of neutralizing antibody directed against the input SHIV were detected by week 10 and persisted throughout the infection; and (iv) no neutralizing antibody against SHIVDH12R ever developed.

Igarashi, Tatsuhiko; Endo, Yasuyuki; Englund, George; Sadjadpour, Reza; Matano, Tetsuro; Buckler, Charles; Buckler-White, Alicia; Plishka, Ron; Theodore, Ted; Shibata, Riri; Martin, Malcolm

1999-01-01

133

Emergence of a highly pathogenic simian/human immunodeficiency virus in a rhesus macaque treated with anti-CD8 mAb during a primary infection with a nonpathogenic virus.  

PubMed

Although simian/human immunodeficiency virus (SHIV) strain DH12 replicates to high titers and causes immunodeficiency in pig-tailed macaques, virus loads measured in SHIV(DH12)-infected rhesus monkeys are consistently 100-fold lower and none of 22 inoculated animals have developed disease. We previously reported that the administration of anti-human CD8 mAb to rhesus macaques at the time of primary SHIV(DH12) infection resulted in marked elevations of virus loads. One of the treated animals experienced rapid and profound depletions of circulating CD4(+) T lymphocytes. Although the CD4(+) T cell number partially recovered, this monkey subsequently suffered significant weight loss and was euthanized. A tissue culture virus stock derived from this animal, designated SHIV(DH12R), induced marked and rapid CD4(+) cell loss after i.v. inoculation of rhesus monkeys. Retrospective analyses of clinical specimens, collected during the emergence of SHIV(DH12R) indicated: (i) the input cloned SHIV remained the predominant virus during the first 5-7 months of infection; (ii) variants bearing only a few of the SHIV(DH12R) consensus changes first appeared 7 months after the administration of anti-CD8 mAb; (iii) high titers of neutralizing antibody directed against the input SHIV were detected by week 10 and persisted throughout the infection; and (iv) no neutralizing antibody against SHIV(DH12R) ever developed. PMID:10570196

Igarashi, T; Endo, Y; Englund, G; Sadjadpour, R; Matano, T; Buckler, C; Buckler-White, A; Plishka, R; Theodore, T; Shibata, R; Martin, M

1999-11-23

134

Anti-Human Globulin Anti-IgG Solid Screen II (Rabbit) ...  

Center for Biologics Evaluation and Research (CBER)

Text Version... Anti-Human Globulin Anti-IgG Solidscreen II ... screening, - identification with the indirect antiglobulin test. ... If testing is delayed, EDTA and clotted ... More results from www.fda.gov/downloads/biologicsbloodvaccines/bloodbloodproducts

135

Simian immunodeficiency virus (SIV) envelope quasispecies transmission and evolution in infant rhesus macaques after oral challenge with uncloned SIVmac251: increased diversity is associated with neutralizing antibodies and improved survival in previously immunized animals  

Microsoft Academic Search

BACKGROUND: Oral infection of infant macaques with simian immunodeficiency virus (SIV) is a useful animal model to test interventions to reduce postnatal HIV transmission via breast-feeding. We previously demonstrated that immunization of infant rhesus macaques with either modified vaccinia virus Ankara (MVA) expressing SIV Gag, Pol and Env, or live-attenuated SIVmac1A11 resulted in lower viremia and longer survival compared to

Jennifer L Greenier; Koen KA Van Rompay; David Montefiori; Patricia Earl; Bernard Moss; Marta L Marthas

2005-01-01

136

Effect of human immunodeficiency virus-1 protease inhibitors on the clearance of human herpesvirus 8 from blood of human immunodeficiency virus-1-infected patients.  

PubMed

The effect of human immunodeficiency virus-1 protease inhibitors on the frequency of human herpesvirus 8 DNA detection from peripheral blood of human immunodeficiency virus-positive persons was evaluated. Thirty-three human immunodeficiency virus-seropositive male patients were studied longitudinally. DNA from open reading frame 26 of the human herpesvirus 8 genome was amplified by the polymerase chain reaction from the CD45+ fraction of peripheral blood before and after the introduction of protease inhibitor therapy. Human herpesvirus 8 IgG status, CD4+ cell counts, and human immunodeficiency virus-1 plasma viral load were also assessed before and after therapy. When both reverse transcriptase inhibitor and protease inhibitor treatment were introduced at the same time, there was an increase in CD4+ T cell counts (P=0.0041), a decrease in human immunodeficiency virus plasma load (P=0.0584), and a decrease in the detection rate of human herpesvirus 8 DNA (P=0.0077). Introducing protease inhibitor to patients already receiving reverse transcriptase inhibitor treatment was associated with an increase in CD4+ T cell counts (P=0.0003), a decrease in human immunodeficiency virus plasma viral load (P=0.0911), and a decrease in the human herpesvirus 8 detection rate (P=0.0412). No significant changes in the titters of anti-human herpesvirus 8 IgG were observed. Treatment with human immunodeficiency virus-1 protease inhibitors is therefore associated with the clearance of human herpesvirus 8 DNA from peripheral blood of human immunodeficiency virus-infected patients. The concomitant decrease in the human immunodeficiency virus plasma load and increase in the peripheral CD4+ cell count suggest that an amelioration in the immune defect following reduction in the burden of human immunodeficiency virus-1 infection is responsible for the clearance of human herpesvirus 8 by protease inhibitors. PMID:11074468

Leao, J C; Kumar, N; McLean, K A; Porter, S R; Scully, C M; Swan, A V; Teo, C G

2000-12-01

137

Stimulation of neutralizing antibodies to human immunodeficiency virus type 1 in three strains of mice immunized with a 22 amino acid peptide of gp41 expressed on the surface of a plant virus  

Microsoft Academic Search

A plant virus, cowpea mosaic virus, expressing a 22 amino acid peptide 731–752 of the gp41 glycoprotein of human immunodeficency virus type 1 (HIV-1 IIIB), was shown previously to stimulate HIV-1 cross reactive neutralizing antibodies in adult C57BL6 mice. Here some parameters concerning the stimulation of HIV-1-specific neutralizing and ELISA antibody have been determined in adult C57BL6, C3HHe-mg and BALBc

Lesley McLain; Zarmina Durrani; Lisa Ann Wisniewski; Claudine Porta; George P. Lomonossoff; Nigel J. Dimmock

1996-01-01

138

New and old immunodeficiencies.  

PubMed

Yesterday's immunodeficiencies emphasized the clinical and familial associations of the syndromes and date from the 1920s (ataxia-telangiectasia, chronic mucocutaneous candidiasis), the 1930s (Wiskott-Aldrich syndrome), skipping the 1940s, but blossoming in the 15-y period from 1950 to 1965. In this period, primary immunodeficiencies affecting all the major limbs of the immune system were first described (1950: severe combined immunodeficiency; 1952: X-linked agammaglobulinemia; 1957: chronic granulomatous disease; 1965: C2 deficiency). Today's immunodeficiencies, as detailed in Stiehm's Immunologic Disorders in Infants and Children (Edition 1, 1973; Edition 2, 1980; and Edition 3, 1989) emphasize the immunologic and genetic aspects of immunodeficiency. These increased from 43 syndromes in the 1973 edition (34 primary, nine secondary) to 94 syndromes in the 1989 edition (66 primary, 28 secondary). This means that about two primary and one secondary immunodeficiencies have been uncovered annually. Tomorrow's immunodeficiencies, to be covered in Edition 4, will include new clinical and immunologic observations and molecular and biochemical studies that characterize some unique immunodeficiencies. These include the following six groups of defects: 1) neutropenic syndromes with hypogammaglobulinemia, including the WHIM syndrome; 2) phenotypic genetic syndromes with immunodeficiency including Bloom's syndrome and Schimke's immuno-osseous dysplasia; 3) natural killer cell defects associated with a) other primary immunodeficiencies, b) other nonimmunologic illness, and c) primary natural killer defects; 4) T-cell membrane defects; 5) IL defects; and 6) miscellaneous phagocytic illnesses including periodontitis and the asplenia syndrome. PMID:8433870

Stiehm, E R

1993-01-01

139

Emergence of a Highly Pathogenic Simian\\/Human Immunodeficiency Virus in a Rhesus Macaque Treated with anti-CD8 mAb during a Primary Infection with a Nonpathogenic Virus  

Microsoft Academic Search

Although simian\\/human immunodeficiency virus (SHIV) strain DH12 replicates to high titers and causes immunodeficiency in pig-tailed macaques, virus loads measured in SHIVDH12-infected rhesus monkeys are consistently 100-fold lower and none of 22 inoculated animals have developed disease. We previously reported that the administration of anti-human CD8 mAb to rhesus macaques at the time of primary SHIVDH12 infection resulted in marked

Tatsuhiko Igarashi; Yasuyuki Endo; George Englund; Reza Sadjadpour; Tetsuro Matano; Charles Buckler; Alicia Buckler-White; Ron Plishka; Ted Theodore; Riri Shibata; Malcolm Martin

1999-01-01

140

Inhibitory effects of (?)-epigallocatechin gallate on the life cycle of human immunodeficiency virus type 1 (HIV1)  

Microsoft Academic Search

Epigallocatechin gallate (EGCg), the major tea catechin, is known as a potent anti-bacterial agent. In addition, anti-tumor promoting, anti-inflammatory, anti-oxidative and antiviral activities have been reported. In the present study, we investigated possible anti-human immunodeficiency virus type-1 (HIV-1) activity of EGCg and its mechanisms of action in the viral life cycle. EGCg impinges on each step of the HIV life

Koushi Yamaguchi; Mitsuo Honda; Hajime Ikigai; Yukihiko Hara; Tadakatsu Shimamura

2002-01-01

141

Human Immunodeficiency Virus Type 1 Viral Background Plays a Major Role in Development of Resistance to Protease Inhibitors  

Microsoft Academic Search

The observed in vitro and in vivo benefit of combination treatment with anti-human immunodeficiency virus (HIV) agents prompted us to examine the potential of resistance development when two protease inhibitors are used concurrently. Recombinant HIV-1 (NL4-3) proteases containing combined resistance mutations associated with BMS-186318 and A-77003 (or saquinavir) were either inactive or had impaired enzyme activity. Subsequent construction of HIV-1

Ronald E. Rose; Yi-Fei Gong; Jill A. Greytok; Clifford M. Bechtold; Brian J. Terry; Brett S. Robinson; Masud Alam; Richard J. Colonno; Pin-Fang Lin

1996-01-01

142

Anti-human cytomegalovirus activity and toxicity of sulfonated anthraquinones and anthraquinone derivatives  

Microsoft Academic Search

Sulfonated anthraquinones and other anthraquinone derivatives were evaluated for anti-human cytomegalovirus (HCMV) activity, cytotoxicity and genotoxicity. Acid blues 40 and 129, acid black 48, alizarin violet R and reactive blue 2 were the most active compounds having selective indices of greater than 30 and EC50 values of 4–30 ?M. When tested against a clinical isolate, the 4 compounds were 2-

D. L. Barnard; D. W. Fairbairn; K. L. O'Neill; T. L. Gage; R. W. Sidwell

1995-01-01

143

Response of the human nasal mucous membrane to anti-human IgE serum  

Microsoft Academic Search

The response of the nasal mucous membrane to anti-human IgE serum was examined. The application of anti-IgE sera to the nasal mucous membrane induced a nasal allergy-like symptom as well as nasal eosinophilia. This symptom was observed in the majority of nasal allergy cases and in some vasomotor rhinitis cases, while not in non-allergic normal persons. The nasal eosinophilia, however,

M. Okuda

1975-01-01

144

Synthetic multimeric peptides derived from the principal neutralization domain (V3 loop) of human immunodeficiency virus type 1 (HIV-1) gp120 bind to galactosylceramide and block HIV-1 infection in a human CD4-negative mucosal epithelial cell line.  

PubMed Central

The glycosphingolipid galactosylceramide (GalCer), which binds gp120 with high affinity and specificity, is a potential alternative receptor for human immunodeficiency virus type 1 (HIV-1) in some CD4-negative neural and epithelial human cells, including the human colonic epithelial cell line HT-29. In the present study, we demonstrate that synthetic multibranched peptides derived from the consensus sequence of the HIV-1 V3 loop block HIV-1 infection in HT-29 cells. The most active peptide was an eight-branched multimer of the motif Gly-Pro-Gly-Arg-Ala-Phe which at a concentration of 1.8 microM induced a 50% inhibition of HIV-1 infection in competition experiments. This peptide was not toxic to HT-29 cells, and preincubation with HIV-1 did not affect viral infectivity, indicating that the antiviral activity was not due to a nonspecific virucidal effect. Using a high-performance thin-layer chromatography binding assay, we found that multibranched V3 peptides recognized GalCer and inhibited binding of recombinant gp120 to the glycosphingolipid. In addition, these peptides abolished the binding of an anti-GalCer monoclonal antibody to GalCer on the surface of live HT-29 cells. These data provide additional evidence that the V3 loop is involved in the binding of gp120 to the GalCer receptor and show that multibranched V3 peptides are potent inhibitors of the GalCer-dependent pathway of HIV-1 infection in CD4-negative mucosal epithelial cells.

Yahi, N; Sabatier, J M; Baghdiguian, S; Gonzalez-Scarano, F; Fantini, J

1995-01-01

145

Severe Combined Immunodeficiency (SCID)  

MedlinePLUS

... Severe combined immunodeficiency (SCID) is a group of inherited immune system disorders. The immune system is made ... or do not work well. The disorders are inherited and are there at birth. Infants born with ...

146

Immunodeficiency in childhood  

Microsoft Academic Search

Primary immunodeficiency disorders (PIDs) continue to illuminate mechanisms of human immunity and hypersensitivity. New discoveries\\u000a in common variable immunodeficiency, the most enigmatic of PID syndromes, reveal molecular pathways of importance in human\\u000a antibody production. FOXP3 mutations demonstrate the essential role that T-regulatory cells play in controlling autoantibody formation and disease.\\u000a Interleukin-1 receptor-associated kinase 4 deficiency emphasizes the key role that

Michelle Hernandez; John F. Bastian

2006-01-01

147

Short- and long-term clinical outcomes in rhesus monkeys inoculated with a highly pathogenic chimeric simian/human immunodeficiency virus.  

PubMed

A highly pathogenic simian/human immunodeficiency virus (SHIV), SHIV(DH12R), isolated from a rhesus macaque that had been treated with anti-human CD8 monoclonal antibody at the time of primary infection with the nonpathogenic, molecularly cloned SHIV(DH12), induced marked and rapid CD4(+) T cell loss in all rhesus macaques intravenously inoculated with 1.0 50% tissue culture infective dose (TCID(50)) to 4.1 x 10(5) TCID(50)s of virus. Animals inoculated with 650 TCID(50)s of SHIV(DH12R) or more experienced irreversible CD4(+) T lymphocyte depletion and developed clinical disease requiring euthanasia between weeks 12 and 23 postinfection. In contrast, the CD4(+) T-cell numbers in four of five monkeys receiving 25 TCID(50)s of SHIV(DH12R) or less stabilized at low levels, and these surviving animals produced antibodies capable of neutralizing SHIV(DH12R). In the fifth monkey, no recovery from the CD4(+) T cell decline occurred, and the animal had to be euthanized. Viral RNA levels, subsequent to the initial peak of infection but not at peak viremia, correlated with the virus inoculum size and the eventual clinical course. Both initial infection rate constants, k, and decay constants, d, were determined, but only the latter were statistically correlated to clinical outcome. The attenuating effects of reduced inoculum size were also observed when virus was inoculated by the mucosal route. Because the uncloned SHIV(DH12R) stock possessed the genetic properties of a lentivirus quasispecies, we were able to assess the evolution of the input virus swarm in animals surviving the acute infection by monitoring the emergence of neutralization escape viral variants. PMID:10888632

Endo, Y; Igarashi, T; Nishimura, Y; Buckler, C; Buckler-White, A; Plishka, R; Dimitrov, D S; Martin, M A

2000-08-01

148

Short- and Long-Term Clinical Outcomes in Rhesus Monkeys Inoculated with a Highly Pathogenic Chimeric Simian/Human Immunodeficiency Virus  

PubMed Central

A highly pathogenic simian/human immunodeficiency virus (SHIV), SHIVDH12R, isolated from a rhesus macaque that had been treated with anti-human CD8 monoclonal antibody at the time of primary infection with the nonpathogenic, molecularly cloned SHIVDH12, induced marked and rapid CD4+ T cell loss in all rhesus macaques intravenously inoculated with 1.0 50% tissue culture infective dose (TCID50) to 4.1 × 105 TCID50s of virus. Animals inoculated with 650 TCID50s of SHIVDH12R or more experienced irreversible CD4+ T lymphocyte depletion and developed clinical disease requiring euthanasia between weeks 12 and 23 postinfection. In contrast, the CD4+ T-cell numbers in four of five monkeys receiving 25 TCID50s of SHIVDH12R or less stabilized at low levels, and these surviving animals produced antibodies capable of neutralizing SHIVDH12R. In the fifth monkey, no recovery from the CD4+ T cell decline occurred, and the animal had to be euthanized. Viral RNA levels, subsequent to the initial peak of infection but not at peak viremia, correlated with the virus inoculum size and the eventual clinical course. Both initial infection rate constants, k, and decay constants, d, were determined, but only the latter were statistically correlated to clinical outcome. The attenuating effects of reduced inoculum size were also observed when virus was inoculated by the mucosal route. Because the uncloned SHIVDH12R stock possessed the genetic properties of a lentivirus quasispecies, we were able to assess the evolution of the input virus swarm in animals surviving the acute infection by monitoring the emergence of neutralization escape viral variants.

Endo, Yasuyuki; Igarashi, Tatsuhiko; Nishimura, Yoshiaki; Buckler, Charles; Buckler-White, Alicia; Plishka, Ronald; Dimitrov, Dimiter S.; Martin, Malcolm A.

2000-01-01

149

Short and Long-Term Clinical Outcomes in Rhesus Monkeys Inoculated with a Highly Pathogenic Chimeric Simian\\/Human Immunodeficiency Virus  

Microsoft Academic Search

A highly pathogenic simian\\/human immunodeficiency virus (SHIV), SHIVDH12R, isolated from a rhesus macaque that had been treated with anti-human CD8 monoclonal antibody at the time of primary infection with the nonpathogenic, molecularly cloned SHIVDH12, induced marked and rapid CD4 1 T cell loss in all rhesus macaques intravenously inoculated with 1.0 50% tissue culture infective dose (TCID50 )t o 4.13

Yasuyuki Endo; Tatsuhiko Igarashi; Yoshiaki Nishimura; Charles Buckler; Alicia Buckler-white; Ronald Plishka; Dimiter S. Dimitrov; Malcolm A. Martin

2000-01-01

150

Evolution of Cytotoxic T Lymphocyte Responses to Human Immunodeficiency Virus Type 1 in Patients with Symptomatic Primary Infection Receiving Antiretroviral Triple Therapy  

Microsoft Academic Search

The impact of highly active antiretroviral treatment (HAART) on anti-human immunodeficiency virus (HIV) cytotoxic T lymphocytes (CTL) was studied in 17 patients with recent symptomatic HIV-1 primary infection receiving triple combination therapy. Anti-HIV CTL were initially detected in 15 patients. In 6, CTL disappeared rapidly and persistently after initiation of therapy. Most of them had a rapid and sustained decrease

Marc Dalod; Martine Harzic; Isabelle Pellegrin; Béatrice Dumon; Bruno Hoen; Daniel Sereni; Jean-Christophe Deschemin; Jean-Paul Levy; Alain Venet; Elisabeth Gomard

1998-01-01

151

ORIGIN OF ANTI-HUMAN BLOOD GROUP B AGGLUTININS IN WHITE LEGHORN CHICKS  

PubMed Central

While anti-human blood group B agglutinins are present in the majority of ordinary White Leghorn chicks by the age of 30 days, none could be demonstrated in germfree chicks up to the age of 60 days. Anti-B agglutinins in trace amounts were first found in germfree chicks 66 days old and increased to an average titer of about 1:2 by 91 days of age. This titer amounts to about 10 per cent of that found in ordinary chicks. The appearance of antibody in low titer is attributed to trace amounts of non-living antigenic contaminants penetrating the germfree barrier. The necessity of appropriate absorption in order to obtain well defined specificities was pointed out. Several means commonly used to differentiate between normal and immune antibodies were employed in this investigation. None showed a difference between anti-B agglutinins from ordinary chicks and from germfree chicks intentionally immunized with blood group B active E. coli O86 or with B active preparations from human meconium. The implications of these findings on the origin of natural agglutinins are discussed. It is concluded, that measurable anti-human blood group B agglutinins in White Leghorn chicks are acquired early in life and are not inherited. The possibilities as well as limitations of present day germfree technique for this kind of immunological research have been considered.

Springer, Georg F.; Horton, Richard E.; Forbes, Martin

1959-01-01

152

Human immunodeficiency virus nephropathy  

Microsoft Academic Search

Varying components of the syndrome of human immunodeficiency virus nephropathy (HIVN) have been described, the most pertinent including proteinuria\\/nephrotic syndrome, progressive azotemia, normal blood pressure, enlarged and hyperechoic kidneys, rapid progression to end-stage renal disease (ESRD), and no response to treatment regimens. The diagnosis of HIVN requires identification of excessive proteinuria or albuminuria, determined by a total protein excretion on

Jose Strauss; Gaston Zilleruelo; Carolyn Abitbol; Brenda Montane; Victoriano Pardo

1993-01-01

153

Neutral Atmospheres  

NASA Astrophysics Data System (ADS)

This paper summarizes the understanding of aeronomy of neutral atmospheres in the solar system, discussing most planets as well as Saturn's moon Titan and comets. The thermal structure and energy balance is compared, highlighting the principal reasons for discrepancies amongst the atmospheres, a combination of atmospheric composition, heliocentric distance and other external energy sources not common to all. The composition of atmospheres is discussed in terms of vertical structure, chemistry and evolution. The final section compares dynamics in the upper atmospheres of most planets and highlights the importance of vertical dynamical coupling as well as magnetospheric forcing in auroral regions, where present. It is shown that a first order understanding of neutral atmospheres has emerged over the past decades, thanks to the combined effects of spacecraft and Earth-based observations as well as advances in theoretical modeling capabilities. Key gaps in our understanding are highlighted which ultimately call for a more comprehensive programme of observation and laboratory measurements.

Mueller-Wodarg, I. C. F.; Strobel, D. F.; Moses, J. I.; Waite, J. H.; Crovisier, J.; Yelle, R. V.; Bougher, S. W.; Roble, R. G.

154

X-linked immunodeficiencies  

Microsoft Academic Search

Recent advances in molecular genetics have allowed identification of at least seven genes involved in X-linked immunodeficiencies.\\u000a This has resulted not only in improved diagnostic possibilities but also in a better understanding of the pathophysiology\\u000a of these disorders. In some cases, mutations in the same gene have been shown to cause distinct clinical and immunologic phenotypes,\\u000a demonstrating a strong genotype-phenotype

Hans D. Ochs; Luigi D. Notarangelo

2004-01-01

155

Gene therapy for immunodeficiency  

Microsoft Academic Search

Since the early 1990s, primary immunodeficiency (ID) disorders have played a major role in the development of human gene therapy.\\u000a Adenosine deaminase (ADA) deficiency was the first disease to be treated with a gene therapy approach in humans, and was also\\u000a the first condition for which therapeutic gene transfer into the hematopoietic stem cell has been attempted in the clinical

Fabio Candotti

2001-01-01

156

Human Immunodeficiency Virus  

Microsoft Academic Search

Oral health is an integral component of overall health and well-being in all patients. However, for an immunocompromised patient,\\u000a many common oral conditions may have a significant impact on quality of life. Intraoral pain, which is a common complaint\\u000a among patients with human immunodeficiency virus (HIV), will compromise patients’ ability to maintain adequate and appropriate\\u000a oral intake. Furthermore, the polypharmacopeia

Anita Patel; Michael Glick

157

Intracellular expression of single-chain variable fragments to inhibit early stages of the viral life cycle by targeting human immunodeficiency virus type 1 integrase.  

PubMed Central

Integration of viral DNA into a chromosome of the infected host cell is required for efficient replication of a retroviral genome, and this reaction is mediated by the virus-encoded enzyme integrase (IN). As IN plays a pivotal role in establishing infection during the early stages of the retroviral life cycle, it is an attractive target for therapeutic intervention. However, the lack of effective antiviral drug therapy against this enzyme has led to the testing of other novel approaches towards its inhibition. In these studies, a panel of anti-human immunodeficiency virus type 1 (anti-HIV-1) IN hybridomas has been used in the construction of single-chain variable antibody fragments (SFvs). The monoclonal antibodies produced by these hybridomas, and derived SFvs, bind to different domains within IN. We now demonstrate that intracellular expression of SFvs which bind to IN catalytic and carboxy-terminal domains results in resistance to productive HIV-1 infection. This inhibition of HIV-1 replication is observed with SFvs localized in either the cytoplasmic or nuclear compartment of the cell. The expression of anti-IN SFvs in human T-lymphocytic cells and peripheral blood mononuclear cells appears to specifically neutralize IN activity prior to integration and, thus, has an effect on the integration process itself. These data support our previous studies with an anti-HIV-1 reverse transcriptase SFv and demonstrate further that intracellularly expressed SFvs can gain access to viral proteins of the HIV-1 preintegration complex. This panel of anti-HIV-1 IN SFvs also provides the tools with which to dissect the molecular mechanism(s) directly involved in integration within HIV-1-infected cells.

Levy-Mintz, P; Duan, L; Zhang, H; Hu, B; Dornadula, G; Zhu, M; Kulkosky, J; Bizub-Bender, D; Skalka, A M; Pomerantz, R J

1996-01-01

158

Inhibition of cytopathic effect of human immunodeficiency virus-1 by water-soluble extract of Ganoderma lucidum  

Microsoft Academic Search

To examine components ofGanoderma lucidum for anti-human immunodeficiency virus (HIV) activity, the aqueous extracts of its basidiocarps were separated into high-molecular-weight\\u000a (HMF) and low-molecular-weight (LMF) fractions. These fractions were used in XTT [2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)\\u000a carbonyl]-2H-tetrazolium hydroxide] antiviral assay which can quantitatively measure cytopathic effects of HIV-1 on CEM, human\\u000a T lymphoblastoid cell line. The CEM cell line added with serial

Ha Won Kim; Mi Ja Shim; Eung Chil Choi; Byong Kak Kim

1997-01-01

159

Follicular dendritic cells and human immunodeficiency virus infectivity  

NASA Astrophysics Data System (ADS)

LARGE amounts of human immunodeficiency virus (HIV) localize on follicular dendritic cells (FDC) in the follicles of secondary lymphoid tissues following viral infection1,2. During clinical latency, active viral infection occurs primarily at these sites3,4. As HIV on FDC is in the form of immune complexes5, some of which may be formed with neutralizing antibody, we investigated whether HIV on FDC is infectious. We report here that HIV on FDC is highly infectious. Furthermore, FDC can convert neutralized HIV into an infectious form even in the presence of a vast excess of neutralizing antibody. Thus FDC may provide a mechanism whereby HIV infection can continue in the presence of neutralizing antibody.

Heath, Sonya L.; Tew, J. Grant; Tew, John G.; Szakal, Andras K.; Burton, Gregory F.

1995-10-01

160

Expansion of CD4+CD25+ Suppressive Regulatory T Cells From Rhesus Macaque Peripheral Blood By FN18/anti-human CD28 Coated Dynal Beads  

PubMed Central

CD4+CD25+ regulatory T cells (Tregs) play an important role in allograft and self-tolerance and thus have potential therapeutic application in transplantation, autoimmunity and allergy. Although non human primate (NHP) provide the most accepted preclinical models for translational studies in allograft tolerance and infectious diseases, CD4+CD25+ Tregs have been rarely studied in NHP. The low frequencies of Tregs in peripheral blood will likely necessitate ex vivo expansion to enable Tregs adaptive immune therapy in NHP and humans. Tregs were isolated by magnetic and flow sorting then stimulated weekly with anti-rhesus CD3 clone FN18 and anti-human CD28 coated Dynal beads plus 100U/ml rhIL-2. Under these conditions, the Tregs were expanded 300–2000-fold in 4 weeks. Expanded CD4+CD25+ Tregs expressed high to moderate levels of FOXP3 as well as CD95, CD62L, CD69 and CCR7 surface antigens. Expanded rhesus Tregs were anergic and suppressed the proliferation of autologous PBMC in a dose-dependent fashion, and the suppression was partially reversed by anti-TGF-?1 neutralizing Ab. These results demonstrate that rhesus macaque suppressive regulatory CD4+CD25+FOXP3+ Tregs can be efficiently expanded in vitro under rhesus specific stimulation, which would enable preclinical testing of Treg therapy in NHP model.

Gansuvd, Balgansuren; Asiedu, Clement K.; Goodwin, Jeanine; Jargal, Uuganbayar; Deckard, Lindsey A.; Andrades, Patricio; Guarcello, Vincenzo; Thomas, Judith M.

2007-01-01

161

Hyperglycosylated Mutants of Human Immunodeficiency Virus (HIV) Type 1 Monomeric gp120 as Novel Antigens for HIV Vaccine Design  

Microsoft Academic Search

The ability to induce broadly neutralizing antibodies should be a key component of any forthcoming vaccine against human immunodeficiency virus type 1. One potential vaccine candidate, monomeric gp120, has generally failed to elicit such antibodies. We postulated that gp120 might be a better immunogen if it could be engineered to preferentially bind known broadly neutralizing antibodies. In a first study,

Ralph Pantophlet; Ian A. Wilson; Dennis R. Burton

2003-01-01

162

Closing the door to human immunodeficiency virus.  

PubMed

The pandemic of human immunodeficiency virus type one (HIV-1), the major etiologic agent of acquired immunodeficiency disease (AIDS), has led to over 33 million people living with the virus, among which 18 million are women and children. Until now, there is neither an effective vaccine nor a therapeutic cure despite over 30 years of efforts. Although the Thai RV144 vaccine trial has demonstrated an efficacy of 31.2%, an effective vaccine will likely rely on a breakthrough discovery of immunogens to elicit broadly reactive neutralizing antibodies, which may take years to achieve. Therefore, there is an urgency of exploring other prophylactic strategies. Recently, antiretroviral treatment as prevention is an exciting area of progress in HIV-1 research. Although effective, the implementation of such strategy faces great financial, political and social challenges in heavily affected regions such as developing countries where drug resistant viruses have already been found with growing incidence. Activating latently infected cells for therapeutic cure is another area of challenge. Since it is greatly difficult to eradicate HIV-1 after the establishment of viral latency, it is necessary to investigate strategies that may close the door to HIV-1. Here, we review studies on non-vaccine strategies in targeting viral entry, which may have critical implications for HIV-1 prevention. PMID:23479426

Kang, Yuanxi; Guo, Jia; Chen, Zhiwei

2013-03-12

163

Inhibition of gallium-67 uptake in melanoma by an anti-human transferrin receptor monoclonal antibody  

SciTech Connect

The effect of an anti-human transferrin receptor (anti-TFR) monoclonal antibody (MoAb), designated B3/25, and an anti-melanoma antibody, designated 96.5, on the uptake of gallium-67 (/sup 67/Ga) by tumor was studied. Three groups of six athymic mice bearing a human melanoma were injected via tail vein with (a) 0.55 mg human serum albumin (HSA) (control group), (b) 0.5 mg MoAb B3/25 + 0.55 mg HSA, and (c) 0.5 mg MoAb 96.5 + 0.55 mg HSA, respectively. Twenty-four hours later, each mouse was given an intravenous dose of 5 microCi (/sup 67/Ga) citrate. Biodistribution of activity (percent injected dose per gram) determined 48 hr after injection of /sup 67/Ga showed a 75% decrease in tumor uptake in the group of mice that received B3/25 (anti-TFR MoAb) compared with the control group. In contrast, MoAb 96.5 did not show any effect on melanoma uptake of /sup 67/Ga. Histologic findings suggest that the decreased uptake was not due to cellular damage resulting from binding of B3/25 to TFR. The results of this study strongly suggest the involvement of TFR in the in vivo tumor uptake of /sup 67/Ga.

Chan, S.M.; Hoffer, P.B.; Maric, N.; Duray, P.

1987-08-01

164

Nature of Nonfunctional Envelope Proteins on the Surface of Human Immunodeficiency Virus Type 1  

Microsoft Academic Search

Human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies are thought be distinguished from nonneutralizing antibodies by their ability to recognize functional gp120\\/gp41 envelope glycoprotein (Env) trimers. The antibody responses induced by natural HIV-1 infection or by vaccine candidates tested to date consist largely of nonneutralizing antibodies. One might have expected a more vigorous neutralizing response, particularly against virus particles that

Penny L. Moore; Emma T. Crooks; Lauren Porter; Ping Zhu; Charmagne S. Cayanan; Henry Grise; Paul Corcoran; Michael B. Zwick; Michael Franti; Lynn Morris; Kenneth H. Roux; Dennis R. Burton; James M. Binley

2006-01-01

165

Screening of milk aspiration in 105 infant death cases by immunostaining with anti-human ?-lactalbumin antibody  

Microsoft Academic Search

To determine the frequency and degree of milk aspiration in infant death cases, immunohistochemical examinations were performed on lung sections from 41 sudden death cases and 64 in-hospital death cases using anti-human ?-lactalbumin antibody. Milk aspiration to some degree was detected in more than half of the sudden death cases and in about one-third of the in-hospital death cases. A

Kimiharu Iwadate; Mikio Doy; Yoko Ito

2001-01-01

166

Lymphocyte Subset Reconstitution in Pediatric Liver Recipients Induced with Steroid-Free Rabbit Anti-Human Thymocyte Globulin  

PubMed Central

Multiple measurements of lymphocyte subsets in 91 children treated with steroid-free Tacrolimus, and rabbit anti-human thymocyte globulin induction demonstrate early reconstitution of T-cytotoxic cells, and gradual reconstitution of all other subsets, which is complete after 1 year. Rejection-prone children demonstrate significantly higher counts of lymphocytes and all subsets prior to liver transplantation, and may exemplify one basis for enhanced baseline immunocompetence.

Talukdar, Anjan; AshokKumar, Chethan; Farrar, Jennifer; Wilson, Patrick; Janakiramanan, Arun; Tregaskes, Mary; Sindhi, Rakesh

2010-01-01

167

Reactivity of an anti-(human gastric carcinoma) monoclonal antibody with core-related peptides of gastrointestinal mucin  

Microsoft Academic Search

Summary A murine anti-(human gastric carcinoma) monoclonal antibody, GL-013 (IgG1), which reacts with a high-molecular-mass glycoprotein from colorectal tumour tissue [Yang and Price (1989) Anticancer Res 9: 1707], was examined for reactivity against a panel of purified and partially purified antigens associated with tumours of the gastrointestinal tract. These included carcinoembryonic antigen (CEA), normal cross-reacting antigen, Y-hapten glycoproteins, and perchloric

M. R. Price; M. Sekowski; G.-Y. Yang; L. G. Durrant; R. A. Robins; R. W. Baldwin

1991-01-01

168

HIV1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites  

Microsoft Academic Search

The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and

Peter D. Kwong; Michael L. Doyle; David J. Casper; Claudia Cicala; Stephanie A. Leavitt; Shahzad Majeed; Tavis D. Steenbeke; Miro Venturi; Irwin Chaiken; Michael Fung; Hermann Katinger; Paul W. I. H. Parren; James Robinson; Donald Van Ryk; Liping Wang; Dennis R. Burton; Ernesto Freire; Richard Wyatt; Joseph Sodroski; Wayne A. Hendrickson; James Arthos

2002-01-01

169

Directed evolution of an anti-human red blood cell antibody.  

PubMed

We have earlier described a haemagglutination-based assay for on-site detection of antibodies to HIV using whole blood. The reagent in this assay comprises of monovalent Fab fragment of an anti-human RBC antibody fused to immunodominant antigens of HIV-1 and HIV-2. In the present work, we describe a rational and systematic method for directed evolution of scFv and Fab antihuman RBC antibody fragments. Based on homology modeling and germline sequence alignments of antibodies, target residues in the anti-RBC MAb B6 sequence were identified for mutagenesis.A combinatorial library of 107 clones was constructed and subjected to selection on whole RBC under competitive binding conditions to identify several phage-displayed B6 scFv clones with improved binding as determined in an agglutination assay.Selected VL and VH sequences were shuffled to generate a second generation phage-displayed Fab library which on panning yielded Fab clones with several fold better binding than wild type. The mutants with better binding also displayed more Fab molecules per phage particle indicating improved in vivo folding which was also confirmed by their increased periplasmic secretion compared to the wild type. The mutant Fab molecules also showed superior characteristics in large scale production by in vitro folding of LC and Fd. The biophysical measurements involving thermal and chemical denaturation and renaturation kinetics clearly showed that two of the mutant Fab molecules possessed significantly improved characteristics as compared to the wild type B6 Fab.Structural modelling revealed that B6 Fab mutants had increased hydrogen bonding resulting in increased stability. Our approach provides a novel and useful strategy to obtain recombinant antibodies with improved characteristics. PMID:20069755

Gupta, Amita; Chaudhary, Vijay K; Bhat, Rajiv

170

Feline immunodeficiency virus latency  

PubMed Central

Despite highly effective anti-retroviral therapy, HIV is thought to persist in patients within long-lived cellular reservoirs in the form of a transcriptionally inactive (latent) integrated provirus. Lentiviral latency has therefore come to the forefront of the discussion on the possibility of a cure for HIV infection in humans. Animal models of lentiviral latency provide an essential tool to study mechanisms of latency and therapeutic manipulation. Of the three animal models that have been described, the feline immunodeficiency virus (FIV)-infected cat is the most recent and least characterized. However, several aspects of this model make it attractive for latency research, and it may be complementary to other model systems. This article reviews what is known about FIV latency and chronic FIV infection and how it compares with that of other lentiviruses. It thereby offers a framework for the usefulness of this model in future research aimed at lentiviral eradication.

2013-01-01

171

Feline immunodeficiency virus latency.  

PubMed

Despite highly effective anti-retroviral therapy, HIV is thought to persist in patients within long-lived cellular reservoirs in the form of a transcriptionally inactive (latent) integrated provirus. Lentiviral latency has therefore come to the forefront of the discussion on the possibility of a cure for HIV infection in humans. Animal models of lentiviral latency provide an essential tool to study mechanisms of latency and therapeutic manipulation. Of the three animal models that have been described, the feline immunodeficiency virus (FIV)-infected cat is the most recent and least characterized. However, several aspects of this model make it attractive for latency research, and it may be complementary to other model systems. This article reviews what is known about FIV latency and chronic FIV infection and how it compares with that of other lentiviruses. It thereby offers a framework for the usefulness of this model in future research aimed at lentiviral eradication. PMID:23829177

McDonnel, Samantha J; Sparger, Ellen E; Murphy, Brian G

2013-07-06

172

Human immunodeficiency virus endocrinopathy  

PubMed Central

Human immunodeficiency virus (HIV) endocrinopathy encompasses a broad spectrum of disorders. Almost all the endocrine organs are virtually affected by HIV infection. HIV can directly alter glandular function. More commonly secondary endocrine dysfunction occurs due to opportunistic infections and neoplasms in immunocompromised state. The complex interaction between HIV infection and endocrine system may be manifested as subtle biochemical and hormonal perturbation to overt glandular failure. Antiretroviral therapy as well as other essential medications often result in adverse endocrinal consequences. Apart from adrenal insufficiency, hypogonadism, diabetes and bone loss, AIDS wasting syndrome and HIV lipodystrophy need special reference. Endocrinal evaluation should proceed as in other patients with suspected endocrine dysfunction. Available treatment options have been shown to improve quality of life and long-term mortality in AIDS patients.

Sinha, Uma; Sengupta, Nilanjan; Mukhopadhyay, Prasanta; Roy, Keshab Sinha

2011-01-01

173

Alpha Interferon Potently Enhances the Anti-Human Immunodeficiency Virus Type 1 Activity of APOBEC3G in Resting Primary CD4 T Cells  

Microsoft Academic Search

The interferon (IFN) system, including various IFNs and IFN-inducible gene products, is well known for its potent innate immunity against wide-range viruses. Recently, a family of cytidine deaminases, functioning as another innate immunity against retroviral infection, has been identified. However, its regulation remains largely unknown. In this report, we demonstrate that through a regular IFN-\\/ signal transduction pathway, IFN- can

Keyang Chen; Jialing Huang; Chune Zhang; Sophia Huang; Giuseppe Nunnari; Feng-xiang Wang; Xiangrong Tong; Ling Gao; Kristi Nikisher; Hui Zhang

2006-01-01

174

Priming of Anti-Human Immunodeficiency Virus (HIV) CD8^+ Cytotoxic T Cells in vivo by Carrier-Free HIV Synthetic Peptides  

NASA Astrophysics Data System (ADS)

The generation of antiviral cytotoxic T lymphocytes (CTLs) is a critical component of the immune response to viral infections. A safe and nontoxic vaccine for AIDS would optimally use a carrier-free synthetic peptide immunogen containing only components of HIV necessary for induction of protective immune responses. We report that hybrid synthetic peptides containing either a HIV envelope gp120 T-cell determinant (T1) or the envelope gp41 fusion domain (F) N-terminal to HIV CTL determinants are capable of priming murine CD8^+, major histocompatibility complex class I-restricted anti-HIV CTLs in vivo. These data demonstrate that carrier-free, nonderivatized synthetic peptides can be used in vivo to induce anti-HIV CTL responses.

Hart, Mary Kate; Weinhold, Kent J.; Scearce, Richard M.; Washburn, Eileen M.; Clark, Cynthia A.; Palker, Thomas J.; Haynes, Barton F.

1991-11-01

175

Micellar electrokinetic chromatography of the anti-human immunodeficiency virus (HIV) agent michellamine B with absorption and laser-induced fluorescence detection.  

PubMed

Micellar electrokinetic chromatography (MEKC) was applied to the separation of the anti-HIV agents, michellamines A and B, and two other structurally related monomers found in the extract of the Ancistrocladus plants. Using buffers containing either 10 mM sodium phosphate (pH 7.0), 50 mM sodium deoxycholate and 10-20% acetonitrile or 5 mM sodium phosphate (pH 7.0), 20 mM sodium dodecyl sulfate and 25% acetonitrile allowed baseline separations of the four components in the mixture in less than 10 min. The MEKC methods gave sharper peaks and better resolution compared to high-performance liquid chromatography. For MEKC separation of the plant extracts, UV absorption detection provided adequate sensitivity; however, higher sensitivity could be achieved with UV laser-induced fluorescence detection (LIF). Using the sodium dodecyl sulfate-containing buffer and LIF, the limit of detection for michellamine B was approximately 2 ng/mL. The sensitivity was degraded approximately 100-fold when using the deoxycholate buffer because of high background fluorescence. Preliminary results show that MEKC with LIF is feasible for the sensitive detection of michellamine B in serum. PMID:7895724

Chan, K C; Majadly, F; McCloud, T G; Muschik, G M; Issaq, H J; Snader, K M

1994-10-01

176

Anti-human immunodeficiency virus (HIV) drug HOE\\/BAY 946 increases membrane hydrophobicity of human lymphocytes and specifically suppresses HIV-protein synthesis  

Microsoft Academic Search

The polysulfated polyxylan HOE\\/BAY 946, which has been tested in two pilot studies in ARC\\/AIDS patients and in asymptomatic HIV carriers in Germany, was believed to act by inhibiting virus attachment to the cell. However, the drug was also found to reduce the amount of HIV particles released from infected peripheral blood mononuclear cells (PBMC) in vitro. Furthermore, preincubation of

Lothar Biesert; Michalina Adamski; Guido Zimmer; Hary Suhartono; Jiirgen Fuchs; Uwe Unkelbach; Rolf J. Mehlhorn; Katman Hideg; Rainer Milbradt; Helga Riibsamen-Waigmann

1990-01-01

177

Mucosal Model of Immunization against Human Immunodeficiency Virus Type 1 with a Chimeric Influenza Virus  

Microsoft Academic Search

Previously, we constructed a chimeric influenza virus that expresses the highly conserved amino acid sequence ELDKWA of gp41 of human immunodeficiency virus type 1 (HIV-1). Antisera elicited in mice by infection with this chimeric virus showed neutralizing activity against distantly related HIV-1 isolates (T. Muster, R. Guinea, A. Trkola, M. Purtscher, A. Klima, F. Steindl, P. Palese, and H. Katinger,

THOMAS MUSTER; BORIS FERKO; ANNELIES KLIMA; MARTIN PURTSCHER; ALEXANDRA TRKOLA; PETRA SCHULZ; ANDREAS GRASSAUER; OTHMAR G. ENGELHARDT; ADOLFO GARCIA-SASTRE; PETER PALESE; ANDHERMANN KATINGER

178

Cryo-Electron Tomographic Structure of an Immunodeficiency Virus Envelope Complex In Situ  

Microsoft Academic Search

The envelope glycoprotein (Env) complexes of the human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate viral entry and are a target for neutralizing antibodies. The receptor binding surfaces of Env are in large part sterically occluded or conformationally masked prior to receptor binding. Knowledge of the unliganded, trimeric Env structure is key for an understanding of viral entry

Giulia Zanetti; John A. G Briggs; Kay Grünewald; Quentin J Sattentau; Stephen D Fuller

2006-01-01

179

Antiviral Drugs for Viruses Other Than Human Immunodeficiency Virus  

PubMed Central

Most viral diseases, with the exception of those caused by human immunodeficiency virus, are self-limited illnesses that do not require specific antiviral therapy. The currently available antiviral drugs target 3 main groups of viruses: herpes, hepatitis, and influenza viruses. With the exception of the antisense molecule fomivirsen, all antiherpes drugs inhibit viral replication by serving as competitive substrates for viral DNA polymerase. Drugs for the treatment of influenza inhibit the ion channel M2 protein or the enzyme neuraminidase. Combination therapy with Interferon-? and ribavirin remains the backbone treatment for chronic hepatitis C; the addition of serine protease inhibitors improves the treatment outcome of patients infected with hepatitis C virus genotype 1. Chronic hepatitis B can be treated with interferon or a combination of nucleos(t)ide analogues. Notably, almost all the nucleos(t) ide analogues for the treatment of chronic hepatitis B possess anti–human immunodeficiency virus properties, and they inhibit replication of hepatitis B virus by serving as competitive substrates for its DNA polymerase. Some antiviral drugs possess multiple potential clinical applications, such as ribavirin for the treatment of chronic hepatitis C and respiratory syncytial virus and cidofovir for the treatment of cytomegalovirus and other DNA viruses. Drug resistance is an emerging threat to the clinical utility of antiviral drugs. The major mechanisms for drug resistance are mutations in the viral DNA polymerase gene or in genes that encode for the viral kinases required for the activation of certain drugs such as acyclovir and ganciclovir. Widespread antiviral resistance has limited the clinical utility of M2 inhibitors for the prevention and treatment of influenza infections. This article provides an overview of clinically available antiviral drugs for the primary care physician, with a special focus on pharmacology, clinical uses, and adverse effects.

Razonable, Raymund R.

2011-01-01

180

Recurrent Infections May Signal Immunodeficiencies  

MedlinePLUS

... adults in the United States. Most PIDD are inherited in our genes, so they are present at ... to three years of additional training to manage allergies, asthma and immunodeficiencies. Some PIDD can mimic other ...

181

Designed oligomers of cyanovirin-N show enhanced HIV neutralization.  

PubMed

Cyanovirin-N (CV-N) is a small, cyanobacterial lectin that neutralizes many enveloped viruses, including human immunodeficiency virus type I (HIV-1). This antiviral activity is attributed to two homologous carbohydrate binding sites that specifically bind high mannose glycosylation present on envelope glycoproteins such as HIV-1 gp120. We created obligate CV-N oligomers to determine whether increasing the number of binding sites has an effect on viral neutralization. A tandem repeat of two CV-N molecules (CVN(2)) increased HIV-1 neutralization activity by up to 18-fold compared to wild-type CV-N. In addition, the CVN(2) variants showed extensive cross-clade reactivity and were often more potent than broadly neutralizing anti-HIV antibodies. The improvement in activity and broad cross-strain HIV neutralization exhibited by these molecules holds promise for the future therapeutic utility of these and other engineered CV-N variants. PMID:21799112

Keeffe, Jennifer R; Gnanapragasam, Priyanthi N P; Gillespie, Sarah K; Yong, John; Bjorkman, Pamela J; Mayo, Stephen L

2011-07-28

182

Designed oligomers of cyanovirin-N show enhanced HIV neutralization  

PubMed Central

Cyanovirin-N (CV-N) is a small, cyanobacterial lectin that neutralizes many enveloped viruses, including human immunodeficiency virus type I (HIV-1). This antiviral activity is attributed to two homologous carbohydrate binding sites that specifically bind high mannose glycosylation present on envelope glycoproteins such as HIV-1 gp120. We created obligate CV-N oligomers to determine whether increasing the number of binding sites has an effect on viral neutralization. A tandem repeat of two CV-N molecules (CVN2) increased HIV-1 neutralization activity by up to 18-fold compared to wild-type CV-N. In addition, the CVN2 variants showed extensive cross-clade reactivity and were often more potent than broadly neutralizing anti-HIV antibodies. The improvement in activity and broad cross-strain HIV neutralization exhibited by these molecules holds promise for the future therapeutic utility of these and other engineered CV-N variants.

Keeffe, Jennifer R.; Gnanapragasam, Priyanthi N. P.; Gillespie, Sarah K.; Yong, John; Bjorkman, Pamela J.; Mayo, Stephen L.

2011-01-01

183

Cutaneous signs of neonatal and infantile immunodeficiency.  

PubMed

Immunodeficiencies frequently present in the skin antepartum and in the first year of life. Although genetic immunodeficiencies are uncommon, the worldwide incidence of the acquired immunodeficiency human immunodeficiency virus (HIV) is growing. Early diagnosis and treatment of neonatal immunodeficiencies and associated infections result in improved quality of life and longer life expectancy for these patients. In developed countries, improvements in therapy of HIV during pregnancy have resulted in reduced transmission to the neonate. This article reviews the common presentations and therapy of genetic and acquired neonatal immunodeficiencies. PMID:15953146

Mirchandani, Nina; Hawit, Faris; Silverberg, Nanette B

184

Early appearance of antibodies to simian immunodeficiency virus in saliva and serum of infected macaques.  

PubMed Central

Simian immunodeficiency virus (SIV) infection in macaques is an important animal model for human immunodeficiency virus infection in humans. This study evaluated the temporal development of antibodies to SIV in the parotid saliva of macaques inoculated with the virus and compared these findings with the development of antibodies to SIV in the animals' sera. Three animals (ages, 14, 18, and 18 years) were inoculated with the macrophagetropic strain SIVmac239. Prior to inoculation and at consecutive weekly intervals during a four-week period following the initial virus inoculations, parotid saliva and serum were collected from each animal. A fourth animal (age, 9 years) served as a negative control, and the fifth and sixth animals (ages, 2 and 22 years) served as positive controls (6 and 18 months postinoculation, respectively) with SIVmac239. Saliva and serum samples were reacted against SIV antigen in Western blots (immunoblots) prepared in the standard fashion to determine the presence of antibodies. The reactions of these antigen-antibody complexes with biotinylated anti-human immunoglobulin A (IgA), IgM, and IgG and biotinylated anti-human secretory component (SC) determined the class of antibody present or the presence of SC in the original parotid saliva or serum samples. In infected animals, the IgM to SIV was detectable in serum and saliva at 13 days, and antiviral IgA and IgG in serum and saliva were detectable at 20 to 27 days postinoculation. The antibody to SC reacted to saliva from only two animals at 20 and 27 days, and long-term positive controls were positive for SC in saliva, indicating that either secretory IgA or secretory IgM was present in these samples. Antibodies to SIVmac239 antigens have therefore been detected in saliva as early as 13 days postinfection. Saliva may be as useful as serum as a diagnostic specimen and/or disease-monitoring method in this important animal model.

Meiller, T F; Narayan, O; Joag, S V; Overholser, C D

1995-01-01

185

Humanization and Characterization of an Anti-Human TNF-alpha Murine Monoclonal Antibody  

Microsoft Academic Search

A murine monoclonal antibody, m357, showing the highly neutralizing activities for human tumor necrosis factor (TNF-?) was chosen to be humanized by a variable domain resurfacing approach. The non-conserved surface residues in the framework regions of both the heavy and light chain variable regions were identified via a molecular modeling of m357 built by computer-assisted homology modeling. By replacing these

Wei-Chun Chiu; Ya-Ping Lai; Min-Yuan Chou; Wei-Chun Chin

2011-01-01

186

A novel anti-human ICOSL monoclonal antibody that enhances IgG production of B cells.  

PubMed

ICOSL, a newly identified member of the B7 superfamily, plays a major role in immune responses. In this study, a functional anti-human ICOSL monoclonal antibody (MAb) 3B3 was obtained and characterized by means of flow cytometry, Western blot, and competition assay. This MAb could specifically recognize a distinct epitope of the ICOSL molecule. As a functional antibody, MAb 3B3 could inhibit the proliferation of T lymphocytes stimulated by ICOSL-L929 transfectants. Furthermore, it could enhance IgG production of PWM-driven B cells. The results indicate that the ICOS-ICOSL signal is critically involved in specific humoral immunity. PMID:23607348

Chen, Jie; Wang, Fengming; Cai, Qiuping; Shen, Shuang; Chen, Youguo; Hao, Chao; Sun, Jing

2013-04-01

187

Actin cytoskeletal defects in immunodeficiency.  

PubMed

The importance of the cytoskeleton in mounting a successful immune response is evident from the wide range of defects that occur in actin-related primary immunodeficiencies (PIDs). Studies of these PIDs have revealed a pivotal role for the actin cytoskeleton in almost all stages of immune system function, from hematopoiesis and immune cell development, through to recruitment, migration, intercellular and intracellular signaling, and activation of both innate and adaptive immune responses. The major focus of this review is the immune defects that result from mutations in the Wiskott-Aldrich syndrome gene (WAS), which have a broad impact on many different processes and give rise to clinically heterogeneous immunodeficiencies. We also discuss other related genetic defects and the possibility of identifying new genetic causes of cytoskeletal immunodeficiency. PMID:24117828

Moulding, Dale A; Record, Julien; Malinova, Dessislava; Thrasher, Adrian J

2013-11-01

188

Common variable immunodeficiency: a review  

Microsoft Academic Search

Common variable immunodeficiency (CVID) is the commonest symptomatic primary antibody deficiency syndrome. The predominant manifestation is hypogammaglobulinemia. CVID is characterized by recurrent bacterial infections, especially of the upper and lower respiratory airways, and is also associated with an increased incidence of autoimmune and neoplastic disorders. Most patients are diagnosed as adults and delay in the recognition of the disease is

M. Di Renzo; A. L. Pasqui; A. Auteri

2004-01-01

189

Failure of a Human Immunodeficiency Virus (HIV) Immune Globulin to Protect Chimpanzees against Experimental Challenge with HIV  

Microsoft Academic Search

To assess the possible efficacy of passive immunization against human immunodeficiency virus (HIV) an immune globulin was prepared from plasma of HIV-seropositive donors selected to be among those having the top 12.5% of virus-neutralizing antibody titers. The immune globulin was treated with pepsin to render it intravenously tolerable. The preparation, which we termed HIVIG, neutralized 100 tissue culture 50% infective

Alfred M. Prince; Bernard Horowitz; Louis Baker; Richard W. Shulman; Harold Ralph; Jay Valinsky; Anthony Cundell; Betsy Brotman; Wolfgang Boehle; Francois Rey; Marcel Piet; Henk Reesink; Nico Lelie; Matthijs Tersmette; Frank Miedema; Luiz Barbosa; George Nemo; Chet L. Nastala; Jonathan S. Allan; D. Rick Lee; Jorg W. Eichberg

1988-01-01

190

Protection of macaques with a simian immunodeficiency virus envelope peptide vaccine based on conserved human immunodeficiency virus type 1 sequences.  

PubMed Central

This report describes the vaccination of rhesus macaques with peptides selected from regions of the simian immunodeficiency virus (SIV) envelope that are hydrophilic, immunoreactive, and highly homologous with corresponding conserved envelope sequences of the human immunodeficiency virus (HIV). The peptides, produced as beta-galactosidase fusion proteins, induced virus-neutralizing and peptide-specific antibodies. After challenge with virulent virus, controls became virus positive and developed gradually rising antibody titers to SIV over 63 weeks. Immunized macaques developed a postchallenge anamnestic response to SIVenv antigens within 3-6 weeks followed by a gradual, fluctuating decline in SIV antibody titers and partial or total suppression of detectable SIV. Virus suppression correlated with prechallenge neutralizing antibody titers. Although the average CD4+ cell count in the blood of immunized macaques remained constant, the control macaques exhibited a progressive decrease developing about week 55 after challenge. The conserved nature of the HIV and SIV peptides and the similar humoral immunoreactivity in the respective hosts suggest that homologous HIV peptides may be important components of a successful immunization strategy. Images

Shafferman, A; Jahrling, P B; Benveniste, R E; Lewis, M G; Phipps, T J; Eden-McCutchan, F; Sadoff, J; Eddy, G A; Burke, D S

1991-01-01

191

Structural basis for HIV1 neutralization by a gp41 fusion intermediate–directed antibody  

Microsoft Academic Search

Elicitation of potent and broadly neutralizing antibodies is an important goal in designing an effective human immunodeficiency virus-1 (HIV-1) vaccine. The HIV-1 gp41 inner-core trimer represents a functionally and structurally conserved target for therapeutics. Here we report the 2.0-Å-resolution crystal structure of the complex between the antigen-binding fragment of D5, an HIV-1 cross-neutralizing antibody, and 5-helix, a gp41 inner-core mimetic.

Micah A Luftig; Marco Mattu; Paolo Di Giovine; Romas Geleziunas; Renee Hrin; Gaetano Barbato; Elisabetta Bianchi; Michael D Miller; Antonello Pessi; Andrea Carfí

2006-01-01

192

Three-Dimensional Culture of Hybridoma Cells Secreting Anti-Human Chorionic Gonadotropin by a New Rolling Culture System  

PubMed Central

Cell growth rate and production of monoclonal antibody (MAb) of hybridoma cells producing anti-human chorionic gonadotropin (hCG) MAb have been used as investigation criteria in double-mouthed rolling bottle (DMRB). Compared with T-flask cell culture, both of the cell number and MAb production increased by approximately 42.5% when the medium was supplemented with 5% fetal calf serum (FCS) and DMRB rotated at 2 turns per minute. Yield of MAb was experimentally related to the number of viable cells. Interestingly, MAb yield was four times as high as that cultured in T-flask in the first 24?hours, and about 75% yield of total MAb was secreted by 48?hours during the culture. It appears that the promoted cell growth and MAb yield are resulted from the three-dimensional growth of hybridoma cells under a suitably revolving condition.

He, Rong-Qiao

2004-01-01

193

A case of transfusion-related acute lung injury induced by anti-human leukocyte antigen antibodies in acute leukemia  

PubMed Central

Transfusion-related acute lung injury (TRALI) is a noncardiogenic pulmonary edema that occurs during or within 6 hours after transfusion. Risk factors for TRALI, which is relatively common in critically ill patients, include recent surgery, hematologic malignancy, and sepsis. Here, we report a case of TRALI induced by anti-human leukocyte antigen (anti-HLA) class II antibodies (HLA-DR) occurring after transfusion of platelet concentrates in a patient with acute leukemia. Although most patients with TRALI show improvement within 48-96 hours, our patient's condition rapidly worsened, and he did not respond to supportive treatment. TRALI is a relatively common and serious adverse transfusion reaction that requires prompt diagnosis and management.

Jin, Sun Mi; Jang, Moon Ju; Huh, Ji Young; Park, Myoung Hee; Song, Eun Young

2012-01-01

194

Inactivation of Human Immunodeficiency Virus Type 1 by Porphyrins  

PubMed Central

We have evaluated the anti-human immunodeficiency virus (HIV) activity of a series of natural and synthetic porphyrins to identify compounds that could potentially be used as microbicides to provide a defense against infection by sexually transmitted virus. For assays we used an epithelial HeLa-CD4 cell line with an integrated long terminal repeat-?-galactosidase gene. For structure-activity analysis, we divided the porphyrins tested into three classes: (i) natural porphyrins, (ii) metallo-tetraphenylporphyrin tetrasulfonate (metallo-TPPS4) derivatives, and (iii) sulfonated tetra-arylporphyrin derivatives. None of the natural porphyrins studied reduced infection by more than 80% at a concentration of 5 ?g/ml in these assays. Some metal chelates of TPPS4 were more active, and a number of sulfonated tetra-aryl derivatives showed significantly higher activity. Some of the most active compounds were the sulfonated tetranaphthyl porphyrin (TNapPS), sulfonated tetra-anthracenyl porphyrin (TAnthPS), and sulfonated 2,6-difluoro-meso-tetraphenylporphine [TPP(2,6-F2)S] and its copper chelate [TPP(2,6-F2)S,Cu], which reduced infection by 99, 96, 94, and 96%, respectively. Our observations indicate that at least some of these compounds are virucidal, i.e., that they render the virus noninfectious. The active compounds were found to inhibit binding of the HIV type 1 gp120 to CD4 and also to completely inhibit the ability of Env proteins expressed from recombinant vectors to induce cell fusion with receptor-bearing target cells. These results support the conclusion that modified porphyrins exhibit substantial activity against HIV and that their target is the HIV Env protein.

Vzorov, Andrei N.; Dixon, Dabney W.; Trommel, Jenna S.; Marzilli, Luigi G.; Compans, Richard W.

2002-01-01

195

Nonpathogenic Simian Immunodeficiency Virus Infections  

PubMed Central

The simian immunodeficiency viruses (SIVs) are a diverse group of viruses that naturally infect a wide range of African primates, including African green monkeys (AGMs) and sooty mangabey monkeys (SMs). Although natural infection is widespread in feral populations of AGMs and SMs, this infection generally does not result in immunodeficiency. However, experimental inoculation of Asian macaques results in an immunodeficiency syndrome remarkably similar to human AIDS. Thus, natural nonprogressive SIV infections appear to represent an evolutionary adaptation between these animals and their primate lentiviruses. Curiously, these animals maintain robust virus replication but have evolved strategies to avoid disease progression. Adaptations observed in these primates include phenotypic changes to CD4+ T cells, limited chronic immune activation, and altered mucosal immunity. It is probable that these animals have achieved a unique balance between T-cell renewal and proliferation and loss through activation-induced apoptosis, and virus-induced cell death. A clearer understanding of the mechanisms underlying the lack of disease progression in natural hosts for SIV infection should therefore yield insights into the pathogenesis of AIDS and may inform vaccine design.

Klatt, Nichole R.; Silvestri, Guido; Hirsch, Vanessa

2012-01-01

196

In vitro Binding Studies of Anti-Human Lymphocyte Globulin: Analysis of Samples Tested for Immunosuppression in the Primate Skin Allograft System.  

National Technical Information Service (NTIS)

Measurements were made of the rates and the quantity of antibody which binds a cultured human lymphoblasts, thymus and, in some cases, Hela cells in 28 anti-human and 2 anti-baboon lymphocyte sera and in 9 normal sera submitted to the National Naval Medic...

R. Garcia-Rinaldi R. D. Rossen K. W. Sell L. Kormeier J. Woody

1976-01-01

197

[Feline immunodeficiency syndrome--a review].  

PubMed

A review is given on Feline Immunodeficiency Syndrome with reference being made to aetiology, epidemiology, pathogenesis and pathology, clinical symptoms, differential diagnosis, immunity, therapy and prophylaxis. PMID:8250822

Muluneh, A

1993-10-01

198

On neutral plasma oscillations  

SciTech Connect

We examine the conditions for the existence of spectrally stable neutral modes in a Vlasov-Poisson plasma and show that for stable equilibria of systems that have unbounded spatial domain, the only possible neutral modes are those with phase velocities that correspond to stationary inflection points of the equilibrium distribution function. It is seen that these neutral modes can possess positive or negative free energy.

Shadwick, B.A.; Morrison, P.J.

1993-06-01

199

ALEX neutral beam probe  

SciTech Connect

A neutral beam probe capable of measuring plasma space potential in a fully 3-dimensional magnetic field geometry has been developed. This neutral beam was successfully used to measure an arc target plasma contained within the ALEX baseball magnetic coil. A computer simulation of the experiment was performed to refine the experimental design and to develop a numerical model for scaling the ALEX neutral beam probe to other cases of fully 3-dimensional magnetic field. Based on this scaling a 30 to 50 keV neutral cesium beam probe capable of measuring space potential in the thermal barrier region of TMX Upgrade was designed.

Pourrezaei, K.

1982-01-01

200

Search for neutral leptons  

SciTech Connect

At present we know of three kinds of neutral leptons: the electron neutrino, the muon neutrino, and the tau neutrino. This paper reviews the search for additional neutral leptons. The method and significance of a search depends upon the model used for the neutral lepton being sought. Some models for the properties and decay modes of proposed neutral leptons are described. Past and present searches are reviewed. The limits obtained by some completed searches are given, and the methods of searches in progress are described. Future searches are discussed. 41 references.

Perl, M.L.

1984-12-01

201

Neutral plasma oscillations.  

National Technical Information Service (NTIS)

We examine the conditions for the existence of spectrally stable neutral modes in a Vlasov-Poisson plasma and show that for stable equilibria of systems that have unbounded spatial domain, the only possible neutral modes are those with phase velocities th...

B. A. Shadwick P. J. Morrison

1993-01-01

202

Energetic neutral atoms  

Microsoft Academic Search

The use of energetic neutral atoms (ENAs), produced by charge exchange between energetic ions and ambient neutral atoms, as a means to image energetic ions in space plasmas has been extended to the investigation of the heliosphere. We explore what can be expected and what is observed of heliospheric ENAs in quiet time interplanetary space. Modeling shows that energetic hydrogen

Martin Hilchenbach; Chiang Hsieh Ke; Andrzej Czechowski

2000-01-01

203

How to remain neutral: An experimental analysis of neutralization  

Microsoft Academic Search

Many patients with obsessive-compulsive problems engage in neutralizing activity to reduce or “cancel out” the effects of the obsession. In many cases, neutralization is covert and therefore difficult to assess or manipulate experimentally. We hypothesize that neutralization resembles overt compulsions. In particular, it was predicted that: (i) neutralization reduces the anxiety evoked by unacceptable thoughts, and (ii) if neutralization is

S. Rachman; R. Shafran; D. Mitchell; J. Trant; B. Teachman

1996-01-01

204

Pathogenesis of human immunodeficiency virus infection.  

PubMed Central

The lentivirus human immunodeficiency virus (HIV) causes AIDS by interacting with a large number of different cells in the body and escaping the host immune response against it. HIV is transmitted primarily through blood and genital fluids and to newborn infants from infected mothers. The steps occurring in infection involve an interaction of HIV not only with the CD4 molecule on cells but also with other cellular receptors recently identified. Virus-cell fusion and HIV entry subsequently take place. Following virus infection, a variety of intracellular mechanisms determine the relative expression of viral regulatory and accessory genes leading to productive or latent infection. With CD4+ lymphocytes, HIV replication can cause syncytium formation and cell death; with other cells, such as macrophages, persistent infection can occur, creating reservoirs for the virus in many cells and tissues. HIV strains are highly heterogeneous, and certain biologic and serologic properties determined by specific genetic sequences can be linked to pathogenic pathways and resistance to the immune response. The host reaction against HIV, through neutralizing antibodies and particularly through strong cellular immune responses, can keep the virus suppressed for many years. Long-term survival appears to involve infection with a relatively low-virulence strain that remains sensitive to the immune response, particularly to control by CD8+ cell antiviral activity. Several therapeutic approaches have been attempted, and others are under investigation. Vaccine development has provided some encouraging results, but the observations indicate the major challenge of preventing infection by HIV. Ongoing research is necessary to find a solution to this devastating worldwide epidemic. Images

Levy, J A

1993-01-01

205

Immunotherapy for primary immunodeficiency diseases.  

PubMed

The 2 most commonly encountered primary immunodeficiency syndromes in adult practice are antibody deficiency disorders and hereditary angioedema.Immunologic therapy for these disorders has significantly improved patient management. Therapy with immunoglobulin leads to improvement in overall quality of life. With increasing survival rates and decreasing levels of life-threatening infections in patients with primary antibody deficiencies, disease complications are more commonly encountered. Treatment of these complications with monoclonal antibody therapy seems promising and is likely to increase in the future. More recently,several additional agents have become available, including novel drugs targeted at different elements of the disease process. PMID:22703850

Wood, Philip

2012-05-22

206

Severe Viral Infections and Primary Immunodeficiencies  

PubMed Central

Patients with severe viral infections are often not thoroughly evaluated for immunodeficiencies. In this review, we summarize primary immunodeficiencies that predispose individuals to severe viral infections. Some immunodeficiencies enhance susceptibility to disease with a specific virus or family of viruses, whereas others predispose to diseases with multiple viruses in addition to disease with other microbes. Although the role of cytotoxic T cells in controlling viral infections is well known, a number of immunodeficiencies that predispose to severe viral diseases have recently been ascribed to defects in the Toll-like receptor–interferon signaling pathway. These immunodeficiencies are rare, but it is important to identify them both for prognostic information and for genetic counseling. Undoubtedly, additional mutations in proteins in the innate and adaptive arms of the immune system will be identified in the future, which will reveal the importance of these proteins in controlling infections caused by viruses and other pathogens.

Cohen, Jeffrey I.

2011-01-01

207

Two novel inhibitory anti-human factor XI antibodies prevent cessation of blood flow in a murine venous thrombosis model.  

PubMed

Coagulation factor XI (FXI) is a promising target for anticoagulation, because of its major role in thrombosis and relatively minor role in haemostasis. This implies that inhibition of FXI can prevent thrombosis without causing bleeding. It was our aim to investigate the antithrombotic properties of two novel inhibitory anti-human FXI antibodies (?FXI-175 and ?FXI-203). The in vitro properties of both antibodies were analysed using standard clotting assays and calibrated automated thrombography. For the in vivo model we used FXI knockout mice, in which FXI plasma levels were restored with purified human FXI. Thrombosis was induced by applying ferric chloride to the vena cava inferior, after which time to occlusion was analysed. A tail bleeding assay was used to investigate the safety of both antibodies. Using calibrated automated thrombography, both antibodies inhibited thrombin generation initiated via the intrinsic pathway. In contrast, upon tissue factor (TF)-initiated thrombin generation, ?FXI-203 did not inhibit thrombin generation, while ?FXI-175 inhibited thrombin generation only at low concentrations of TF. In the murine thrombosis model, the vena cava inferior remained patent for 25 minutes (min) in mice treated with ?FXI-175 and for 12.5 min in ?FXI-203 treated animals, which was significantly longer than in placebo-treated animals (5 min, p<0.05). Neither antibody caused severe blood loss in a tail bleeding assay. In conclusion, the two inhibitory antibodies against FXI prevented cessation of blood flow in a murine thrombosis model without inducing a bleeding tendency. PMID:23925504

van Montfoort, M L; Knaup, V L; Marquart, J A; Bakhtiari, K; Castellino, F J; Hack, C E; Meijers, J C M

2013-08-08

208

Common variable immunodeficiency - an update  

PubMed Central

Common variable immunodeficiency (CVID) describes a heterogeneous subset of hypogammaglobulinemias of unknown etiology. Typically, patients present with recurrent bacterial infections of the respiratory and gastrointestinal tract. A significant proportion of CVID patients develops additional autoimmune, inflammatory or lymphoproliferative complications. CVID is the most frequent symptomatic primary immunodeficiency encountered in adults. Informative monogenetic defects have been found in single patients and families but in most cases the pathogenesis is still elusive. Numerous immunological studies have demonstrated phenotypic and functional abnormalities of T cells, B cells and antigen-presenting cells. A hallmark is the impaired memory B-cell formation that has been taken advantage of for classifying CVID patients. Clinical multi-center studies have demonstrated a correlation between immunological markers and clinical presentation. Long-term outcome is significantly influenced by delay of diagnosis and treatment and the presence of chronic inflammatory complications. While immunoglobulin replacement therapy plus antibiotics can control infections in most cases, patients with non-infectious inflammatory complications such as granulomatous inflammation, interstitial lung disease, inflammatory bowel disease, lymphoproliferation and developing malignancies still represent a therapeutic challenge. In this review we provide a systematic overview of the immunological, clinical, diagnostic and therapeutic aspects of CVID and highlight recent developments in these fields.

2012-01-01

209

Envelope Vaccination Shapes Viral Envelope Evolution following Simian Immunodeficiency Virus Infection in Rhesus Monkeys?  

PubMed Central

The evolution of envelope mutations by replicating primate immunodeficiency viruses allows these viruses to escape from the immune pressure mediated by neutralizing antibodies. Vaccine-induced anti-envelope antibody responses may accelerate and/or alter the specificity of the antibodies, thus shaping the evolution of envelope mutations in the replicating virus. To explore this possibility, we studied the neutralizing antibody response and the envelope sequences in rhesus monkeys vaccinated with either gag-pol-nef immunogens or gag-pol-nef immunogens in combination with env and then infected with simian immunodeficiency virus (SIV). Using a pseudovirion neutralization assay, we demonstrate that envelope vaccination primed for an accelerated neutralizing antibody response following virus challenge. To monitor viral envelope evolution in these two cohorts of monkeys, full-length envelopes from plasma virus isolated at weeks 37 and 62 postchallenge were sequenced by single genome amplification to identify sites of envelope mutations. We show that env vaccination was associated with a change in the pattern of envelope mutations. Prevalent mutations in sequences from gag-pol-nef vaccinees included deletions in both variable regions 1 and 4 (V1 and V4), whereas deletions in the env vaccinees occurred only in V1. These data show that env vaccination altered the focus of the antibody-mediated selection pressure on the evolution of envelope following SIV challenge.

Basavapathruni, Aravind; Yeh, Wendy W.; Coffey, Rory T.; Whitney, James B.; Hraber, Peter T.; Giri, Ayush; Korber, Bette T.; Rao, Srinivas S.; Nabel, Gary J.; Mascola, John R.; Seaman, Michael S.; Letvin, Norman L.

2010-01-01

210

Characterization of Antibody Responses Elicited by Human Immunodeficiency Virus Type 1 Primary Isolate Trimeric and Monomeric Envelope Glycoproteins in Selected Adjuvants  

Microsoft Academic Search

We previously reported that soluble, stable YU2 gp140 trimeric human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein immunogens could elicit improved breadth of neutralization against HIV-1 isolates compared to monomeric YU2 gp120 proteins. In this guinea pig immunization study, we sought to extend these data and determine if adjuvant could quantitatively or qualitatively alter the neutralizing response elicited by trimeric

Y. Li; K. Svehla; N. L. Mathy; G. Voss; J. R. Mascola; R. Wyatt

2006-01-01

211

Neutralized ion beam spectroscopy  

Microsoft Academic Search

Research on the neutralization of ion beams by electron-capture collisions with atomic particles has largely been within the domain of atomic and high-energy physics with the emphasis on understanding the fundamentals of ion-atom interactions. This account presented a chemist's perception of the possibilities to obtain new information about molecules formed by neutralization of beams of molecular ions. Only reactions in

Gregory I. Gellene; Richard F. Porter

1983-01-01

212

Disseminated cytomegalovirus infection in immunodeficient rhesus monkeys.  

PubMed Central

Rhesus monkeys experimentally infected with the lentivirus SIV/Delta become immunodeficient and often die of opportunistic infections. The most frequent of these is cytomegalovirus (CMV). The lesions due to reactivated CMV infection in 14 SIV-infected monkeys were reviewed. Changes due to CMV were observed in the brain, lung, lymph node, liver, spleen, small intestine, testicle, nerves, and arteries. Disseminated CMV infection in immunodeficient rhesus monkeys is a useful model for studying the pathogenesis, treatment, and prevention of similar infections in immunodeficient human beings. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8

Baskin, G. B.

1987-01-01

213

[Granulomatosis and primary immunodeficiency in adulthood].  

PubMed

Primary immunodeficiency with granulomatosis in the adulthood mainly concern common variable immunodeficiency (CVID). Hypogammaglobulinemia in the adulthood is usually related to a secondary immunodeficiency. When a patient presents with the association of a hypogammaglobulinemia and a granulomatosis, an opportunistic infection must first be ruled out. For unknown reasons, about 10% of the patients affected by CVID also present with granulomatosis. Lesions usually affect the pulmonary tract or the mediastinum. Half of these patients are also affected by an autoimmune cytopenia. Treatment is not codified. Severe pulmonary complications can occur in about 50% of the patients. PMID:22425132

Pavic, M; Pasquet, F; Fieschi, C; Malphettes, M; Sève, P

2012-03-15

214

Diagnostic value of anti-human citrullinated fibrinogen ELISA and comparison with four other anti-citrullinated protein assays  

PubMed Central

We studied the diagnostic performance of the anti-human citrullinated fibrinogen antibody (AhFibA) ELISA for rheumatoid arthritis (RA) in a consecutive cohort (population 1) and evaluated the agreement between the AhFibA ELISA and four other assays for anti-citrullinated protein/peptide antibodies (ACPAs) as well as rheumatoid factor in patients with longstanding RA (population 2). Population 1 consisted of 1024 patients with rheumatic symptoms; serum samples from these patients were sent to our laboratory for ACPA testing within the context of a diagnostic investigation for RA. Ninety-two of these patients were classified as having RA according to the American College of Rheumatology criteria and 463 were classified as non-RA patients. Population 2 consisted of 180 patients with longstanding RA and was used to assess agreement and correlations between five ACPA assays: anti-cyclic citrullinated peptide (CCP)1 and anti-CCP2 antibodies were detected using a commercially available ELISA, AhFibA using ELISA, and anti-PepA and anti-PepB antibodies using line immunoassay. Applying previously proposed cut-offs for AhFibA, we obtained a sensitivity of 60.9% and a specificity of 98.7% in population 1. Receiver operating characteristic curve analysis could not detect a significant difference in diagnostic performance between the AhFibA ELISA and anti-CCP2 assay. Performing a hierarchical nearest neighborhood cluster analysis of the five different ACPA assays in population 2, we identified two clusters: a cluster of anti-pepA, anti-pepB and anti-CCP1, and a cluster of AhFibA and anti-CCP2. In conclusion, we found that AhFibA and anti-CCP2 antibodies had similar diagnostic performance. However, disagreement between ACPA tests may occur.

Vander Cruyssen, Bert; Cantaert, Tineke; Nogueira, Leonor; Clavel, Cyril; De Rycke, Leen; Dendoven, Amelie; Sebag, Mireille; Deforce, Dieter; Vincent, Christian; Elewaut, Dirk; Serre, Guy; De Keyser, Filip

2006-01-01

215

Preclinical evaluation of light-activatable, bispecific anti-human CD3 antibody conjugates as anti-ovarian cancer therapeutics  

PubMed Central

The administration of anti-CD3 antibodies, either unmodified or in bispecific formats, has been shown to kill tumors. However, their activity needs to be carefully controlled. We have approached this problem by inhibiting their anti-CD3 activity until it is required. Folated anti-human CD3 antibody bispecific conjugates were therefore synthesised in which the folate portion of the conjugates remained free to bind to folate receptor (FR) expressing cancer cells, whilst their anti-CD3 activity was reversibly inhibited. On irradiation with UV-A light, the T-cell binding activity of the anti-CD3 antibody can be restored only when and where it is required, i.e., adjacent to a tumor. Conjugate bound to FR expressed on normal tissues in other parts of the body remains inactive. This report describes the preclinical in vivo testing of these conjugates in transgenic mice whose T-cells express human CD3 molecules. When the ‘cloaked’ conjugates were reactivated in the region of the primary tumor, both primary tumor growth and liver metastasis were markedly reduced. That the deliberate targeting of T-cell activity locally to the primary tumor also resulted in reduced distant metastatic growth was a key finding. Light-activatable bispecific antibody conjugates similar to those described here offer a means to control T-cell targeting with a much higher degree of specificity to tumors because they minimize potentially dangerous and unwanted side effects in non-illuminated areas. The addition of light-specific targeting to the inherent tumor specific targeting of therapeutic antibody conjugates could result in the development of safer treatments for patients.

Dessi, John

2009-01-01

216

Autoimmunity in Common Variable Immunodeficiency  

PubMed Central

Common variable immunodeficiency (CVID) is the most common clinically significant primary immune defect. Although the hallmark of CVID is hypogammaglobulinemia, the intrinsic dysregulation of the immune system leads to defective T-cell activation and proliferation, as well as dendritic cell and cytokine defects. Although 70% to 80% of patients have had recurrent sinopulmonary infections, auto-immunity and inflammatory complications are also common. The most common autoimmune conditions are immune thrombocytopenic purpura and hemolytic anemia, but other autoimmune complications arise, including rheumatoid arthritis, pernicious anemia, primary biliary cirrhosis, thyroiditis, sicca syndrome, systemic lupus, and inflammatory bowel disease. Treatment of autoimmunity includes high-dose immunoglobulins, corticosteroids, selected immunosuppressants, and other immune modulators. This review focuses on autoimmune conditions associated with CVID, potential mechanisms of immune dysregulation, and therapeutic strategies.

Agarwal, Shradha; Cunningham-Rundles, Charlotte

2010-01-01

217

Gene Therapy for Primary Immunodeficiencies  

PubMed Central

Abstract For over 40 years, primary immunodeficiencies (PIDs) have featured prominently in the development and refinement of human allogeneic hematopoietic stem cell transplantation. More recently, ex vivo somatic gene therapy using autologous cells has provided remarkable evidence of clinical efficacy in patients without HLA-matched stem cell donors and in whom toxicity of allogeneic procedures is likely to be high. Together with improved preclinical models, a wealth of information has accumulated that has allowed development of safer, more sophisticated technologies and protocols that are applicable to a much broader range of diseases. In this review we summarize the status of these gene therapy trials and discuss the emerging application of similar strategies to other PIDs.

Rivat, Christine; Santilli, Giorgia; Gaspar, H. Bobby

2012-01-01

218

Use of Human Immunodeficiency Virus Nucleoside-Analog Reverse Transcriptase Inhibitors to Control Human Immunodeficiency Virus  

NSDL National Science Digital Library

This animation illustrates how human immunodeficiency virus (HIV) nucleoside-analog reverse transcriptase inhibitors (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, and abacavir) inhibit replication of the HIV.

American Society For Microbiology;

2005-03-11

219

Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys  

Microsoft Academic Search

The key to an effective HIV vaccine is development of an immunogen that elicits persisting antibodies with broad neutralizing activity against field strains of the virus. Unfortunately, very little progress has been made in finding or designing such immunogens. Using the simian immunodeficiency virus (SIV) model, we have taken a markedly different approach: delivery to muscle of an adeno-associated virus

Bruce C Schnepp; Jianchao Zhang; Mary J Connell; Sean M Greene; Eloisa Yuste; Ronald C Desrosiers; K Reed Clark; Philip R Johnson

2009-01-01

220

HIV (Human Immunodeficiency Virus) Envelope Drift.  

National Technical Information Service (NTIS)

The consensus sequences for (HIV) the Human Immunodeficiency Virus, envelope proteins can also be examined with regard to what might be called differential drift. Conserved and hypervariable regions, or domains, of the envelope were defined in 1986, when ...

G. Myers

1988-01-01

221

EMPIRICAL EVALUATION OF NEUTRAL THEORY  

Microsoft Academic Search

We describe a general framework for testing neutral theory. We summarize similarities and differences between ten different versions of neutral theory. Two central predictions of neutral theory are that species abundance distributions will follow a zero-sum multinomial distribution and that community composition will change over space due to dispersal limitation. We review all published empirical tests of neutral theory. With

Brian J. McGill; Brian A. Maurer; Michael D. Weiser

2006-01-01

222

Warts and All: HPV in Primary Immunodeficiencies  

PubMed Central

Infection with human papilloma virus (HPV) is almost universal and eventually asymptomatic, but pathologic infection with HPV is severe, recurrent, and recalcitrant to therapy. It is also an underappreciated manifestation of primary immunodeficiency. Mutations in EVER1, EVER2, GATA2, CXCR4, and DOCK8 are typically associated with extensive HPV infections, whereas several other primary immune defects have severe HPV much less frequently. We review immunodeficiencies with severe HPV infections and the mechanisms underlying them.

Leiding, Jennifer W.; Holland, Steven M.

2012-01-01

223

Inhibition of human immunodeficiency virus type 1 replication by SDZ NIM 811, a nonimmunosuppressive cyclosporine analog.  

PubMed Central

(Me-Ile-4)cyclosporin (SDZ NIM 811) is a 4-substituted cyclosporin which is devoid of immunosuppressive activity but retains full capacity for binding to cyclophilin and exhibits potent anti-human immunodeficiency virus type 1 (HIV-1) activity. SDZ NIM 811 selectively inhibits HIV-1 replication in T4 lymphocyte cell lines, in a monocytic cell line, and in HeLa T4 cells. Furthermore, its antiviral activity against laboratory strains and against clinical isolates from geographically distinct regions in primary T4 lymphocytes and in primary monocytes (50% inhibitory concentration = 0.011 to 0.057 micrograms/ml) was demonstrated. SDZ NIM 811 does not inhibit proviral gene expression or virus-specific enzyme functions, either free or bound to cyclophilin. The compound does not influence CD4 expression or inhibit fusion between virus-infected and uninfected cells. SDZ NIM 811 was, however, found to block formation of infectious particles from chronically infected cells. Oral administration to mice, rats, dogs, and monkeys resulted in levels in blood considerably exceeding the drug concentration, which completely blocked virus replication in primary cells. SDZ NIM 811 caused changes of toxicity parameters in rats to a smaller degree than cyclosporine (formerly cyclosporin A). Thus, the potent and selective anti-HIV-1 activity of SDZ NIM 811 and its favorable pharmacokinetic behavior together with its lower nephrotoxicity than that of cyclosporine make this compound a promising candidate for development as an anti-HIV drug.

Rosenwirth, B; Billich, A; Datema, R; Donatsch, P; Hammerschmid, F; Harrison, R; Hiestand, P; Jaksche, H; Mayer, P; Peichl, P

1994-01-01

224

Neutralization and system effectiveness  

SciTech Connect

Security forces that can neutralize an attack force are essential to effectively safeguard special nuclear material (SNM) against theft or sabotage. Probability of neutralization, P(N), estimates the likelihood that security forces will win given that security forces interrupt the attackers and begin an armed engagement. Brief Adversary Threat Loss Estimator (BATLE) calculates P(N). BATLE was developed for the Nuclear Regulatory Commission in 1980. This paper describes a total repackaging of BATLE which will be called the Threat Neutralization Model. New features and capabilities are (1) guidance to the user in setting up the input parameters, (2) faster software, (3) graphical output and sensitivity curves to assist the user in interpreting the results, (4) compatibility with the SAVI vulnerability analysis program, and (5) operation under Microsoft Windows on personal computers.

Paulus, W.K.

1988-01-01

225

History of Primary Immunodeficiency Diseases in Iran  

PubMed Central

Pediatric immunology came into sight in the second half of 20th century, when pediatricians and basic immunologists began to give attention to diagnosis and treatment of children with primary immunodeficiency diseases (PIDs). Understanding the genetic and mechanistic basis of PIDs provides unique insight into the functioning of the immune system. By progress in basic and clinical immunology, many infrastructural organizations and academic centers have been established in many countries worldwide to focus on training and research on the immune system and related disorders. Along with progress in basic and clinical immunology in the world, pediatric immunology had a good progress in Iran during the last 33-year period. Now, patients with PIDs can benefit from multidisciplinary comprehensive care, which is provided by clinical immunologists in collaboration with other specialists. Patients with history of recurrent and/or chronic infections suggestive of PIDs are evaluated by standard and research-based testing and receive appropriate treatment. The progress in PIDs can be described in three periods. Development of training program for clinical fellowship in allergy and immunology, multidisciplinary and international collaborative projects, primary immunodeficiency diseases textbooks, meetings on immunodeficiency disorders, improvement in diagnosis and treatment, and construction of Iranian primary immunodeficiency association, Students' research group for immunodeficiencies, Iranian primary immunodeficiency registry, and the immunological societies and centers were the main activities on PIDs during these years. In this article, we review the growth of modern pediatric immunology and PIDs status in Iran.

Aghamohammadi, Asghar; Moin, Mostafa; Rezaei, Nima

2010-01-01

226

Chimeric Plant Virus Particles as Immunogens for Inducing Murine and Human Immune Responses against Human Immunodeficiency Virus Type 1  

Microsoft Academic Search

The high-yield expression of a neutralizing epitope from human immunodeficiency virus type 1 (HIV-1) on the surface of a plant virus and its immunogenicity are presented. The highly conserved ELDKWA epitope from glycoprotein (gp) 41 was expressed as an N-terminal translational fusion with the potato virus X (PVX) coat protein. The resulting chimeric virus particles (CVPs), purified and used to

CARLA MARUSIC; PAOLA RIZZA; LAURA LATTANZI; CAMILLO MANCINI; MASSIMO SPADA; FILIPPO BELARDELLI; EUGENIO BENVENUTO; IMERIO CAPONE

2001-01-01

227

Inhibition of Anti-V3 Domain Antibody Binding to Human Immunodeficiency Virus Type1Infected Cells by Sulfated Polysaccharides  

Microsoft Academic Search

The third variable domain (V3 domain) of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 is an immunodominant region. Anti-V3 domain antibodies neutralize both HTV-1 infection and syncytium formation. The V3 domain has a high density of positive charge which is a potential binding site for anti-HTV-1 sulfated polysaccharides. To investigate the inhibitory effect of sulfated polysaccharides on

T. Okada; B. K. Patterson; M. E. Gurney

1995-01-01

228

Prevention and treatment of human immunodeficiency virus\\/acquired immunodeficiency syndrome in resource- limited settings  

Microsoft Academic Search

Strategies for confronting the epidemic of human immunodeficiency virus\\/acquired immunodeficiency syndrome (HIV\\/AIDS) have included a range of different approaches that focus on prevention and treatment. However, debate persists over what levels of emphasis are appropriate for the different components of the global response. This paper presents an overview of this debate and briefly summarizes the evidence on a range of

Daniel R. Hogan; Joshua A. Salomon

2005-01-01

229

Antiretroviral therapeutic possibilities for human immunodeficiency virus\\/acquired immunodeficiency syndrome  

Microsoft Academic Search

In human immunodeficiency virus (HIV)\\/acquired immunodeficiency syndrome (AIDS) illness, the reverse transcriptase and protease (PRT) enzymes of HIV are currently the targets of antiretroviral (ARV) therapy. Nucleoside analogues were the first group of ARV drugs that exerted antiviral activity in patients. More recently, PRT inhibitors have provided new approaches in the treatment of HIV infection and AIDS. Impressive clinical results

G. A Balint

2001-01-01

230

Simian Immunodeficiency Virus Integration Preference Is Similar to That of Human Immunodeficiency Virus Type 1  

Microsoft Academic Search

Simian immunodeficiency virus (SIV) is a useful model for studying human immunodeficiency virus (HIV) pathogenesis and vaccine efficacy. As with all other retroviruses, integration is a necessary step in the replication cycle of SIV. The location of the retrovirus integration site is known to impact on viral gene expression, establishment of viral latency, and other aspects of the replication cycle

Bruce Crise; Yuan Li; Chiuchin Yuan; David R. Morcock; Denise Whitby; David J. Munroe; Larry O. Arthur; Xiaolin Wu

2005-01-01

231

Association of Non-Acquired Immunodeficiency Syndrome-Defining Cancers With Human Immunodeficiency Virus Infection  

Microsoft Academic Search

Kaposi's sarcoma and non-Hodgkin's lymphoma were among the earliest recognized manifestations of the acquired immunodeficiency syndrome (AIDS) epidemic. Excluding these two tumors, the overall risk of all other cancers in human immunodeficiency virus (HIV)-infected individuals is similar to that of the general population. However, varying levels of evidence link several additional neoplasms to HIV infection. The evidence is strongest for

Charles S. Rabkin

232

Human Papillomavirus-Associated Cancers in Patients With Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome  

Microsoft Academic Search

Background: Human papillomavirus (HPV)-associated ano- genital malignancies occur frequently in patients with hu- man immunodeficiency virus (HIV) infection and the ac- quired immunodeficiency syndrome (AIDS). The purpose of our study was to determine if the high frequency of these cancers is due to lifestyle factors associated with both HPV and HIV infections or to immunosuppression following HIV infection. Methods: We

Morten Frisch; Robert J. Biggar; James J. Goedert

233

CCR5 Signal Transduction in Macrophages by Human Immunodeficiency Virus and Simian Immunodeficiency Virus Envelopes  

Microsoft Academic Search

The capacity of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) envelopes to transduce signals through chemokine coreceptors on macrophages was examined by measuring the ability of recombinant envelope proteins to mobilize intracellular calcium stores. Both HIV and SIV envelopes mobilized calcium via interactions with CCR5. The kinetics of these responses were similar to those observed when macrophages were

JAMES ARTHOS; ANDREA RUBBERT; RONALD L. RABIN; CLAUDIA CICALA; ELIZABETH MACHADO; KATHRYNE WILDT; MEREDITH HANBACH; TAVIS D. STEENBEKE; RUTH SWOFFORD; JOSHUA M. FARBER; ANTHONY S. FAUCI

2000-01-01

234

Bleach Neutralizes Mold Allergens  

ERIC Educational Resources Information Center

|Researchers at National Jewish Medical and Research Center have demonstrated that dilute bleach not only kills common household mold, but may also neutralize the mold allergens that cause most mold-related health complaints. The study, published in the Journal of Allergy and Clinical Immunology, is the first to test the effect on allergic…

Science Teacher, 2005

2005-01-01

235

Ultracold Neutral Plasmas.  

National Technical Information Service (NTIS)

By photoionizing a sample of laser-cooled xenon atoms, we create ultracold neutral plasmas with initial temperatures of 1-1000 K and densities as high as l0(exp10)/cu cm. The plasma is formed by the trapping of electrons by the residual positive charge th...

M. J. Lim S. Kulin S. L. Rolston T. C. Killian

2002-01-01

236

Bleach Neutralizes Mold Allergens  

ERIC Educational Resources Information Center

Researchers at National Jewish Medical and Research Center have demonstrated that dilute bleach not only kills common household mold, but may also neutralize the mold allergens that cause most mold-related health complaints. The study, published in the Journal of Allergy and Clinical Immunology, is the first to test the effect on allergic…

Science Teacher, 2005

2005-01-01

237

Solar Neutral Particles  

NASA Video Gallery

This animation shows a neutral solar particle's path leaving the sun, following the magnetic field lines out to the heliosheath. The solar particle hits a hydrogen atom, stealing its electron, and we follow it until we see it hit one of IBEX's detectors.

Holly Zell

2010-08-12

238

Neutralizing antibodies against calcitonin.  

PubMed

The use of calcitonin (CT) is established as a treatment of Paget's disease of bone and postmenopausal osteoporosis (PMO). Salmon calcitonin (sCT), which differs in 14 of the 32 amino acids from human calcitonin, has found a wider distribution world wide, although antibody formation against sCT has been reported in more than 70% of the patients on continuous sCT treatment. The clinical significance of these antibodies has been discussed controversially, because the occurrence of antibodies is not always associated with the development of secondary resistance. Using an in vitro bioassay, based on the CT-mediated increase of the cyclic AMP (cAMP) production of the human breast cancer cell line T 47 D we could identify a neutralizing activity against sCT in the serum of a subset of patients with formation of antibodies against sCT which was related to the development of secondary resistance. Antibody formation against human calcitonin (hCT) has been reported only once before. Binding and neutralizing antibodies were now observed in 1 of 33 patients with PMO treated with hCT. Due to a low neutralizing activity, clinical sequelae were not to be expected in this patient. The formation of neutralizing antibodies against calcitonin is common after treatment with salmon but a rare phenomenon after treatment with human calcitonin. We recommend monitoring of patients with postmenopausal osteoporosis and Paget's disease of bone on long term treatment with sCT or hCT for neutralizing antibody formation in order to evaluate the therapeutic effect of treatment. PMID:8225203

Grauer, A; Reinel, H H; Ziegler, R; Raue, F

1993-09-01

239

Protection in Macaques Immunized with HIV-1 Candidate Vaccines Can Be Predicted Using the Kinetics of Their Neutralizing Antibodies  

PubMed Central

Background A vaccine is needed to control the spread of human immunodeficiency virus type 1 (HIV-1). An in vitro assay that can predict the protection induced by a vaccine would facilitate the development of such a vaccine. A potential candidate would be an assay to quantify neutralization of HIV-1. Methods and Findings We have used sera from rhesus macaques that have been immunized with HIV candidate vaccines and subsequently challenged with simian human immunodeficiency virus (SHIV). We compared neutralization assays with different formats. In experiments with the standardized and validated TZMbl assay, neutralizing antibody titers against homologous SHIVSF162P4 pseudovirus gave a variable correlation with reductions in plasma viremia levels. The target cells used in the assays are not just passive indicators of virus infection but are actively involved in the neutralization process. When replicating virus was used with GHOST cell assays, events during the absorption phase, as well as the incubation phase, determine the level of neutralization. Sera that are associated with protection have properties that are closest to the traditional concept of neutralization: the concentration of antibody present during the absorption phase has no effect on the inactivation rate. In GHOST assays, events during the absorption phase may inactivate a fixed number, rather than a proportion, of virus so that while complete neutralization can be obtained, it can only be found at low doses particularly with isolates that are relatively resistant to neutralization. Conclusions Two scenarios have the potential to predict protection by neutralizing antibodies at concentrations that can be induced by vaccination: antibodies that have properties close to the traditional concept of neutralization may protect against a range of challenge doses of neutralization sensitive HIV isolates; a window of opportunity also exists for protection against isolates that are more resistant to neutralization but only at low challenge doses.

Davis, David; Koornstra, Wim; Mortier, Daniella; Fagrouch, Zahra; Verschoor, Ernst J.; Heeney, Jonathan L.; Bogers, Willy M. J. M.

2011-01-01

240

Neutral particle beam intensity controller  

DOEpatents

A neutral beam intensity controller is provided for a neutral beam generator in which a neutral beam is established by accelerating ions from an ion source into a gas neutralizer. An amplitude modulated, rotating magnetic field is applied to the accelerated ion beam in the gas neutralizer to defocus the resultant neutral beam in a controlled manner to achieve intensity control of the neutral beam along the beam axis at constant beam energy. The rotating magnetic field alters the orbits of ions in the gas neutralizer before they are neutralized, thereby controlling the fraction of neutral particles transmitted out of the neutralizer along the central beam axis to a fusion device or the like. The altered path or defocused neutral particles are sprayed onto an actively cooled beam dump disposed perpendicular to the neutral beam axis and having a central open for passage of the focused beam at the central axis of the beamline. Virtually zero therough 100% intensity control is achieved by varying the magnetic field strength without altering the ion source beam intensity or its species yield.

Dagenhart, William K. (Oak Ridge, TN)

1986-01-01

241

True Neutrality, Complementary Principle and the Neutrality of Our Universe  

Microsoft Academic Search

The criteria of true neutrality would infer that the neutrino is not a truly neutral particle and thus would imply that betabetaonu decay is forbidden, in agreement with the absence of any evidence of this process so far. Any fundamental interaction admits at least one truly neutral particle as messenger. Materialization through SM interactions corresponds to the creation of a

Tsan Ung Chan

1998-01-01

242

Heterosis or Neutrality?  

PubMed Central

Various statistics have been proposed on an ad hoc basis to test whether alleles at a locus are selectively neutral. By considering population models in which selection operates, this paper shows that the population homozygosity is a powerful test statistic for testing departures from neutrality, in the direction of heterozygote advantage or disadvantage. The sample homozygosity plays a similar role when only sample data are available. Some numerical examples are included, showing the application of the test.—An analysis is made of the effect of heterosis on such quantities as the expected number of alleles in the population or sample, the effective number of alleles, the expected homozygosity, and on the population and sample allele frequency distributions generally.

Watterson, G. A.

1977-01-01

243

Antihypertensive neutral lipid  

DOEpatents

The invention relates to the discovery of a class of neutral acetylated ether-linked glycerolipids having the capacity to lower blood pressure in warm-blooded animals. This physiological effect is structure sensitive requiring a long chain alkyl group at the sn-1 position and a short carbon chain acyl group (acetyl or propionyl) at the sn-2 position, and a hydroxyl group at the sn-3 position.

Snyder, Fred L. (Oak Ridge, TN); Blank, Merle L. (Oak Ridge, TN)

1986-01-01

244

Neutral beams for mirrors  

SciTech Connect

An important demonstration of negative ion technology is proposed for FY92 in the MFTF-..cap alpha..+T, an upgrade of the Mirror Fusion Test Facility at the Lawrence Livermore National Laboratory. This facility calls for 200-keV negative ions to form neutral beams that generate sloshing ions in the reactor end plugs. Three different beam lines are considered for this application. Their advantages and disadvantages are discussed.

Fink, J.H.

1983-08-31

245

Common variable immunodeficiency complicated with hemolytic uremic syndrome  

PubMed Central

Common variable immunodeficiency is a primary immunodeficiency disease characterized by reduced serum immunoglobulins and heterogeneous clinical features. Recurrent pyogenic infections of upper and lower respiratory tracts are the main clinical manifestations of common variable immunodeficiency. Hemolytic uremic syndrome is a multisystemic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia due to platelet aggregation in the arterial microvasculature. This is one of the rare cases of patients diagnosed with common variable immunodeficiency, which was complicated by hemolytic uremic syndrome.

2012-01-01

246

[Adenosine deaminase in severe combined immunodeficiency syndrome].  

PubMed

Adenosine deaminase is an enzyme of the purine metabolism whose function is to convert adenosine to inosine and deoxyadenosine to deoxyinosine. The ecto-ADA1 binding to the cell surface through CD26 contributes to the regulation of cytokines and stimulates the proliferation of T cells by activating CD45. The deficiency of this enzyme generates the severe combined immunodeficiency syndrome, characterized by the accumulation of deoxyadenosine and adenine metabolites, which have toxic effects on lymphocytes, affecting DNA synthesis and consequently, clonal expansion. Early diagnosis of this immunodeficiency is essential, as it significantly reduces morbidity and mortality associated with recurrent infections. Recent advances in molecular biology and genetics have led to the identification of genetic defects of many primary immunodeficiencies and the development of promising diagnostic tools and treatment. PMID:23248974

Pérez-Aguilar, Mary Carmen; Goncalves, Loredana; Bonfante-Cabarcas, Rafael

2012-09-01

247

Gene therapy of primary T cell immunodeficiencies.  

PubMed

Gene therapy of severe combined immunodeficiencies has been proven to be effective to provide sustained correction of the T cell immunodeficiencies. This has been achieved for 2 forms of SCID, i.e SCID-X1 (?c deficiency) and adenosine deaminase deficiency. Occurrence of gene toxicity generated by integration of first generation retroviral vectors, as observed in the SCID-X1 trials has led to replace these vectors by self inactivated (SIN) retro(or lenti) viruses that may provide equivalent efficacy with a better safety profile. Results of ongoing clinical studies in SCID as well as in other primary immunodeficiencies, such as the Wiskott Aldrich syndrome, will be thus very informative. PMID:23583799

Fischer, Alain; Hacein-Bey-Abina, Salima; Cavazzana-Calvo, Marina

2013-04-10

248

Structure of simian immunodeficiency virus regulatory genes.  

PubMed Central

Three full-length cDNA clones were obtained from cells infected with the simian immunodeficiency virus (SIV) isolated from captive macaques (SIVMAC). Nucleotide sequence analyses suggested that these represented mRNA for the SIV MAC genes tat, rev (formerly, art/trs), and nef (formerly, 3'orf). The putative tat-specific clone was active in trans-activation of the SIV MAC long terminal repeat in COS-1 and Jurkat cells. In contrast, the human immunodeficiency virus 1 long terminal repeat was significantly trans-activated only in the COS-1 cells. This suggests that trans-activation by the SIV tat gene is modulated by cell-specific factors. The structure of all of the clones suggested an mRNA splicing pattern more complex than that described for human immunodeficiency virus 1. Images

Colombini, S; Arya, S K; Reitz, M S; Jagodzinski, L; Beaver, B; Wong-Staal, F

1989-01-01

249

DNA Banking of Primary Immunodeficiency Disorders in Iran  

Microsoft Academic Search

Primary immunodeficiency disorders are a heterogeneous group of genetic disorders, with different modes of inheritance, consisting of more than 100 different types. We constructed the DNA banking of primary immunodeficiency disorders for the first time in Iran. The DNA of 31 immunodeficient patients and their families (total of 92 samples) were collected, as the first step for construction of DNA

Anna Isaian; Mostafa Moin; Zahra Pourpak; Nima Rezaei; Asghar Aghamohammadi; Masoud Movahedi; Mohammad Gharagozlou; Javad Ghaffari; Fariborz Zandieh; Mahboubeh Mansouri; Abolhassan Farhoudi

250

Retrovirus-induced Immunodeficiency and Cancer  

Microsoft Academic Search

\\u000a Malignant disease represents a major complication of human immunodeficiency virus-1 (HIV)-induced immunodeficiency in the\\u000a setting of AIDS. Three cancers have been identified as AIDS-defining conditions, including Kaposi’s sarcoma, non-Hodgkin’s\\u000a lymphomas, and invasive cervical carcinoma. In addition, classical Hodgkin’s lymphoma, anal cancer, and other cancers are\\u000a increased in incidence and\\/or severity in the context of HIV infection and AIDS. AIDS-associated malignancies

Laura S. Levy

251

Anti-human IG and B lymphocytes reconstitute the proliferative response to Con A of T lymphocytes depleted of accessory cells  

SciTech Connect

The requirements for the induction of proliferation of human peripheral blood mononuclear cells (PBM) by low concentrations of Concanavalin A (Con A) were studied using /sup 3/H-thymidine incorporation to assay DNA synthesis. Removal of plastic-adherent cells from PBM reduced the proliferative response of lymphocytes to Con A by 80%. Passage of these cells over nylon wool columns totally eliminated their response to Con A. Addition of adherent monocytes or rabbit anti-human IgG conjugated to polyacrylamide beads (anti-IgG beads) to the non-adherent lymphocyte population reconstituted the proliferative response. The lymphoblasts activated in these cultures were more than 90% T11 positive. Anti-IgG beads did not activate lymphocyte proliferation in the absence of Con A. The response of non-adherent lymphocytes to Con A could also be reconstituted by unconjugated rabbit anti-human IgG antiserium. Purified T cells could only be activated by anti-IgG beads and low concentrations of Con A in the presence of irradiated B cells. These results suggest that /sup 3/H-thymidine incorporation by T cells induced by anti-IgG beads and a low concentration of Con A depends on the interaction of anti-IgG and B cells. The authors suggest that B cell produce growth factors for T cells after interacting with anti-IgG.

Tsuda, T.; Kim, Y.T.; Schwab, R.; Siskind, G.W.; Weksler, M.E.

1986-03-01

252

Therapeutic Drug Monitoring in Human Immunodeficiency Virus\\/Acquired Immunodeficiency Syndrome  

Microsoft Academic Search

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), and it is estimated that 42 million people\\u000a are infected with HIV. Four classes of drugs are used today to treat people with AIDS; nucleoside reverse transcriptase (NRTIs),\\u000a non-NRTIs (NNRTIs), protease inhibitors (PIs), and entry blockers (EIs). Evidence is accumulating that both PIs and NNRTIs\\u000a are good candidates for therapeutic drug

Steven J. Soldin

253

Metabolic Syndromes in Human Immunodeficiency Virus Infection  

Microsoft Academic Search

Infection with human immunodeficiency virus (HIV) is associated with marked disturbance of metabolism affecting the metabolism of carbohydrates, fats and proteins. In the first decade of clinical experience of HIV, the primary clinical manifestation of such disturbed metabolism was wasting. Such wasting was often severe and contributed significantly to the morbidity and mortality of AIDS. Mechanistic studies demonstrated that in

Derek C. Macallan

2001-01-01

254

Women at Risk for Human Immunodeficiency Virus.  

ERIC Educational Resources Information Center

|This article reports results from a survey among women at risk for contracting Human Immunodeficiency Virus (HIV) as well as transmitting it in a vertical (to offspring) and horizontal (sexual partner or intravenous [IV] drug usage) mode. Little is known about the extent of HIV knowledge, sexual behaviors, and IV drug usage for women at risk for…

Quadagno, David; And Others

255

Prevalence of Primary Immunodeficiency in Korea  

PubMed Central

This study represents the first epidemiological study based on the national registry of primary immunodeficiencies (PID) in Korea. Patient data were collected from 23 major hospitals. A total of 152 patients with PID (under 19 yr of age), who were observed from 2001 to 2005, have been entered in this registry. The period prevalence of PID in Korea in 2005 is 11.25 per million children. The following frequencies were found: antibody deficiencies, 53.3% (n = 81), phagocytic disorders, 28.9% (n = 44); combined immunodeficiencies, 13.2% (n = 20); and T cell deficiencies, 4.6% (n = 7). Congenital agammaglobulinemia (n = 21) and selective IgA deficiency (n = 21) were the most frequently reported antibody deficiency. Other reported deficiencies were common variable immunodeficiencies (n = 16), X-linked agammaglobulinemia (n = 15), IgG subclass deficiency (n = 4). Phagocytic disorder was mostly chronic granulomatous disease. A small number of patients with Wiskott-Aldrich syndrome, hyper-IgE syndrome, and severe combined immunodeficiency were also registered. Overall, the most common first manifestation was pneumonia. This study provides data that permit a more accurate estimation PID patients in Korea.

Rhim, Jung Woo; Kim, Kyung Hyo; Kim, Dong Soo; Kim, Bong Seong; Kim, Jung Soo; Kim, Chang Hwi; Kim, Hwang Min; Park, Hee Ju; Pai, Ki Soo; Son, Byong Kwan; Shin, Kyung Sue; Oh, Moo Young; Woo, Young Jong; Yoo, Young; Lee, Kun Soo; Lee, Kyung Yil; Lee, Chong Guk; Lee, Joon Sung; Chung, Eun Hee; Choi, Eun Hwa; Hahn, Youn Soo; Park, Hyun Young

2012-01-01

256

Histopathology of acute human immunodeficiency virus exanthema  

Microsoft Academic Search

Acute exanthema occurs in patients who are human immunodeficiency virus (HIV) positive before they become seropositive. The patients have influenza like symptoms and a macular skin rash on the upper trunk. Histopathological investigation of skin punch biopsy specimens from four patients with acute HIV exanthema showed a normal epidermis and a sparse dermal, mainly perivascular, lymphocytic\\/histiocytic infiltrate around vessels of

E Balslev; H K Thomsen; K Weismann

1990-01-01

257

A recombinant live attenuated measles vaccine vector primes effective HLA-A0201-restricted cytotoxic T lymphocytes and broadly neutralizing antibodies against HIV1 conserved epitopes  

Microsoft Academic Search

Live attenuated measles vaccine (MV) could provide a safe and efficient pediatric vaccination vector to immunize children simultaneously against measles and human immunodeficiency virus type 1 (HIV-1). To evaluate the capacity of a vector derived from the certified Schwarz measles vaccine (MVSchw) to prime effective cytotoxic T cells (CTL) and broad neutralizing antibodies against HIV-1 conserved epitopes, we generated recombinant

Clarisse Lorin; Frédéric Delebecque; Valérie Labrousse; Lucie Da Silva; François Lemonnier; Michel Brahic; Frédéric Tangy

2005-01-01

258

Duodenal enteroglucagonoma revealed by differential comparison of serum and tissue glucagon reactivity with Siemens' Double Glucagon Antibody and DakoCytomation's Polyclonal Rabbit Anti-Human Glucagon: a case report  

PubMed Central

Introduction This case report demonstrates that the differential immunohistochemical reactivities of Siemens' Double Antibody Glucagon compared to DakoCytomation's Polyclonal Rabbit Anti-Human Glucagon allow for pathologic distinction of enteral versus pancreatic glucagonoma. Case presentation A 64-year-old Caucasian man was diagnosed with a duodenal enteroglucagonoma following presentation with obstructive jaundice. He had a low serum glucagon level using Siemens' Double Antibody Glucagon, a clinical syndrome consistent with glucagon hypersecretion. A periampullary mass biopsy proved to be a neuroendocrine tumor, with positive immunohistochemical reactivity to DakoCytomation's Polyclonal Rabbit Anti-Human Glucagon. Conclusions Differential comparison of the immunohistochemical reactivities of Siemens' Double Antibody Glucagon and DakoCytomation's Polyclonal Rabbit Anti-Human Glucagon discerns enteroglucagon from pancreatic glucagon.

2010-01-01

259

Depletion of alveolar macrophages decreases the dissemination of a glucosylceramide-deficient mutant of Cryptococcus neoformans in immunodeficient mice.  

PubMed

In previous studies we showed that a Cryptococcus neoformans mutant lacking glucosylceramide (Deltagcs1) is avirulent and unable to reach the brain when it is administered intranasally into an immunocompetent mouse and is contained in a lung granuloma. To determine whether granuloma formation is key for containment of C. neoformans Deltagcs1, we studied the role of C. neoformans glucosylceramide in a T- and NK-cell-immunodeficient mouse model (Tgepsilon26) in which alveolar macrophages (AMs) are not activated and granuloma formation is not expected. The results show that Tgepsilon26 mice infected with Deltagcs1 do not produce a lung granuloma and that the Deltagcs1 mutant proliferates in the lungs and does disseminate to the brain, although its virulence phenotype is dramatically reduced. Since Deltagcs1 can grow only in acidic niches, such as the phagolysosome of AMs, and not in neutral or alkaline environments, such as the extracellular spaces, we hypothesize that in immunodeficient mice Deltagcs1 proliferates inside AMs. Indeed, we found that depletion of AMs significantly improved Tgepsilon26 mouse survival and decreased the dissemination of Deltagcs1 cells to the central nervous system. Thus, these results suggest that the growth of Deltagcs1 in immunodeficient mice is maintained within AMs. This study highlights the hypothesis that AMs may exacerbate C. neoformans infection in conditions in which there is severe host immunodeficiency. PMID:17664261

Kechichian, Talar B; Shea, John; Del Poeta, Maurizio

2007-07-30

260

Neutrals as brokers of peacebuilding ideas?  

Microsoft Academic Search

Neutral and alliance-free states continue to exist. Even though neutrality has lost its realistic survival function, it continues to serve as provider of national identity for neutral states. This identity is rooted in neutrality’s idealistic function, according to which neutral states used to engage for humanitarian issues and the reduction of violence in international relations. The argument developed suggests an

Laurent Goetschel

2011-01-01

261

Cryoprotectant toxicity neutralization.  

PubMed

Cryoprotectant toxicity is a fundamental limiting factor for the successful cryopreservation of living systems by both freezing and vitrification, and the ability to negate it would be attractive. Past attempts to demonstrate "cryoprotectant toxicity neutralization" (CTN) have had many ups and downs. First convincingly introduced by Baxter and Lathe in 1971, the concept that certain amides can block toxic effects of dimethyl sulfoxide (Me(2)SO) was contradicted by direct experiments in 1990. But in 1995, the opposite mode of CTN, in which Me(2)SO blocked the damaging effects of formamide, was robustly demonstrated. Recent experiments have verified the original 1995 results and extended them to urea and acetamide, but no CTN was detected for N-methylamides (N-methylformamide, N,N-dimethylformamide, and N-methylacetamide). On the theory that the latter amides and acetamide might serve as low-toxicity structural analogs of formamide, urea, or Me(2)SO, competition experiments were carried out between them and formamide or urea, but CTN was not observed for these amide-amide systems. The idea that the N-methylamides might have non-specific rather than specific toxicity was supported by the fact that the concentrations of these amides that cause toxicity are similar to the concentrations that denature model proteins. Clear examples of neutralization of the toxicity of glycerol, propylene glycol, ethylene glycol, or Me(2)SO are presently lacking, but effects of the latter that depend on sulfhydryl oxidation have been reversed with reducing agents. In summary, CTN is a useful phenomenon with significant theoretical and practical implications. PMID:19501081

Fahy, Gregory M

2009-06-06

262

Fish oil enhancement of 131I-conjugated anti-human milk fat globule monoclonal antibody experimental radioimmunotherapy of breast cancer.  

PubMed

BALB/c nude mice (nu/nu) carrying established human transplantable breast tumors (MX-1) and fed fat from either fish oil (MaxEPA), corn oil, or lard, were treated with either an unconjugated mixture or an 131I-labeled cocktail of Mc1, Mc3, Mc5 and Mc8 four anti-human milk fat globule monoclonal antibodies (MoAbs). MaxEPA diet by itself reduced mean volume of tumor MX-1 to 36% below that of both the corn oil and lard diets. Injection of unconjugated MoAbs reduced tumor volumes only in corn oil fed nude mice when each group was compared to their respective controls. Treatment with 131I-MoAbs produced large tumor volume reductions in all groups with the three different diets. The greatest reduction was obtained with the synergistic effect of MaxEPA and 131I-labeled MoAbs. PMID:2626013

Blank, E W; Cerian, R L

1989-01-01

263

Novel Inhibitory Effects of ?-Glutamylcysteine Ethyl Ester against Human Immunodeficiency Virus Type 1 Production and Propagation  

PubMed Central

The anti-human immunodeficiency virus type I (anti-HIV-1) effects of ?-glutamylcysteine ethyl ester (?-GCE; TEI-2306) were examined in vitro. In initial studies using a vigorously HIV-1-producing human T-lymphocytic cell line, ?-GCE displayed a novel biphasic repressive effect on chronic HIV-1 infection that was unlike that of other glutathione prodrugs or other reported antioxidants. In high doses, up to a concentration of 2.5 mM, at which neither glutathione (GSH) nor another GSH precursor has shown inhibitory effects, ?-GCE potently inhibited the production of HIV-1 by a selective cytopathic effect against infected cells, while the viability and growth of uninfected cells were unaffected at the same ?-GCE concentrations. At lower concentrations (200 to 400 ?M), ?-GCE significantly repressed the virus production from chronically HIV-1-expressing cells without affecting their viability. The discrepancy of the thresholds of the toxic doses between infected and uninfected cells was found to be more than 10-fold. Relatively high doses of ?-GCE, utilized in acute HIV-1 infection of T-lymphocytic cells, entirely blocked the propagation of HIV-1 and rescued the cells from HIV-1-induced cell death. Furthermore, ?-GCE at such concentrations was found to directly inhibit the infectivity of HIV-1 within 4 h. Repressive effects of ?-GCE on acute HIV-1 infection in human primary human peripheral blood mononuclear cells were also demonstrated. Here, the anti-HIV-1 strategy utilizing ?-GCE is removal of both HIV-1-producing cells and free infectious HIV-1 in vitro, in place of specific immunoclearance in vivo, which might lead to an arrest or slowing of viral propagation in HIV-1-infected individuals.

Kubota, Satoshi; Shetty, Shubhra; Zhang, Huizhong; Kitahara, Shigehisa; Pomerantz, Roger J.

1998-01-01

264

Neutralizing antibody prevents type D retrovirus viremia in Celebes black macaques.  

PubMed

The Celebes black macaque (Macaca nigra) colony at the Oregon Regional Primate Research Center has a high incidence of simian acquired immunodeficiency syndrome (SAIDS-RF) that may be caused by type D retrovirus type 2 (SRV-2). During the spring and autumn screening of the colony, seven monkeys previously aviremic were found to be viremic on the basis of the Raji co-culture assay. These monkeys and control groups were selected for further study, which included titration of neutralizing antibody activity and immunofluorescent antibody (IFA) activity before and at the time that the animals became viremic. Results indicated that neutralizing antibody was not present before or at the time that monkeys became viremic and that control monkeys who were IFA+ and did not become viremic had high levels of neutralizing antibody. The IFA titre did not change significantly or predictably at the time the animals became viremic. PMID:3791698

Wilson, B J; Shiigi, S M; Zeigler, J L; Olson, L C; Malley, A; Howard, C F

1986-08-01

265

Michellamine B, a novel plant alkaloid, inhibits human immunodeficiency virus-induced cell killing by at least two distinct mechanisms.  

PubMed Central

Studies of the mechanism of action of michellamine B, a novel anti-human immunodeficiency virus (HIV) alkaloid from the tropical plant Ancistrocladus korupensis, have revealed that the compound acts at two distinct stages of the HIV life cycle. The compound had no direct effect on HIV virions and did not block the initial binding of HIV to target cells. Postinfection time course studies revealed that the agent partially inhibited HIV-induced cell killing and syncytium formation when added up to 48 h following acute infection; however, viral reproduction was fully inhibited only when the compound was added immediately after infection. Time-limited treatments of HIV-infected cells revealed that michellamine B had to be present continuously to provide maximum antiviral protection. HIV replication in cells in which infection was already fully established or in chronically infected cells was unaffected by michellamine B. Biochemical studies showed that michellamine B inhibited the enzymatic activities of reverse transcriptases (RTs) from both HIV type 1 and HIV type 2 as well as two different nonnucleoside drug-resistant RTs with specific amino acid substitutions. In addition, human DNA polymerases alpha and beta were inhibited by the alkaloid. Michellamine B exerted a potent dose-dependent inhibition of cell fusion in two independent cell-based fusion assays. Thus, michellamine B acts both at an early stage of the HIV life cycle by inhibiting RT as well as at later stages by inhibiting cellular fusion and syncytium formation.

McMahon, J B; Currens, M J; Gulakowski, R J; Buckheit, R W; Lackman-Smith, C; Hallock, Y F; Boyd, M R

1995-01-01

266

Organising pneumonia in common variable immunodeficiency.  

PubMed

Common variable immunodeficiency (CVID) is the most common of the primary immunodeficiency disorders. Pulmonary manifestations are characterised by recurrent rhinosinusitis, respiratory tract infections and bronchiectasis. Less commonly the lung may be affected by lymphoid disorders and sarcoid-like granulomas. Organising pneumonia (OP) is a rare pulmonary manifestation. We report the case of a 32-year-old woman with CVID who presented with fever, dyspnoea and persistent lung infiltrates despite antibiotic therapy. CT of the chest showed bilateral patchy alveolar infiltrates. Pulmonary function tests revealed moderate restriction and reduction in diffusion capacity. Initial bronchoscopy with transbronchial biopsies did not yield a diagnosis but surgical lung biopsies identified OP. Significant clinical, radiographic and physiological improvement was achieved after institution of corticosteroid therapy. PMID:23749855

Boujaoude, Ziad; Arya, Rohan; Rafferty, William; Dammert, Pedro

2013-06-07

267

NEUTRAL-BEAM INJECTION  

SciTech Connect

The emphasis in the preceding chapters has been on magnetic confinement of high temperature plasmas. The question of production and heating of such plasmas has been dealt with relatively more briefly. It should not be inferred, however, that these matters must therefore be either trivial or unimportant. A review of the history reveals that in the early days all these aspects of the controlled fusion problem were considered to be on a par, and were tackled simultaneously and with equal vigor. Only the confinement problem turned out to be much more complex than initially anticipated, and richer in challenge to the plasma physicist than the questions of plasma production and heating. On the other hand, the properties of high-temperature plasmas and plasma confinement can only be studied experimentally after the problems of production and of heating to adequate temperatures are solved. It is the purpose of this and the next chapter to supplement the preceding discussions with more detail on two important subjects: neutral-beam injection and radio-frequency heating. These are the major contenders for heating in present and future tokamak and mirror fusion experiments, and even in several proposed reactors. For neutral beams we emphasize here the technology involved, which has undergone a rather remarkable development. The physics of particle and energy deposition in the plasma, and the discussion of the resulting effects on the confined plasma, have been included in previous chapters, and some experimental results are quoted there. Other heating processes of relevance to fusion are mentioned elsewhere in this book, in connection with the experiments where they are used: i.e. ohmic heating, adiabatic compression heating, and alpha-particle heating in Chapter 3 by H.P. Furth; more ohmic heating in Chapter 7, and shock-implosion heating, laser heating, and relativistic-electron beam heating in Chapter 8, both by W. E. Quinn. These methods are relatively straightforward in their physics and their technology, or in any case they are considered to be adequately covered by these other authors.

Kunkel, W.B.

1980-06-01

268

Human Immunodeficiency Virus Infection and Pregnancy  

PubMed Central

The human immunodeficiency virus (HIV) epidemic is clearly one of the most serious health-care crises in the professional lives of contemporary physicians. It cannot be regarded as a curiosity to be dealt with by inner-city infectious-disease experts, but rather must be considered a problem for all health-care providers and a problem in which the obstetrician-gynecologist has a special role to play.

1994-01-01

269

Genetic Defects of Apoptosis and Primary Immunodeficiency  

PubMed Central

Synopsis Programmed cell death is important for maintaining lymphocyte homeostasis. Several human inherited diseases with impaired apoptosis have been identified at the genetic level: autoimmune lymphoproliferative syndrome (ALPS), caspase-8 deficiency state (CEDS), and X-linked lymphoproliferative syndrome (XLP). These diseases feature excess lymphocyte accumulation, autoimmunity, and/or immunodeficiency. Elucidating their molecular pathogenesis has also provided new insights into the signaling mechanisms regulating apoptosis and lymphocyte activation.

Su, Helen C.; Lenardo, Michael J.

2009-01-01

270

Otitis Media in Children with Congenital Immunodeficiencies  

Microsoft Academic Search

Otitis media represents one of the most common infections in childhood. Within the first 3 years of life, up to 80% of children\\u000a experience at least one episode of otitis media. It is often resolved with supportive therapies and consequently not considered\\u000a a worrisome problem. However, it may be an early manifestation of a severe underlying disease. Primary immunodeficiencies\\u000a are rare

Simon Urschel

2010-01-01

271

Relationship between autoimmunity and immunodeficiency in CLL  

Microsoft Academic Search

B-CLL patients have a high prevalence of autoimmune phenomena due to polyclonal autoantibodies (Abs) restricted to blood cell self-antigens (Ag) and progressively develop a severe hypogammaglobulinemia. Autoimmunity and immunodeficiency have been related to B-CLL biological properties and cellular origin. Three major issues have emerged: 1) the relevance of B cell receptor abnormalities. More specifically, the importance of the defective expression

F. Caligaris-Cappio

1997-01-01

272

Immunodeficient Mouse Models of Lymphoid Tumors  

Microsoft Academic Search

Severe combined immunodeficient (SCID) mice lack functional T- and B-cells and readily accept human xenografts, including\\u000a hematopoietic malignancies.Accordingly, SCID mice have been used to study the growth and behavior of lymphoid tumors in vivo.\\u000a The SCID mouse models of disease mimic human diseases and have provided valuable information. However, this mouse strain has\\u000a some residual immunity that somewhat limits posttransplantation

Kazunori Imada

2003-01-01

273

Cytotoxicological Analysis of a gp120 Binding Aptamer with Cross-Clade Human Immunodeficiency Virus Type 1 Entry Inhibition Properties: Comparison to Conventional Antiretrovirals  

Microsoft Academic Search

The long-term cumulative cytotoxicity of antiretrovirals (ARVs) is among the major causes of treatment failure in patients infected with human immunodeficiency virus (HIV) and patients with AIDS. This calls for the development of novel ARVs with less or no cytotoxicity. In the present study, we compared the cytotoxic effects of a cross-clade HIV type 1-neutralizing aptamer called B40 with those

W. R. L. de Campos; D. Coopusamy; L. Morris; B. M. Mayosi; M. Khati

2009-01-01

274

Four nightmares for net neutrality  

Microsoft Academic Search

What is the economic substance behind net neutrality, the populist policy debate du jour? The authors assesses the basic economics behind net neutrality. To be sure, this debate has many arcane facets. For example, a couple years ago the FCC legally exempted US broadband firms - cable modem and DSL providers - from what are known as \\

Shane Greenstein

2006-01-01

275

Net neutrality and investment incentives  

Microsoft Academic Search

This article analyzes the effects of net neutrality regulation on investment incentives for Internet service providers (ISPs) and content providers (CPs), and their implications for social welfare. Concerning the ISPs' investment incentives, we find that capacity expansion decreases the sale price of the priority right under the discriminatory regime. Thus, contrary to ISPs' claims that net neutrality regulations would have

Jay Pil Choi; Byung-Cheol Kim

2010-01-01

276

The delusions of net neutrality  

Microsoft Academic Search

Service providers argue that if net neutrality is not enforced, they will have sufficient incentives to build special high-quality channels that will take the Internet to the next level of its evolution. But what if they do get their wish, net neutrality is consigned to the dustbin, and they do build their new services, but nobody uses them? If the

Andrew Odlyzko

2008-01-01

277

A general neutral profits tax  

Microsoft Academic Search

It is widely agreed that, in the absence of specific corrective aims, the corporate tax system should aim for neutrality. A fully neutral tax would not affect the scale of a company's activities, nor the allocation of investment spending between different assets, nor the method by which this investment is financed. Moreover these properties should also hold under changing economic

Michael P. Devereux; Harold Freeman

1991-01-01

278

Neutral hydrogen in interplanetary space  

Microsoft Academic Search

The theory and observations relevant to the problem of neutral hydrogen in interplanetary space are reviewed. Emphasis is placed on those theoretical problems whose treatment in the existing literature is not entirely satisfactory, but discussion of all significant observational and theoretical aspects of the interplanetary H problem is provided. Attention is also given to other neutral constituents (particularly He) that

Thomas E. Holzer

1977-01-01

279

Neutral theory and community ecology  

Microsoft Academic Search

I review the mathematical and biological aspects of Hubbell's (2001) neutral theory of species abundance for ecological communities, and clarify its historical connections with closely related approaches in population genetics. A selective overview of the empirical evidence for and against this theory is provided, with a special emphasis on tropical plant communities. The neutral theory predicts many of the basic

J. Chave

2004-01-01

280

High energy neutral particle analyzer  

Microsoft Academic Search

The paper describes a high energy neutral particle analyzer (HENPA) developed in the Ioffe Institute for the diagnostics of alpha particles in the megaelectronvolt energy range, as well as other charged fusion products and ion cyclotron resonance frequency-driven minority ions in a plasma. Megaelectronvolt ions can be neutralized in the plasma by charge exchange reactions with low energy atoms or

A. I Kislyakov; A. V Khudoleev; S. S Kozlovskij; M. P Petrov

1997-01-01

281

Nonprogressive and Progressive Primate Immunodeficiency Lentivirus Infections  

PubMed Central

Natural hosts for simian immunodeficiency virus (SIV)can be, and are often naturally, infected with species-specific SIVs, but do not develop acquired immunodeficiency syndrome (AIDS). These natural hosts maintain high SIV viral loads, but avoid immunodeficiency. Elucidating the mechanisms that allow natural hosts to co-exist with SIV without overt disease may provide crucial information for understanding AIDS pathogenesis. Over the past few years, several key features of natural SIV infections have been described in studies conducted predominantly in sooty mangabeys (SMs), African green monkeys (AGMs), and mandrills. Natural SIV hosts are able to avoid the chronic, generalized immune system activation that is associated with disease progression in HIV-infected individuals and are known to down-modulate the expression of the receptors for SIV. In this perspective we propose that a critical factor that differentiates nonprogressive from progressive HIV or SIV infection is the maintenance of T cell immune competence in the face of a virus that infects and kills CD4+ T cells Elucidation of the mechanisms underlying the preservation of immune function during and after the acute phase of natural SIV infection may lead to the design of novel preventive and therapeutic interventions for treatment of chronic HIV infection.

Brenchley, Jason M.; Silvestri, Guido; Douek, Daniel C.

2010-01-01

282

Attentiveness of pediatricians to primary immunodeficiency disorders  

PubMed Central

Background Primary immunodeficiency (PID) is a cluster of serious disorders that requires special alertness on the part of the medical staff for prompt diagnosis and management of the patient. This study explored PID knowledge and experience among pediatricians of wide educational backgrounds, practicing in the United Arab Emirates (UAE). Method A self-administered questionnaire was used to determine the competency of pediatricians in their knowledge of PID disorders. This study questionnaire included questions on PID signs and symptoms, syndromes associated with immunodeficiency, screening tests, interpreting laboratory tests and case management. The participants were 263 pediatricians of diverse education working in the 27 governmental hospitals in all regions of UAE. Results The overall performance of the pediatricians did not differ based on their age, gender, origin of certification, rank, or years of experience. Of the 50 questions, 20% of pediatricians answered correctly <60% of the questions, 76% answered correctly 60 to 79% of the questions, and 4% answered correctly ?80% of the questions. Seventeen of the 19 PID signs and symptoms were identified by 55 to 97%. Four of 5 syndromes associated with immunodeficiency were identified by 50 to 90%. Appropriate screening tests were chosen by 64 to 96%. Attention to the laboratory reference range values as function of patient age was notably limited. Conclusions There was a noteworthy deficiency in PID work-up. Therefore, implementing effective educational strategies is needed to improve the competency of pediatricians to diagnose and manage PID disorders.

2012-01-01

283

Feline Immunodeficiency Virus in South America  

PubMed Central

The rapid emergence of AIDS in humans during the period between 1980 and 2000 has led to extensive efforts to understand more fully similar etiologic agents of chronic and progressive acquired immunodeficiency disease in several mammalian species. Lentiviruses that have gene sequence homology with human immunodeficiency virus (HIV) have been found in different species (including sheep, goats, horses, cattle, cats, and several Old World monkey species). Lentiviruses, comprising a genus of the Retroviridae family, cause persistent infection that can lead to varying degrees of morbidity and mortality depending on the virus and the host species involved. Feline immunodeficiency virus (FIV) causes an immune system disease in domestic cats (Felis catus) involving depletion of the CD4+ population of T lymphocytes, increased susceptibility to opportunistic infections, and sometimes death. Viruses related to domestic cat FIV occur also in a variety of nondomestic felids. This is a brief overview of the current state of knowledge of this large and ancient group of viruses (FIVs) in South America.

Teixeira, Bruno M.; Hagiwara, Mitika K.; Cruz, Juliano C. M.; Hosie, Margaret J.

2012-01-01

284

Feline immunodeficiency virus in South America.  

PubMed

The rapid emergence of AIDS in humans during the period between 1980 and 2000 has led to extensive efforts to understand more fully similar etiologic agents of chronic and progressive acquired immunodeficiency disease in several mammalian species. Lentiviruses that have gene sequence homology with human immunodeficiency virus (HIV) have been found in different species (including sheep, goats, horses, cattle, cats, and several Old World monkey species). Lentiviruses, comprising a genus of the Retroviridae family, cause persistent infection that can lead to varying degrees of morbidity and mortality depending on the virus and the host species involved. Feline immunodeficiency virus (FIV) causes an immune system disease in domestic cats (Felis catus) involving depletion of the CD4+ population of T lymphocytes, increased susceptibility to opportunistic infections, and sometimes death. Viruses related to domestic cat FIV occur also in a variety of nondomestic felids. This is a brief overview of the current state of knowledge of this large and ancient group of viruses (FIVs) in South America. PMID:22590677

Teixeira, Bruno M; Hagiwara, Mitika K; Cruz, Juliano C M; Hosie, Margaret J

2012-03-14

285

V3 Loop Truncations in HIV1 Envelope Impart Resistance to Coreceptor Inhibitors and Enhanced Sensitivity to Neutralizing Antibodies  

Microsoft Academic Search

The V1\\/V2 region and the V3 loop of the human immunodeficiency virus type I (HIV-1) envelope (Env) protein are targets for neutralizing antibodies and also play an important functional role, with the V3 loop largely determining whether a virus uses CCR5 (R5), CXCR4 (X4), or either coreceptor (R5X4) to infect cells. While the sequence of V3 is variable, its length

Meg M. Laakso; Fang-Hua Lee; Beth Haggarty; Caroline Agrawal; Katrina M. Nolan; Mark Biscone; Josephine Romano; Andrea P. O. Jordan; George J. Leslie; Eric G. Meissner; Lishan Su; James A. Hoxie; Robert W. Doms

2007-01-01

286

Is science metaphysically neutral?  

PubMed

This paper challenges the claim that science is metaphysically neutral upheld by contenders of the separation of peacefully co-existent science and religion and by evolutionary theists. True, naturalistic metaphysical claims can neither be refuted nor proved and are thus distinct from empirical hypotheses. However, metaphysical assumptions not only regulate the theoretical and empirical study of nature, but are increasingly supported by the growing empirical body of science. This historically evolving interaction has contributed to the development of a naturalistic worldview that renounces the necessity of a transcendent god and of purposeful design. The thesis presented here differs not only from the claims of the "separatists" and of evolutionary theists. In pointing to the metaphysical aspects of science, I also criticize the failure of some evolutionary naturalists to distinguish between empirical and metaphysical contentions. Most important, based on the examination of science suggested here, creationists' false accusation that science is only a naturalistic dogma is refuted. Finally, the difficulties involved in the position endorsed here for the public support of evolution are acknowledged, taking into account the high religious profile of the American society and the social and political context in the US and in other countries. PMID:22771725

Fry, Iris

2012-07-05

287

Severe combined immunodeficiency due to adenosine deaminase deficiency.  

PubMed

Severe Combined Immunodeficiency is the term applied to a group of rare genetic disorders characterised by defective or absent T and B cell functions. Patients usually present in first 6 months of life with respiratory/gastrointestinal tract infections and failure to thrive. Among the various types of severe combined immunodeficiency, enzyme deficiencies are relatively less common. We report the case of a 6 years old girl having severe combined immunodeficiency due to adenosine deaminase deficiency. PMID:22764473

Hussain, Waqar; Batool, Asma; Ahmed, Tahir Aziz; Bashir, Muhammad Mukarram

2012-03-01

288

21 CFR 610.46 - Human immunodeficiency virus (HIV) âlookbackâ requirements.  

Code of Federal Regulations, 2013 CFR

...2013-04-01 false Human immunodeficiency virus (HIV) âlookbackâ requirements. 610...Agents § 610.46 Human immunodeficiency virus (HIV) âlookbackâ requirements...reactive for evidence of human immunodeficiency virus (HIV) infection when tested...

2013-04-01

289

21 CFR 610.46 - Human immunodeficiency virus (HIV) âlookbackâ requirements.  

Code of Federal Regulations, 2010 CFR

... false Human immunodeficiency virus (HIV) âlookbackâ requirements. 610.46...610.46 Human immunodeficiency virus (HIV) âlookbackâ requirements. ...evidence of human immunodeficiency virus (HIV) infection when tested under §...

2010-04-01

290

21 CFR 610.46 - Human immunodeficiency virus (HIV) âlookbackâ requirements.  

Code of Federal Regulations, 2010 CFR

... false Human immunodeficiency virus (HIV) âlookbackâ requirements. 610.46...610.46 Human immunodeficiency virus (HIV) âlookbackâ requirements. ...evidence of human immunodeficiency virus (HIV) infection when tested under §...

2009-04-01

291

Immunodeficiency and autoimmunity: lessons from systemic lupus erythematosus  

PubMed Central

Recent evidence suggests that systemic autoimmunity and immunodeficiency are not separate entities, but rather interconnected processes. Immunodeficiency results from distinct defects of the immune response and primarily presents as infections, but also frequently with autoimmune features. Systemic autoimmunity is the combined effect of multiple genetic variations, infectious and immunoregulatory factors that result in dominant autoimmune manifestations in addition to frequent and opportunistic infections. The overlap in disease manifestations and symptoms suggests that immunodeficiency should be considered in the presence of autoimmunity, and vice versa. In this review, we present the shared or similar aspects of immunodeficiency and autoimmunity using systemic lupus erythematosus as a paradigm and discuss the implications for clinical care.

Grammatikos, Alexandros P.; Tsokos, George C.

2011-01-01

292

Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus.  

PubMed

Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination. PMID:23552890

Liao, Hua-Xin; Lynch, Rebecca; Zhou, Tongqing; Gao, Feng; Alam, S Munir; Boyd, Scott D; Fire, Andrew Z; Roskin, Krishna M; Schramm, Chaim A; Zhang, Zhenhai; Zhu, Jiang; Shapiro, Lawrence; Mullikin, James C; Gnanakaran, S; Hraber, Peter; Wiehe, Kevin; Kelsoe, Garnett; Yang, Guang; Xia, Shi-Mao; Montefiori, David C; Parks, Robert; Lloyd, Krissey E; Scearce, Richard M; Soderberg, Kelly A; Cohen, Myron; Kamanga, Gift; Louder, Mark K; Tran, Lillian M; Chen, Yue; Cai, Fangping; Chen, Sheri; Moquin, Stephanie; Du, Xiulian; Joyce, M Gordon; Srivatsan, Sanjay; Zhang, Baoshan; Zheng, Anqi; Shaw, George M; Hahn, Beatrice H; Kepler, Thomas B; Korber, Bette T M; Kwong, Peter D; Mascola, John R; Haynes, Barton F

2013-04-03

293

Neutral current interactions in MINOS  

SciTech Connect

The Main Injector Neutrino Oscillation Search (MINOS) long-baseline experiment has been actively collecting beam data since 2005, having already accumulated 3 x 10{sup 20} protons-on-target (POT). The several million neutrinos per year observed at the Near detector may improve the existing body of knowledge of neutrino cross-sections and the Near-Far comparison of the observed energy spectrum neutral current events constrains oscillations into sterile neutrinos. MINOS capabilities of observing neutral current neutrino events are described and the employed methodology for event selection is discussed, along with preliminary results obtained. An outlook on the expected neutral current related contributions from MINOS is also presented.

Sousa, Alexandre; /Oxford U.

2007-07-01

294

Antigenicity and Immunogenicity of Transmitted/Founder, Consensus, and Chronic Envelope Glycoproteins of Human Immunodeficiency Virus Type 1  

PubMed Central

Human immunodeficiency virus type 1 (HIV-1) vaccine development requires selection of appropriate envelope (Env) immunogens. Twenty HIV-1 Env glycoproteins were examined for their ability to bind human anti-HIV-1 monoclonal antibodies (MAbs) and then used as immunogens in guinea pigs to identify promising immunogens. These included five Envs derived from chronically infected individuals, each representing one of five common clades and eight consensus Envs based on these five clades, as well as the consensus of the entire HIV-1 M group, and seven transmitted/founder (T/F) Envs from clades B and C. Sera from immunized guinea pigs were tested for neutralizing activity using 36 HIV-1 Env-pseudotyped viruses. All Envs bound to CD4 binding site, membrane-proximal, and V1/V2 MAbs with similar apparent affinities, although the T/F Envs bound with higher affinity to the MAb 17b, a CCR5 coreceptor binding site antibody. However, the various Envs differed in their ability to induce neutralizing antibodies. Consensus Envs elicited the most potent responses, but neutralized only a subset of viruses, including mostly easy-to-neutralize tier 1 and some more-difficult-to-neutralize tier 2 viruses. T/F Envs elicited fewer potent neutralizing antibodies but exhibited greater breadth than chronic or consensus Envs. Finally, chronic Envs elicited the lowest level and most limited breadth of neutralizing antibodies overall. Thus, each group of Env immunogens elicited a different antibody response profile. The complementary benefits of consensus and T/F Env immunogens raise the possibility that vaccines utilizing a combination of consensus and T/F Envs may be able to induce neutralizing responses with greater breadth and potency than single Env immunogens.

Tsao, Chun-Yen; Alam, S. Munir; Muldoon, Mark; Vandergrift, Nathan; Ma, Ben-Jiang; Lu, Xiaozhi; Sutherland, Laura L.; Scearce, Richard M.; Bowman, Cindy; Parks, Robert; Chen, Haiyan; Blinn, Julie H.; Lapedes, Alan; Watson, Sydeaka; Xia, Shi-Mao; Foulger, Andrew; Hahn, Beatrice H.; Shaw, George M.; Swanstrom, Ron; Montefiori, David C.; Gao, Feng; Haynes, Barton F.; Korber, Bette

2013-01-01

295

Severe immunodeficiency associated with a human immunodeficiency virus 1 NEF/3'-long terminal repeat transgene  

PubMed Central

We have generated several transgenic mouse strains carrying a human immunodeficiency virus 1 (HIV-1) NEF/3' long terminal repeat (LTR) transgene under control of a T cell-specific promoter-enhancer element, showing a depletion of CD4+ T cells in the thymus and periphery. The immunological functions of the line with the most dramatic changes in lymphocyte populations, B6/338L, were analyzed in greater detail. The presence of the transgene in the heterozygous animal is associated with a dominant severe immunodeficiency. Older animals develop lymph- adenopathy and splenomegaly. CD4+CD8+ and CD4+CD8- single positive thymocytes already are depleted in these mice at the earliest stages in ontogeny, and peripheral T cells are reduced in frequency and present cell surface marker expression, which is characteristic for memory and activated T cells. The immunological response of B6/338L mice to several viral infections is also greatly impaired. Thus, the HIV-1 NEF/3' LTR as transgene in T cells can cause immunodeficiency and disease with striking similarities to a known retrovirus-induced immunodeficiency called murine AIDS (H. C. Morse III, S. K. Chattopadhyay, M. Makino, T. N. Frederickson, A. W. Hugin, and J. W. Hartley. 1992. AIDS. 6:607).

1994-01-01

296

Gene-Based Immunotherapy for Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome  

Microsoft Academic Search

ABSTRACT More than 40 million people are infected with human immunodeficiency virus (HIV), and a successful vac- cine is at least a decade away. Although highly active antiretroviral therapy prolongs life, the maintenance of viral latency requires life-long treatment and results in cumulative toxicities and viral escape mutants. Gene therapy offers the promise to cure or prevent progressive HIV infection

Boro Dropulic; Carl H. June

2006-01-01

297

Update on the treatment of primary immunodeficiencies.  

PubMed

A general review of advances in the treatment of Primary Immunodeficiencies (PID) has been performed. Treatment with immunoglobulins is indicated in cases of humoral immunodeficiencies and in selected cases of combined immunodeficiencies. The use of intramuscular immunoglobulins in the treatment of PID was abandoned after obtaining the intravenous immunoglobulins, since these are much more effective and have fewer adverse effects. Now subcutaneous immunoglobulins are also available. Immunoglobulins help to keep the patients free of symptoms and infections as these substances are able to neutralise infectious agents, modulate and promote the immune response and favour phagocytosis. Adverse effects have been reported in 5-15 % of patients receiving IVIg, and patients with deficiencies of subclasses of IgG with IgA deficiency and/or anti-IgA antibodies are at risk of severe reactions. No severe adverse effects of subcutaneous immuneglobulins have been reported and the medication can be self-administered. The efficacy and safety of IVIg and SCIg are similar and SCIg administered at home is associated with better quality of life. Stem Cell Transplantation (SCT) in Primary Immunodeficiencies is aimed at restoring the number and/or function of lymphocytes or phagocytes. Matched, related or unrelated donors, or related haploidentical donors are selected. HLA class II mismatched unrelated donors are avoided owing to the risk of severe graft versus host disease (GVHD). Stem cells are obtained from bone marrow, cord blood or peripheral blood. Prophylactic immunossupression (as well as donor T lymphocyte depletion in haploidentical and unrelated donors) is performed to avoid or minimize GVHD. Less toxic "reduced intensity" protocols now exist for pre-transplantation conditioning, indicated to avoid graft rejection if there is residual T-lymphocyte immunity in the host. In the majority of Severe Combined Immunodeficiencies (SCID), SCT results in T lymphocytes graft and the antibody immunodeficiency persists in many cases. The results are better the earlier it is performed, with the absence of previous infections, and with the degree of matching. The patient must be maintained in a laminar flow room with broad anti-infectious prophylaxis and with the intravenous administration of gammaglobulin for a variable period. Many other complications can be expected. Gene therapy. Patients with PID are ideal candidates, as they are monogenic, the haematopoietic cells are easily obtained and virus replication is easy within them. Vectors (viruses) "infect" the stem cells of the patient's bone marrow, producing the transfection of the wild (healthy) gene in these cells. Encouraging results have been achieved in X-linked SCID as there are a number of patients who are considered "cured", although neoplastic processes have occurred due to the activation of proto-oncogenes close to the point of insertion of the external gene, using retroviruses as vectors; there are now trials with adenovirus, physical methods (direct injection...) and chemical methods (viral modification, artificial viruses...). Gene therapy has also been performed in patients with Chronic Granulomatous Disease and trials will improve in the future with changes in protocols used in oncology and infectious diseases. PMID:17923072

García, J M; Español, T; Gurbindo, M D; Casas C, C

298

Selective neutrality and enzyme kinetics  

Microsoft Academic Search

This article appeals to a recent theory of enzyme evolution to show that the properties, neutral or adaptive, which characterize\\u000a the observed allelic variation in natural populations can be inferred from the functional parameters, substrate specificity,\\u000a and reaction rate. This study delineates the following relations between activity variables, and the forces—adaptive or neutral—determining\\u000a allelic variation: (1) Enzymes with broad substrate

Lloyd Demetrius

1997-01-01

299

Sexual modes of transmission of the human immunodeficiency virus (HIV)  

Microsoft Academic Search

Soon after the Acquired Immunodeficiency Syndrome (AIDS) was initially described, the epidemiology of the syndrome suggested that a blood-borne, sexually transmitted agent was an important factor in the development of the syndrome. The identification and isolation of the human immunodeficiency virus (HIV) as the etiologic agent of AIDS, followed by the development of sensitive and specific assays for the detection

Randall A. Coates; Martin T. Schechter

1988-01-01

300

Topical Review Article: The Neuropathology of Pediatric Acquired Immunodeficiency Syndrome  

Microsoft Academic Search

Central nervous system disease has emerged as an important manifestation of acquired immunodeficiency syndrome in both the adult and pediatric populations, with neurologic abnormalities occurring in up to 90% of pediatric patients in some series. Neuropathologic studies, based primarily on the autopsy, have provided valuable insights into the spectrum and pathogenesis of acquired immunodeficiency syndrome-associated neurologic disorders, including primary human

Dennis K. Burns

1992-01-01

301

Skeletal muscle involvement in human immunodeficiency virus infection  

Microsoft Academic Search

In addition to muscle changes due to peripheral nervous system involvement, primary myopathic changes associated with the human immunodeficiency virus (HIV) have also been described. We studied seven cases: two had developed an acquired immunodeficiency syndrome (AIDS) four had seroconverted to HIV but were otherwise asymptomatic, one was HIV seronegative when the biopsy was performed and one was biopsied twice.

D. Hantai; J.-G. Fournier; R. Vazeux; H. Collin; M. Baudrimont; M. Fardeau

1991-01-01

302

Zidovudine Is Beneficial in Human Immunodeficiency Virus Associated Nephropathy  

Microsoft Academic Search

Human immunodeficiency virus associated nephropathy (Hivan) is a distinct renal disease described in patients infected with the human immunodeficiency virus (HIV). Hivan is characterized by a nephrotic syndrome, enlarged kidneys, a histologic finding of focal and segmental glomerulosclerosis, and a very rapid progression to end-stage renal disease (ESRD). No therapeutic intervention has been shown, in a prospective evaluation, to either

Onyekachi Ifudu; Sreepada Rao; Caridad C. Tan; Heidi Fleischman; Keith Chirgwin; Eli A. Friedman

1995-01-01

303

Immunological and genetic bases of new primary immunodeficiencies  

Microsoft Academic Search

Since 1952, when congenital agammaglobulinaemia was described by Bruton, the characterization of genetically defined immunodeficiencies in humans has been crucial for a better understanding of the biology of the innate and adaptive immune responses. This Review focuses on the characterization of new primary immunodeficiencies and disease-related genes. A series of primary defects of innate immunity have recently been discovered and

László Maródi; Luigi D. Notarangelo

2007-01-01

304

Impact of Simian Immunodeficiency Virus Infection on Chimpanzee Population Dynamics  

Microsoft Academic Search

Like human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus of chimpanzees (SIVcpz) can cause CD4+ T cell loss and premature death. Here, we used molecular surveillance tools and mathematical modeling to estimate the impact of SIVcpz infection on chimpanzee population dynamics. Habituated (Mitumba and Kasekela) and non-habituated (Kalande) chimpanzees were studied in Gombe National Park, Tanzania. Ape population sizes

Rebecca S. Rudicell; James Holland Jones; Emily E. Wroblewski; Gerald H. Learn; Yingying Li; Joel D. Robertson; Elizabeth Greengrass; Falk Grossmann; Shadrack Kamenya; Lilian Pintea; Deus C. Mjungu; Elizabeth V. Lonsdorf; Anna Mosser; Clarence Lehman; D. Anthony Collins; Brandon F. Keele; Jane Goodall; Beatrice H. Hahn; Anne E. Pusey; Michael L. Wilson

2010-01-01

305

The problem of human immunodeficiency virus (HIV) infection and transplantation  

Microsoft Academic Search

The problem of human immunodeficiency virus (HIV) infection and that of the acquired immunodeficiency syndrome (AIDS) are becoming increasingly important in clinical transplantation. The epidemiologic characteristics of this infection are important factors in determining the impact of this infection on transplant patients: in particular, the presence of a transmissible virus in the blood, tissues, and body fluids of even asymptomatic

Robert H. Rubin; Nina E. Tolkoff-Rubin

1988-01-01

306

Immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF)  

Microsoft Academic Search

The Immunodeficiency, Centromeric region instability, Facial anomalies syndrome (ICF) is a rare autosomal recessive disease described in about 50 patients worldwide and characterized by immunodeficiency, although B cells are present, and by characteristic rearrangements in the vicinity of the centromeres (the juxtacentromeric heterochromatin) of chromosomes 1 and 16 and sometimes 9. Other variable symptoms of this probably under-diagnosed syndrome include

Melanie Ehrlich; Kelly Jackson; Corry Weemaes

2006-01-01

307

Vendor neutral archive in PACS  

PubMed Central

An archive is a location containing a collection of records, documents, or other materials of historical importance. An integral part of Picture Archiving and Communication System (PACS) is archiving. When a hospital needs to migrate a PACS vendor, the complete earlier data need to be migrated in the format of the newly procured PACS. It is both time and money consuming. To address this issue, the new concept of vendor neutral archive (VNA) has emerged. A VNA simply decouples the PACS and workstations at the archival layer. This is achieved by developing an application engine that receives, integrates, and transmits the data using the different syntax of a Digital Imaging and Communication in Medicine (DICOM) format. Transferring the data belonging to the old PACS to a new one is performed by a process called migration of data. In VNA, a number of different data migration techniques are available to facilitate transfer from the old PACS to the new one, the choice depending on the speed of migration and the importance of data. The techniques include simple DICOM migration, prefetch-based DICOM migration, medium migration, and the expensive non-DICOM migration. “Vendor neutral” may not be a suitable term, and “architecture neutral,” “PACS neutral,” “content neutral,” or “third-party neutral” are probably better and preferred terms. Notwithstanding this, the VNA acronym has come to stay in both the medical IT user terminology and in vendor nomenclature, and radiologists need to be aware of its impact in PACS across the globe.

Agarwal, Tapesh Kumar; Sanjeev

2012-01-01

308

Immunodeficiency and infantile bone and joint infection.  

PubMed Central

Fifteen patients with infantile bone and joint infections were studied immunologically and clinically, 3 at the time of illness and 12 later. Abnormality of immunoglobulins, or complement, or phagocytes was found in 9 patients; 6 were within normal limits for the tests undertaken. Immunodeficiency is probably responsible for the subdued clinical signs of infection and for delayed diagnosis in some patients. It was also related to the extent of femoral head damage in infective arthritis of the hip and to the incidence of wound infection in late elective surgery. Images FIG. 1. FIG. 2. FIG. 3.

Kuo, K N; Lloyd-Roberts, G C; Orme, I M; Soothill, J F

1975-01-01

309

Screening for severe combined immunodeficiency in neonates  

PubMed Central

Severe combined immunodeficiency (SCID) is a rare disease that severely affects the cellular and humoral immune systems. Patients with SCID present with recurrent or severe infections and often with chronic diarrhea and failure to thrive. The disease is uniformly fatal, making early diagnosis essential. Definitive treatment is hematopoietic stem cell transplantation, with best outcomes prior to 3.5 months of age. Newborn screening for SCID using the T-cell receptor excision circle assay has revolutionized early identification of infants with SCID or severe T-cell lymphopenia.

Kelly, Brian T; Tam, Jonathan S; Verbsky, James W; Routes, John M

2013-01-01

310

HSV Neutralization by the Microbicidal Candidate C5A  

PubMed Central

Genital herpes is a major risk factor in acquiring human immunodeficiency virus type-1 (HIV-1) infection and is caused by both Herpes Simplex virus type 1 (HSV-1) and HSV-2. The amphipathic peptide C5A, derived from the non-structural hepatitis C virus (HCV) protein 5A, was shown to prevent HIV-1 infection but neither influenza nor vesicular stomatitis virus infections. Here we investigated the antiviral function of C5A on HSV infections. C5A efficiently inhibited both HSV-1 and HSV-2 infection in epithelial cells in vitro as well as in an ex vivo epidermal infection model. C5A destabilized the integrity of the viral HSV membrane. Furthermore, drug resistant HSV strains were inhibited by this peptide. Notably, C5A-mediated neutralization of HSV-1 prevented HIV-1 transmission. An in vitro HIV-1 transmigration assay was developed using primary genital epithelial cells and HSV infection increased HIV-1 transmigration. Treatment with C5A abolished HIV-1 transmigration by preventing HSV infection and by preserving the integrity of the genital epithelium that was severely compromised by HSV infection. In conclusion, this study demonstrates that C5A represents a multipurpose microbicide candidate, which neutralizes both HIV-1 and HSV, and which may interfere with HIV-1 transmission through the genital epithelium.

Chatterji, Udayan; van Loenen, Freek B.; Verjans, Georges M. G. M.; Geijtenbeek, Teunis B. H.; Gallay, Philippe A.

2011-01-01

311

HSV neutralization by the microbicidal candidate C5A.  

PubMed

Genital herpes is a major risk factor in acquiring human immunodeficiency virus type-1 (HIV-1) infection and is caused by both Herpes Simplex virus type 1 (HSV-1) and HSV-2. The amphipathic peptide C5A, derived from the non-structural hepatitis C virus (HCV) protein 5A, was shown to prevent HIV-1 infection but neither influenza nor vesicular stomatitis virus infections. Here we investigated the antiviral function of C5A on HSV infections. C5A efficiently inhibited both HSV-1 and HSV-2 infection in epithelial cells in vitro as well as in an ex vivo epidermal infection model. C5A destabilized the integrity of the viral HSV membrane. Furthermore, drug resistant HSV strains were inhibited by this peptide. Notably, C5A-mediated neutralization of HSV-1 prevented HIV-1 transmission. An in vitro HIV-1 transmigration assay was developed using primary genital epithelial cells and HSV infection increased HIV-1 transmigration. Treatment with C5A abolished HIV-1 transmigration by preventing HSV infection and by preserving the integrity of the genital epithelium that was severely compromised by HSV infection. In conclusion, this study demonstrates that C5A represents a multipurpose microbicide candidate, which neutralizes both HIV-1 and HSV, and which may interfere with HIV-1 transmission through the genital epithelium. PMID:21573158

de Witte, Lot; Bobardt, Michael D; Chatterji, Udayan; van Loenen, Freek B; Verjans, Georges M G M; Geijtenbeek, Teunis B H; Gallay, Philippe A

2011-05-06

312

The discovery, engineering and characterisation of a highly potent anti-human IL-13 fab fragment designed for administration by inhalation.  

PubMed

We describe the discovery, engineering and characterisation of a highly potent anti-human interleukin (IL)-13 Fab fragment designed for administration by inhalation. The lead candidate molecule was generated via a novel antibody discovery process, and the selected IgG variable region genes were successfully humanised and reformatted as a human IgG ?1 Fab fragment. Evaluation of the biophysical properties of a selection of humanised Fab fragments in a number of assays allowed us to select the molecule with the optimal stability profile. The resulting lead candidate, CA652.g2 Fab, was shown to have comparable activity to the parental IgG molecule in a range of in vitro assays and was highly stable. Following nebulisation using a mesh nebuliser, CA652.g2 Fab retained full binding affinity, functional neutralisation potency and structural integrity. Epitope mapping using solution nuclear magnetic resonance confirmed that the antibody bound to the region of human IL-13 implicated in the interaction with IL-13R?1 and IL-13R?2. The work described here resulted in the discovery and design of CA652.g2 human ?1 Fab, a highly stable and potent anti-IL-13 molecule suitable for delivery via inhalation. PMID:23219467

Lightwood, Daniel; O'Dowd, Victoria; Carrington, Bruce; Veverka, Vaclav; Carr, Mark D; Tservistas, Markus; Henry, Alistair J; Smith, Bryan; Tyson, Kerry; Lamour, Sabrina; Bracher, Marguerite; Sarkar, Kaushik; Turner, Alison; Lawson, Alastair D; Bourne, Tim; Gozzard, Neil; Palframan, Roger

2012-12-03

313

Magnetic nanocomposite of anti-human IgG/COOH-multiwalled carbon nanotubes/Fe?O? as a platform for electrochemical immunoassay.  

PubMed

An electrochemical immunosensing method was developed based on a magnetic nanocomposite. The multiwalled carbon nanotubes (MWCNTs) were treated with nitric acid to produce carboxyl groups at the open ends. Then, Fe?O? nanoparticles were deposited on COOH-MWCNTs by chemical coprecipitation of Fe²? and Fe³? salts in an alkaline solution. Goat anti-human IgG (anti-hIgG) was covalently attached to magnetic nanocomposite through amide bond formation between the carboxylic groups of MWCNTs and the amine groups of anti-hIgG. The prepared bio-nanocomposite was used for electrochemical sensing of human tetanus IgG (hIgG) as a model antigen. The anti-hIgG magnetic nanocomposite was fixed on the surface of a gold plate electrode using a permanent magnet. The hIgG was detected using horseradish peroxidase (HRP)-conjugated anti-hIgG in a sandwich model. Electrochemical detection of hIgG was carried out in the presence of H?O? and KI as substrates of HRP. Using this method, hIgG was detected in a concentration range from 30 to 1000 ng ml?¹ with a correlation coefficient of 0.998 and a detection limit of 25 ng ml?¹ (signal/noise=3). The designed immunosensor was stable for 1 month. PMID:22245258

Zarei, Hajar; Ghourchian, Hedayatollah; Eskandari, Khadijeh; Zeinali, Majid

2011-12-28

314

C-terminal tail of human immunodeficiency virus gp41: functionally rich and structurally enigmatic.  

PubMed

The human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) pandemic is amongst the most important current worldwide public health threats. While much research has been focused on AIDS vaccines that target the surface viral envelope (Env) protein, including gp120 and the gp41 ectodomain, the C-terminal tail (CTT) of gp41 has received relatively little attention. Despite early studies highlighting the immunogenicity of a particular CTT sequence, the CTT has been classically portrayed as a type I membrane protein limited to functioning in Env trafficking and virion incorporation. Recent studies demonstrate, however, that the Env CTT has other important functions. The CTT has been shown to additionally modulate Env ectodomain structure on the cell and virion surface, affect Env reactivity and viral sensitivity to conformation-dependent neutralizing antibodies, and alter cell-cell and virus-cell fusogenicity of Env. This review provides an overview of the Env structure and function with a particular emphasis on the CTT and recent studies that highlight its functionally rich nature. PMID:23079381

Steckbeck, Jonathan D; Kuhlmann, Anne-Sophie; Montelaro, Ronald C

2012-10-17

315

Risk of Immunodeficiency Virus Infection May Increase with Vaccine-Induced Immune Response  

PubMed Central

To explore the efficacy of novel complementary prime-boost immunization regimens in a nonhuman primate model for HIV infection, rhesus monkeys primed by different DNA vaccines were boosted with virus-like particles (VLP) and then challenged by repeated low-dose rectal exposure to simian immunodeficiency virus (SIV). Characteristic of the cellular immune response after the VLP booster immunization were high numbers of SIV-specific, gamma interferon-secreting cells after stimulation with inactivated SIV particles, but not SIV peptides, and the absence of detectable levels of CD8+ T cell responses. Antibodies specific to SIV Gag and SIV Env could be induced in all animals, but, consistent with a poor neutralizing activity at the time of challenge, vaccinated monkeys were not protected from acquisition of infection and did not control viremia. Surprisingly, vaccinees with high numbers of SIV-specific, gamma interferon-secreting cells were infected fastest during the repeated low-dose exposures and the numbers of these immune cells in vaccinated macaques correlated with susceptibility to infection. Thus, in the absence of protective antibodies or cytotoxic T cell responses, vaccine-induced immune responses may increase the susceptibility to acquisition of immunodeficiency virus infection. The results are consistent with the hypothesis that virus-specific T helper cells mediate this detrimental effect and contribute to the inefficacy of past HIV vaccination attempts (e.g., STEP study).

Tenbusch, Matthias; Ignatius, Ralf; Temchura, Vladimir; Nabi, Ghulam; Tippler, Bettina; Stewart-Jones, Guillaume; Salazar, Andres M.; Sauermann, Ulrike; Stahl-Hennig, Christiane

2012-01-01

316

Health Administrator Perspectives on Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome Prevention and Services at Historically Black Colleges and Universities  

ERIC Educational Resources Information Center

|Objective: Due to the disproportionate impact of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) among African American young adults, the authors explored (1) number of historically black college and university (HBCU) campuses with existing HIV prevention policies and services and (2) perceived barriers for implementing…

Warren-Jeanpiere, Lari; Jones, Sandra; Sutton, Madeline Y.

2011-01-01

317

Determinants of risk behavior for human immunodeficiency virus\\/acquired immunodeficiency syndrome in people with severe mental illness  

Microsoft Academic Search

We examined the prevalence and correlates of human immunodeficiency virus (HIV)\\/acquired immunodeficiency syndrome (AIDS) risk behaviors in a large sample of severely mentally ill (SMI) patients. Risk levels were correlated with demographic factors, diagnosis, symptom severity, trauma history, post-traumatic stress disorder (PTSD), substance use disorder (SUD), and sexual orientation. SMI clients from urban and rural settings (N = 275) were

Stanley D. Rosenberg; Susan L. Trumbetta; Kim T. Mueser; Lisa A. Goodman; Fred C. Osher; Robert M. Vidaver; David S. Metzger

2001-01-01

318

Health Administrator Perspectives on Human Immunodeficiency Virus\\/Acquired Immunodeficiency Syndrome Prevention and Services at Historically Black Colleges and Universities  

Microsoft Academic Search

Objective: Due to the disproportionate impact of human immunodeficiency virus\\/acquired immunodeficiency syndrome (HIV\\/AIDS) among African American young adults, the authors explored (1) number of historically black college and university (HBCU) campuses with existing HIV prevention policies and services and (2) perceived barriers for implementing HIV prevention services. Methods: Semistructured telephone surveys were conducted with health administrators from 25 HBCUs. Results:

Lari Warren-Jeanpiere; Sandra Jones; Madeline Y. Sutton

2011-01-01

319

Modulation of Human Immunodeficiency Virus Type 1 Protease Autoprocessing by Charge Properties of Surface Residue 69?  

PubMed Central

Mature, fully active human immunodeficiency virus protease (PR) is liberated from the Gag-Pol precursor via regulated autoprocessing. A chimeric protease precursor, glutathione S-transferase-transframe region (TFR)-PR-FLAG, also undergoes N-terminal autocatalytic maturation when it is expressed in Escherichia coli. Mutation of the surface residue H69 to glutamic acid, but not to several neutral or basic amino acids, impedes protease autoprocessing in bacteria and mammalian cells. Only a fraction of mature PR with an H69E mutation (PRH69E) folds into active enzymes, and it does so with an apparent Kd (dissociation constant) significantly higher than that of the wild-type protease, corroborating the marked retardation of the in vitro N-terminal autocatalytic processing of TFR-PRH69E and suggesting a folding defect in the precursor.

Huang, Liangqun; Sayer, Jane M.; Swinford, Marie; Louis, John M.; Chen, Chaoping

2009-01-01

320

Modulation of human immunodeficiency virus type 1 protease autoprocessing by charge properties of surface residue 69.  

PubMed

Mature, fully active human immunodeficiency virus protease (PR) is liberated from the Gag-Pol precursor via regulated autoprocessing. A chimeric protease precursor, glutathione S-transferase-transframe region (TFR)-PR-FLAG, also undergoes N-terminal autocatalytic maturation when it is expressed in Escherichia coli. Mutation of the surface residue H69 to glutamic acid, but not to several neutral or basic amino acids, impedes protease autoprocessing in bacteria and mammalian cells. Only a fraction of mature PR with an H69E mutation (PR(H69E)) folds into active enzymes, and it does so with an apparent Kd (dissociation constant) significantly higher than that of the wild-type protease, corroborating the marked retardation of the in vitro N-terminal autocatalytic processing of TFR-PR(H69E) and suggesting a folding defect in the precursor. PMID:19457992

Huang, Liangqun; Sayer, Jane M; Swinford, Marie; Louis, John M; Chen, Chaoping

2009-05-20

321

Anti-V3 Humanized Antibody KD-247 Effectively Suppresses Ex Vivo Generation of Human Immunodeficiency Virus Type 1 and Affords Sterile Protection of Monkeys against a Heterologous Simian/Human Immunodeficiency Virus Infection  

PubMed Central

In an accompanying report (Y. Eda, M. Takizawa, T. Murakami, H. Maeda, K. Kimachi, H. Yonemura, S. Koyanagi, K. Shiosaki, H. Higuchi, K. Makizumi, T. Nakashima, K. Osatomi, S. Tokiyoshi, S. Matsushita, N. Yamamoto, and M. Honda, J. Virol. 80:5552-5562, 2006), we discuss our production of a high-affinity humanized monoclonal antibody, KD-247, by sequential immunization with V3 peptides derived from human immunodeficiency virus type 1 (HIV-1) clade B primary isolates. Epitope mapping revealed that KD-247 recognized the Pro-Gly-Arg V3 tip sequence conserved in HIV-1 clade B isolates. In this study, we further demonstrate that in vitro, KD-247 efficiently neutralizes CXCR4- and CCR5-tropic primary HIV-1 clade B and clade B? with matching neutralization sequence motifs but does not neutralize sequence-mismatched clade B and clade E isolates. Monkeys were provided sterile protection against heterologous simian/human immunodeficiency virus challenge by the passive transfer of a single high dose (45 mg per kg of body weight) of KD-247 and afforded partial protection by lower antibody doses (30 and 15 mg per kg). Protective neutralization endpoint titers in plasma at the time of virus challenge were 1:160 in animals passively transferred with a high dose of the antibody. The antiviral efficacy of the antibody was further confirmed by its suppression of the ex vivo generation of primary HIV-1 quasispecies in peripheral blood mononuclear cell cultures from HIV-infected individuals. Therefore, KD-247 promises to be a valuable tool not only as a passive immunization antibody for the prevention of HIV infection but also as an immunotherapy for the suppression of HIV in phenotype-matched HIV-infected individuals.

Eda, Yasuyuki; Murakami, Toshio; Ami, Yasushi; Nakasone, Tadashi; Takizawa, Mari; Someya, Kenji; Kaizu, Masahiko; Izumi, Yasuyuki; Yoshino, Naoto; Matsushita, Shuzo; Higuchi, Hirofumi; Matsui, Hajime; Shinohara, Katsuaki; Takeuchi, Hiroaki; Koyanagi, Yoshio; Yamamoto, Naoki; Honda, Mitsuo

2006-01-01

322

Common Themes of Antibody Maturation to Simian Immunodeficiency Virus, Simian-Human Immunodeficiency Virus, and Human Immunodeficiency Virus Type 1 Infections  

Microsoft Academic Search

Characterization of virus-specific immune responses to human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) is important to understanding the early virus-host interactions that may determine the course of virus infection and disease. Using a comprehensive panel of serological assays, we have previously demonstrated a complex and lengthy maturation of virus-specific antibody responses elicited by attenuated strains of

KELLY STEFANO COLE; MICHAEL MURPHEY-CORB; OPENDRA NARAYAN; SANJAY V. JOAG; GEORGE M. SHAW; RONALD C. MONTELARO; Marion Merrell Dow

1998-01-01

323

Primary immunodeficiencies of pattern recognition receptors.  

PubMed

Primary immunodeficiencies (PIDs) are severe defects in the capacity of the host to mount a proper immune response, and are characterized by an increased susceptibility to infections. Although classical immunodeficiencies have been characterized based on broad defects in cell populations (e.g. T/B cells or polymorphonuclear leukocytes) or humoral factors (e.g. antibodies or complement), specific immune defects based on well-defined molecular targets have been described more recently. Among these, genetic defects in pattern recognition receptors (PRRs), leading to impaired recognition of invading pathogens by the innate immune system, play an important role in specific defects against human pathogens. Defects have been described in three of the major families of PRRs: the Toll-like receptors, the C-type lectin receptors and the nucleotide-binding domain leucine-rich repeat-containing receptors. By contrast, no defects in the intracellular viral receptors of the RigI helicase family have been described to date. Defects in the PRRs show a broad variation in severity, have a narrow specificity for certain classes of pathogens, and often decrease in severity with age; these characteristics distinguish them from other forms of PIDs. Their discovery has led to important insights into the pathophysiology of infections, and may offer potential novel therapeutic targets for immunotherapy. PMID:22891878

Netea, M G; van de Veerdonk, F L; van der Meer, J W M

2012-09-12

324

Human immunodeficiency virus infection in childhood.  

PubMed

Acquired immunodeficiency syndrome is associated with considerable morbidity in infants and children. It is caused by human immunodeficiency virus (HIV) which can be transmitted vertically from mother to infant early in pregnancy. Transmission might also occur via breast milk. Although the exact transmission rate of HIV from mother to infant is not known, HIV can become a major threat to child survival. This threat is already present in Africa where high seroprevalences have been reported among infants and young children. Transmission via blood products is decreasing due to reliable methods of screening donors for HIV antibody. Where these tests are not available, parenteral transmission will increase the incidence of HIV infection. The clinical picture of HIV infection in children presents with failure to thrive, pulmonary interstitial pneumonitis, hepatosplenomegaly and recurrent bacterial infections. These are common manifestations of diseases prevalent in children in Africa where malnutrition and recurrent parasitic infections already cause immunosuppression. Recognition of the syndrome is therefore difficult. There is no available cure for HIV infection. Supportive treatment and relief of pain and suffering are the only means of management at present. Prevention of spread of the illness to infants and young children is therefore of paramount importance. PMID:2456715

Blokzijl, M L

1988-03-01

325

Combined Immunodeficiency Associated with DOCK8 Mutations  

PubMed Central

BACKGROUND Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown. METHODS We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss-of-expression mutations were confirmed by means of a quantitative reverse-transcriptase –polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry. RESULTS Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections. Most patients had severe atopy with anaphylaxis; several had squamous-cell carcinomas, and one had T-cell lymphoma –leukemia. Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common. Expansion in vitro of activated CD8 T cells was impaired. Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes. CONCLUSIONS Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency.

Zhang, Qian; Davis, Jeremiah C.; Lamborn, Ian T.; Freeman, Alexandra F.; Jing, Huie; Favreau, Amanda J.; Matthews, Helen F.; Davis, Joie; Turner, Maria L.; Uzel, Gulbu; Holland, Steven M.; Su, Helen C.

2010-01-01

326

[Human immunodeficiency virus-associated thrombotic microangiopathies].  

PubMed

Human immunodeficiency virus (HIV) infection represents a risk factor for thrombotic microangiopathy. HIV-associated thrombotic microangiopathies encompass two entities with distinct pathophysiology, clinical presentation, treatment and prognosis. Thrombotic thrombocytopenic purpura associated with human immunodeficiency virus is typically characterized by a sudden onset in a patient with a moderate immune deficiency and a few events of opportunistic diseases, and a profound acquired deficiency in the von Willebrand factor cleaving protease ADAMTS13. This diagnosis requires a well-codified management including daily therapeutic plasma exchanges, a highly active antiretroviral therapy and eventually immunomodulatory drugs. The prognosis is good with a response rate and an overall survival comparable to that of HIV-negative thrombotic thrombocytopenic purpura. On the opposite, HIV-associated thrombotic microangiopathy with a progressive onset that occurs in profoundly immunocompromised patients with past history of multiple opportunistic diseases usually have a detectable ADAMTS13 activity and a worse prognosis. Usual treatment is poorly efficient. Forthcoming studies should assess the role of immunomodulatory drugs such as rituximab in the setting of HIV-associated thrombotic microangiopathy, and identify possible risk factors associated with the occurrence of these diseases. PMID:22280852

Gilardin, L; Malak, S; Schoindre, Y; Galicier, L; Veyradier, A; Coppo, P

2012-01-26

327

Anti-idiotype monoclonal antibody elicits broadly neutralizing anti-gp120 antibodies in monkeys.  

PubMed Central

Murine monoclonal antibodies (mAbs) were raised against human, polyclonal, anti-gp120 antibodies (Ab1) and were selected for binding to broadly neutralizing anti-gp120 antibodies in sera positive for human immunodeficiency virus (HIV). One anti-idiotype mAb (Ab2), 3C9, was found to be specific for human anti-gp120 antibodies directed against an epitope around the conserved CD4 attachment site of gp120. The 3C9 reactive human anti-gp120 antibodies (3C9+ Ab) neutralized MN, IIIB, RF, and four primary isolates of HIV type 1 (HIV-1). Cynomolgus monkeys were immunized with 3C9 in adjuvant to test whether this anti-idiotype mAb could induce neutralizing anti-gp120 antibodies. The results show that purified anti-anti-idiotype antibodies (Ab3) from 3C9 immune sera bind to an epitope around the CD4 attachment site of gp120SF and gp120IIIB. Furthermore, purified gp120-specific Ab3 neutralize MN, IIIB, and RF isolates. These results demonstrate that primates immunized with an anti-idiotype mAb produce broadly neutralizing anti-HIV-1 antibodies. Since this anti-idiotype mAb was selected by identifying a clonotypic marker, its biological activity can be explained as the results of clonotypic B-cell stimulation.

Kang, C Y; Nara, P; Chamat, S; Caralli, V; Chen, A; Nguyen, M L; Yoshiyama, H; Morrow, W J; Ho, D D; Kohler, H

1992-01-01

328

Generation of infectious molecular clones of simian immunodeficiency virus from fecal consensus sequences of wild chimpanzees.  

PubMed

Studies of simian immunodeficiency viruses (SIVs) in their endangered primate hosts are of obvious medical and public health importance, but technically challenging. Although SIV-specific antibodies and nucleic acids have been detected in primate fecal samples, recovery of replication-competent virus from such samples has not been achieved. Here, we report the construction of infectious molecular clones of SIVcpz from fecal viral consensus sequences. Subgenomic fragments comprising a complete provirus were amplified from fecal RNA of three wild-living chimpanzees and sequenced directly. One set of amplicons was concatenated using overlap extension PCR. The resulting clone (TAN1.24) contained intact genes and regulatory regions but was replication defective. It also differed from the fecal consensus sequence by 76 nucleotides. Stepwise elimination of all missense mutations generated several constructs with restored replication potential. The clone that yielded the most infectious virus (TAN1.910) was identical to the consensus sequence in both protein and long terminal repeat sequences. Two additional SIVcpz clones were constructed by direct synthesis of fecal consensus sequences. One of these (TAN3.1) yielded fully infectious virus, while the second one (TAN2.69) required modification at one ambiguous site in the viral pol gene for biological activity. All three reconstructed proviruses produced infectious virions that replicated in human and chimpanzee CD4(+) T cells, were CCR5 tropic, and resembled primary human immunodeficiency virus type 1 isolates in their neutralization phenotype. These results provide the first direct evidence that naturally occurring SIVcpz strains already have many of the biological properties required for persistent infection of humans, including CD4 and CCR5 dependence and neutralization resistance. Moreover, they outline a new strategy for obtaining medically important "SIV isolates" that have thus far eluded investigation. Such isolates are needed to identify viral determinants that contribute to cross-species transmission and host adaptation. PMID:17494082

Takehisa, Jun; Kraus, Matthias H; Decker, Julie M; Li, Yingying; Keele, Brandon F; Bibollet-Ruche, Fréderic; Zammit, Kenneth P; Weng, Zhiping; Santiago, Mario L; Kamenya, Shadrack; Wilson, Michael L; Pusey, Anne E; Bailes, Elizabeth; Sharp, Paul M; Shaw, George M; Hahn, Beatrice H

2007-05-09

329

Generation of Infectious Molecular Clones of Simian Immunodeficiency Virus from Fecal Consensus Sequences of Wild Chimpanzees?  

PubMed Central

Studies of simian immunodeficiency viruses (SIVs) in their endangered primate hosts are of obvious medical and public health importance, but technically challenging. Although SIV-specific antibodies and nucleic acids have been detected in primate fecal samples, recovery of replication-competent virus from such samples has not been achieved. Here, we report the construction of infectious molecular clones of SIVcpz from fecal viral consensus sequences. Subgenomic fragments comprising a complete provirus were amplified from fecal RNA of three wild-living chimpanzees and sequenced directly. One set of amplicons was concatenated using overlap extension PCR. The resulting clone (TAN1.24) contained intact genes and regulatory regions but was replication defective. It also differed from the fecal consensus sequence by 76 nucleotides. Stepwise elimination of all missense mutations generated several constructs with restored replication potential. The clone that yielded the most infectious virus (TAN1.910) was identical to the consensus sequence in both protein and long terminal repeat sequences. Two additional SIVcpz clones were constructed by direct synthesis of fecal consensus sequences. One of these (TAN3.1) yielded fully infectious virus, while the second one (TAN2.69) required modification at one ambiguous site in the viral pol gene for biological activity. All three reconstructed proviruses produced infectious virions that replicated in human and chimpanzee CD4+ T cells, were CCR5 tropic, and resembled primary human immunodeficiency virus type 1 isolates in their neutralization phenotype. These results provide the first direct evidence that naturally occurring SIVcpz strains already have many of the biological properties required for persistent infection of humans, including CD4 and CCR5 dependence and neutralization resistance. Moreover, they outline a new strategy for obtaining medically important “SIV isolates” that have thus far eluded investigation. Such isolates are needed to identify viral determinants that contribute to cross-species transmission and host adaptation.

Takehisa, Jun; Kraus, Matthias H.; Decker, Julie M.; Li, Yingying; Keele, Brandon F.; Bibollet-Ruche, Frederic; Zammit, Kenneth P.; Weng, Zhiping; Santiago, Mario L.; Kamenya, Shadrack; Wilson, Michael L.; Pusey, Anne E.; Bailes, Elizabeth; Sharp, Paul M.; Shaw, George M.; Hahn, Beatrice H.

2007-01-01

330

Mutations in IRF8 and Human Dendritic Cell Immunodeficiency  

PubMed Central

Background The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in host defense against infections. Disseminated infection caused by BCG vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected individuals, the etiology of disseminated BCG disease is unexplained. Methods We investigated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, requiring hematopoietic stem cell transplantation. We also studied two otherwise healthy adults with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic cells compartments in these three persons and sequenced candidate genes, mutation of which could plausibly confer susceptibility to BCG disease. Results We detected two distinct disease-causing mutations affecting the transcriptional regulator IRF8. Both K108A and T80A mutations impair IRF8 transcriptional activity by disrupting IRF8 interaction with DNA. Mutation K108E was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. Mutation T80A was associated with an autosomal dominant milder immunodeficiency and a selective depletion of CD11c+ CD1c+ circulating dendritic cells. Conclusions These findings define a new class of human primary immunodeficiency, affecting the differentiation of mononuclear phagocytes. They also demonstrate that human IRF8 is critically required for the development of monocytes and dendritic cells and for anti-mycobacterial immunity.

Hambleton, Sophie; Salem, Sandra; Bustamante, Jacinta; Bigley, Venetia; Boisson-Dupuis, Stephanie; Azevedo, Joana; Fortin, Anny; Haniffa, Muzlifah; Ceron-Gutierrez, Lourdes; Bacon, Chris; Menon, Geetha; Trouillet, Celine; McDonald, David; Carey, Peter; Ginhoux, Florent; Alsina, Laia; Zumwalt, Timothy J; Kong, Xiaofei; Kumararatne, Dinakantha; Butler, Karina; Hubeau, Marjorie; Feinberg, Jacqueline; Al-Muhsen, Saleh; Cant, Andrew; Abel, Laurent; Chaussabel, Damien; Doffinger, Rainer; Talesnik, Eduardo; Grumach, Anete; Duarte, Alberto; Abarca, Katia; Moraes-Vasconcelos, Dewton; Burk, David; Berghuis, Albert; Geissmann, Frederic; Collin, Matthew; Casanova, Jean-Laurent; Gros, Philippe

2011-01-01

331

ATF neutral beam injection system  

SciTech Connect

The Advanced Toroidal Facility is a stellarator torsatron being built at Oak Ridge National Laboratory to investigate improved plasma confinement schemes. Plasmas heating will be carried out predominantly by means of neutral beam injection. This paper describes the basic parameters of the injection system. Numerical calculations were done to optimize the aiming of the injectors. The results of these calculations and their implications on the neutral power to the machine are elaborated. The effects of improving the beam optics and altering the focal length on the power transmitted to the plasma are discussed.

Menon, M.M.; Morris, R.N.; Edmonds, P.H.

1985-01-01

332

NEUTRALIZATION OF EPIDEMIC INFLUENZA VIRUS  

PubMed Central

A linear relationship exists between the logarithm of the quantity of epidemic influenza virus neutralized and the logarithm of the quantity of antiserum which is capable of achieving this result. This relationship is the same for the serum of a ferret convalescent from experimental influenza as for the serum of a rabbit immunized with the virus. By means of the linear relationship between virus and antiserum it is possible to determine a fixed, rather than a relative, value for the neutralizing capacity of a serum.

Horsfall, Frank L.

1939-01-01

333

Sensory neuropathy in human immunodeficiency virus\\/acquired immunodeficiency syndrome patients: Protease inhibitorâ??mediated neurotoxicity  

Microsoft Academic Search

Objective: Human immunodeficiency virus-associated sensory neuropathy (HIV-SN) is a common and disabling disorder, often associated with antiretroviral therapy (ART) use. We investigated the clinical features and associated pathogenic determinants of HIV-SN in a neurological cohort of HIV-infected patients, together with a novel model of HIV-SN. Methods: HIV-infected patients with neurological disease were investigated in terms of clinical and laboratory aspects

Jacqueline A. Pettersen; Gareth Jones; Catherine Worthington; Hartmut B. Krentz; Oliver T. Keppler; Ahmet Hoke; M. John Gill; Christopher Power

2006-01-01

334

Acquired Immunodeficiency Syndrome (AIDS), Human Immunodeficiency Virus (HIV) Infection, and Dialysis  

Microsoft Academic Search

\\u000a A new disease, Acquired Immuno Deficiency Syndrome (AIDS) was identified in the early 1980’s, when it was observed that an\\u000a unusually high number of otherwise healthy gay men in San Francisco, developed Kaposi’s sarcoma, and pneumocystis carinii\\u000a pneumonia (1, 2). Before the discovery of Human Immunodeficiency Virus (HIV) as the causative agent, and refinements were made in various\\u000a serological methods

T. K. Sreepada Rao

335

Elimination of nonspecific cytomegalovirus immunoglobulin M activities in the enzyme-linked immunosorbent assay by using anti-human immunoglobulin G.  

PubMed Central

Direct enzyme-linked immunosorbent assay methods offer several advantages in assessing past or recent exposure to cytomegalovirus (CMV) infection, but there persist many pitfalls in the use of these methods for determining specific immunoglobulin M (IgM). The efficiency of absorption of sera by IgG-coated latex beads, aggregated human IgG, or Staphylococcus aureus, i.e., for removing nonspecific CMV IgM activities, was evaluated in comparison with the effect of an anti-human IgG hyperimmune serum. Large routine series comprising serum samples from patients of various clinical groups and healthy individuals were examined. The CMV IgM-positive samples were at first treated with latex or aggregated IgG, but these absorptions left too many CMV IgM-positive individuals. S. aureus increased the nonspecific activity of some sera and, in other cases, removed or impaired specific IgM activities. The anti-IgG treatment caused the disappearance of nonspecific CMV IgM activities that had resisted the other treatments, whereas specific activities remained intact. Utilizing this method, only 1.03% of the routine series patients remained CMV IgM positive by the enzyme-linked immunosorbent assay, a figure in good agreement with a mean probability of CMV antibody acquisition of 0.33% for the population living in Belgium. On the other hand, in a series of patients who were investigated for serological response to several viruses, eight individuals displayed multiple IgM activities after anti-IgG treatment. In these cases, most IgM activities were found in patients who had IgG toward the related antigen for a long time before transient IgM was detected. This result implies that to assess a diagnosis of primary infection, it is necessary to examine serial specimens for IgG acquisition accompanying specific IgM.

Joassin, L; Reginster, M

1986-01-01

336

Elevated myeloid: plasmacytoid dendritic cell ratio associates with late, but not early liver rejection in children induced with, anti-human thymocyte globulin1  

PubMed Central

Background Dendritic cells (DC) play an important role in the induction and regulation of immune responses. Methods Myeloid CD11c+DC (MDC), which may have inflammatory functions, and plasmacytoid CD123+ DC (PDC), which may have tolerogenic potential, were measured by flow cytometric analysis, cross-sectionally, once, in 48 children, and longitudinally (pre-transplant, and at days 1–60, 61–200, 201–400 post transplant) in 30 children following liver transplantation (LTx). All children received 53/25 cadaveric/live donor liver allografts with rabbit anti-human thymocyte globulin (rATG) induction, and steroid-free Tacrolimus therapy. Rejectors in both groups were those children (n=35), who experienced biopsy-proven acute cellular rejection (ACR) within 60 days of DC monitoring. Results Among rejectors in the longitudinal and cross-sectional cohorts, the MDC: PDC ratio was higher, and was associated with decreased PDC frequencies. Logistic regression analysis, leave-one out cross-validation, and receiver operating characteristic analysis applied to 30 cross-sectional subjects revealed that an MDC:PDC ratio 1.78 was associated with rejector status with sensitivity/specificity of 76.9/88.2%. Sensitivity and specificity were replicated in the 18 remaining cross-sectional subjects (88.8 and 78.8%, respectively), but not in longitudinally-monitored subjects, during the early, 60-day period after LTx (30.76 and 62.50%, respectively). A significant negative correlation was observed between Tacrolimus whole blood concentrations and PDC frequencies (Spearman r = ?0.370, p=0.005) in 48 cross-sectional subjects in whom DC subsets were monitored 1–3 years after LTx, but not during the early post-LTx period. Conclusion We conclude that an elevated MDC: PDC ratio associates with liver graft rejection, which occurs after first year in children induced with rATG.

Gupta, Ankit; AshokKumar, Chethan; Ningappa, Mylarappa; Sun, Qing; Higgs, Brandon W; Snyder, Sara; Zeevi, Adriana; Thomson, Angus W; Mazariegos, George V; Sindhi, Rakesh

2009-01-01

337

Anti-human IgE monoclonal antibodies recognizing epitopes related to the binding sites of high and low affinity IgE receptors.  

PubMed

Anti-human IgE monoclonal antibodies (mAbs) were produced and eight clones recognizing epitopes on native IgE were selected. Epitopes were mapped by a competitive inhibition enzyme-linked immunosorbent assay, Western blotting and a multi-pin peptide technology. Four sites (one each in the C epsilon 1, C epsilon 2, C epsilon 2/C epsilon 3 junction and C epsilon 3) were recognized by the mAbs. The relationship between the four epitopes and the binding sites of high and low affinity IgE receptors (Fc epsilon RI and Fc epsilon RII, respectively) was studied using a monovalent Fab fragment of each mAb as a binding inhibitor. The IgE-Fc epsilon RII binding was clearly inhibited by the mAb recognizing the C epsilon 2/C epsilon 3 junction, suggesting that Fc epsilon RII binds to a rather limited area around the C epsilon 2/C epsilon 3 junction. The IgE-Fc epsilon RI binding, on the other hand, was scarcely inhibited by any single mAb. However, the binding was inhibited when the epitope in C epsilon 2 was blocked simultaneously with that at the C epsilon 2/C epsilon 3 junction or with that in C epsilon 3, indicating that these three distinct epitopes are related to the Fc epsilon RI binding sites. When these three epitopes were shown in the stereograph of human IgE, the Fc epsilon RI binding area was spread largely on the groove side between C epsilon 2 and C epsilon 3 domains. These results suggest that Fc epsilon RI acquires the high affinity through multiple bindings. PMID:7519718

Takemoto, H; Nishimura, S; Kosada, Y; Hata, S; Takagi, S; Hosoi, S; Ezumi, K; Ide, M; Harada, S

1994-01-01

338

Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti-human DEC205 monoclonal antibody  

PubMed Central

Protein vaccines for T-cell immunity are not being prioritized because of poor immunogenicity. To overcome this hurdle, proteins are being targeted to maturing dendritic cells (DCs) within monoclonal antibodies (mAbs) to DC receptors. To extend the concept to humans, we immunized human immunoglobulin-expressing mice with human DEC205 (hDEC205) extracellular domain. 3D6 and 3G9 mAbs were selected for high-affinity binding to hDEC205. In addition, CD11c promoter hDEC205 transgenic mice were generated, and 3G9 was selectively targeted to DCs in these animals. When mAb heavy chain was engineered to express HIV Gag p24, the fusion mAb induced interferon-?– and interleukin-2–producing CD4+ T cells in hDEC205 transgenic mice, if polynocinic polycytidylic acid was coadministered as an adjuvant. The T-cell response was broad, recognizing at least 3 Gag peptides, and high titers of anti-human immunoglobulin G antibody were made. Anti-hDEC205 also improved the cross-presentation of Gag to primed CD8+ T cells from HIV-infected individuals. In all tests, 3D6 and 3G9 targeting greatly enhanced immunization relative to nonbinding control mAb. These results provide preclinical evidence that in vivo hDEC205 targeting increases the efficiency with which proteins elicit specific immunity, setting the stage for proof-of-concept studies of these new protein vaccines in human subjects.

Cheong, Cheolho; Choi, Jae-Hoon; Vitale, Laura; He, Li-Zhen; Trumpfheller, Christine; Bozzacco, Leonia; Do, Yoonkyung; Nchinda, Godwin; Park, Sung Ho; Dandamudi, Durga Bhavani; Shrestha, Elina; Pack, Maggi; Lee, Han-Woong; Keler, Tibor

2010-01-01

339

Secondary Plasma Formation in Neutralization Cells associated with High Energy Neutral Beam Injectors  

Microsoft Academic Search

Neutral-beam injection is one of the more important techniques employed to heat the plasma in magnetically confined nuclear fusion experiments. Energetic neutral-beams are produced by accelerating charged particles, which are then neutralized in collisions with a low density gas in a neutralizer cell. The efficiency of such neutralizer cells is less in practice than is expected in theory on the

N. J. Fitzgerald; A. R. Ellingboe; M. M. Turner; B. Crowley

2004-01-01

340

Binding of Anti-Membrane-Proximal gp41 Monoclonal Antibodies to CD4-Liganded and -Unliganded Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus Virions  

PubMed Central

The broadly neutralizing monoclonal antibodies (MAbs) 4E10, 2F5, and Z13e1 target membrane-proximal external region (MPER) epitopes of HIV-1 gp41 in a manner that remains controversial. The requirements for initial lipid bilayer binding and/or CD4 ligation have been proposed. To further investigate these issues, we probed for binding of these MAbs to human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) virions with protein A-conjugated gold (PAG) nanoparticles using negative-stain electron microscopy. We found moderate levels of PAG associated with unliganded HIV-1 and SIV virions incubated with the three MAbs. Significantly higher levels of PAG were associated with CD4-liganded HIV-1 (epitope-positive) but not SIV (epitope-negative) virions. A chimeric SIV virion displaying the HIV-1 4E10 epitope also showed significantly higher PAG association after CD4 ligation and incubation with 4E10. MAbs accumulated rapidly on CD4-liganded virions and slowly on unliganded virions, although both reached similar levels in time. Anti-MPER epitope-specific binding was stable to washout. Virions incubated with an irrelevant MAb or CD4-only (no MAb) showed negligible PAG association, as did a vesicle-rich fraction devoid of virions. Preincubation with Fab 4E10 inhibited both specific and nonspecific 4E10 IgG binding. Our data provide evidence for moderate association of anti-MPER MAbs to viral surfaces but not lipid vesicles, even in the absence of cognate epitopes. Significantly greater MAb interaction occurs in epitope-positive virions following long incubation or CD4 ligation. These findings are consistent with a two-stage binding model where these anti-MPER MAbs bind first to the viral lipid bilayer and then to the MPER epitopes following spontaneous or induced exposure.

Rathinakumar, Ramesh; Dutta, Moumita; Zhu, Ping; Johnson, Welkin E.

2012-01-01

341

Acquired immunodeficiency syndrome: Ga-67 citrate imaging  

SciTech Connect

All gallium-67 citrate scans obtained in patients with acquired immunodeficiency syndrome (AIDS) at the Clinical Center, National Institutes of Health (Bethesda, Md.) were retrospectively analyzed and correlated with the results of bronchoscopy, chest radiography, and endoscopy. There were 164 scans of 95 patients. Twenty scans were from patients with Pneumocystis carinii pneumonia; 19 were abnormal, for a sensitivity of 95%. Ga-67 uptake tended to be less in patients receiving therapy for P. carinii pneumonia. Chest radiographs were normal at least initially in three patients with abnormal scans and P. carinii pneumonia. Unusually prominent colonic activity was associated with infection in some patients. No lesions of Kaposi sarcoma showed tracer uptake. Gallium scanning is useful for detecting P. carinii pneumonia and other opportunistic infections in patients with AIDS, but it is not useful for localizing Kaposi sarcoma.

Woolfenden, J.M.; Carrasquillo, J.A.; Larson, S.M.; Simmons, J.T.; Masur, H.; Smith, P.D.; Shelhamer, J.H.; Ognibene, F.P.

1987-02-01

342

Human immunodeficiency virus infection and the liver  

PubMed Central

Liver disease in human immunodeficiency virus (HIV)-infected individuals encompasses the spectrum from abnormal liver function tests, liver decompensation, with and without evidence of cirrhosis on biopsy, to non-alcoholic liver disease and its more severe form, non-alcoholic steatohepatitis and hepatocellular cancer. HIV can infect multiple cells in the liver, leading to enhanced intrahepatic apoptosis, activation and fibrosis. HIV can also alter gastro-intestinal tract permeability, leading to increased levels of circulating lipopolysaccharide that may have an impact on liver function. This review focuses on recent changes in the epidemiology, pathogenesis and clinical presentation of liver disease in HIV-infected patients, in the absence of co-infection with hepatitis B virus or hepatitis C virus, with a specific focus on issues relevant to low and middle income countries.

Crane, Megan; Iser, David; Lewin, Sharon R

2012-01-01

343

Mucosal Transmission of Human Immunodeficiency Virus  

PubMed Central

Since the beginning of the AIDS pandemic, and following the discovery of the human immunodeficiency virus (HIV) as the etiological agent of the disease, it was clear that the virus gains access to the human host predominantly through the mucosal tissue after sexual exposure. As a consequence, the female genital tract (vaginal and cervical), as well as the rectal, penile, and oral mucosae have been extensively studied over the last thirty years towards a better understanding of - and to develop strategies to prevent - sexual HIV transmission. This review seeks to describe the biology of the events leading to HIV infection through the human mucosa and introduce some of the approaches attempted to prevent the sexual transmission of HIV.

Tebit, Denis M.; Ndembi, Nicaise; Weinberg, Aaron; Quinones-Mateu, Miguel E.

2013-01-01

344

Aging, human immunodeficiency virus, and bone health  

PubMed Central

Highly active antiretroviral therapy (HAART) has had a profound impact on improving the long-term prognosis for individuals infected with human immunodeficiency virus (HIV). HAART has been available for close to two decades, and now a significant number of patients with access to HAART are over the age of 50 years. Many clinical studies have indicated that HIV infection, as well as components of HAART, can increase the risk in these individuals to a variety of noninfectious complications, including a risk to bone health. There is a significant need for detailed mechanistic analysis of the aging, HIV-infected population regarding the risk of HIV infection and therapy in order to maintain bone health. Insights from basic mechanistic studies will help to shed light on the role of HIV infection and the components of HAART that impact bone health, and will help in identifying preventative countermeasures, particularly for individuals 50 years of age and older.

Mansky, Kim C

2010-01-01

345

Autoimmune Cytopenias In Common Variable Immunodeficiency  

PubMed Central

Common variable immunodeficiency (CVID) is a humoral immunodeficiency whose primary diagnostic features include hypogammaglobulinemia involving two or more immunoglobulin isotypes and impaired functional antibody responses in the majority of patients. While increased susceptibility to respiratory and other infections is a common thread that binds a large cross-section of CVID patients, the presence of autoimmune complications in this immunologically and clinically heterogeneous disorder is recognized in up to two-thirds of patients. Among the autoimmune manifestations reported in CVID (20–50%; Chapel et al., 2008; Cunningham-Rundles, 2008), autoimmune cytopenias are by far the most common occurring variably in 4–20% (Michel et al., 2004; Chapel et al., 2008) of these patients who have some form of autoimmunity. Association of autoimmune cytopenias with granulomatous disease and splenomegaly has been reported. The spectrum of autoimmune cytopenias includes thrombocytopenia, anemia, and neutropenia. While it may seem paradoxical “prima facie” that autoimmunity is present in patients with primary immune deficiencies, in reality, it could be considered two sides of the same coin, each reflecting a different but inter-connected facet of immune dysregulation. The expansion of CD21 low B cells in CVID patients with autoimmune cytopenias and other autoimmune features has also been previously reported. It has been demonstrated that this unique subset of B cells is enriched for autoreactive germline antibodies. Further, a correlation has been observed between various B cell subsets, such as class-switched memory B cells and plasmablasts, and autoimmunity in CVID. This review attempts to explore the most recent concepts and highlights, along with treatment of autoimmune hematological manifestations of CVID.

Podjasek, Jenna C.; Abraham, Roshini S.

2012-01-01

346

Potent activity of 2'-beta-fluoro-2',3'-dideoxyadenosine against human immunodeficiency virus type 1 infection in hu-PBL-SCID mice.  

PubMed Central

A new antiretroviral agent, 2'-beta-fluoro-2',3'-dideoxyadenosine (FddA), is an acid-stable compound whose triphosphate form is a potent reverse transcriptase inhibitor with in vitro anti-human immunodeficiency virus (HIV) activity and a favorable pharmacokinetic profile. Severe combined immunodeficiency (SCID) mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID mice) provide a useful small-animal model for HIV research. In the present study we utilized this experimental system for the in vivo evaluation of the anti-HIV activity of this new compound when administered prior to infection. Initial studies revealed that, following a challenge with 50 100% tissue culture infective doses of HIV type 1 lymphadenopathy-associated virus, 39 of 42 (93%) control mice developed HIV infection, as evidenced by positive coculture or positive PCR. Administration of zidovudine decreased the infection rate to 5 of 16 (31%), while administration of FddA decreased the infection rate to 0 of 44 (0%). In follow-up controlled studies, the anti-HIV activity of FddA was confirmed, with 18 of 20 control mice showing evidence of HIV infection, compared with 4 of 20 FddA-treated mice. In addition to having direct anti-HIV effects, FddA was found to have a protective effect on human CD4+ T cells in the face of HIV infection. Mice treated with FddA were found to have a significantly higher percentage of CD4+ T cells than controls (10.3% +/- 3.4% versus 0.27% +/- 0.21%; P = 0.01). Thus, FddA, with its potent anti-HIV activity in vivo, high oral bioavailability, long intracellular half-life, and ability to preserve CD4+ cells in the presence of HIV, appears to be a promising agent for clinical investigation.

Ruxrungtham, K; Boone, E; Ford, H; Driscoll, J S; Davey, R T; Lane, H C

1996-01-01

347

The Economics of Net Neutrality  

Microsoft Academic Search

Robert Hahn and Scott Wallsten argue that mandating net neutrality, like most other forms of price regulation, is poor policy; instead, the government should focus on creating competition in the broadband market by liberalizing more spectrum and reducing entry barriers created by certain local regulations.

Robert W. Hahn; Scott Wallsten

2006-01-01

348

Net neutrality: A user's guide  

Microsoft Academic Search

Net neutrality is a complex issue that has generated intense levels of political discussion in the United States, but which has yet to attract significant attention from regulators in the UK. Nevertheless, the question of whether network operators should be prevented from blocking or prioritising certain network traffic or traffic from particular sources is a significant one for a wide range

Paul Ganley; Ben Allgrove

2006-01-01

349

Net Neutrality... Seriously this Time  

Microsoft Academic Search

The net neutrality debate began a few years ago, prematurely, with overheated rhetoric about potential disasters for the Internet but little in the way of real threats requiring immediate government action. Beginning around May 2007, one of the largest ISPs in the US, Comcast, began a program of discriminatory blocking of certain Internet communications protocols. The blocking has focused on

Daniel J. Weitzner

2008-01-01

350

Net Neutrality Paradox: Regulator's Dilemma  

Microsoft Academic Search

Internet has emerged as a disruptive force for the conventional communication model. Internet evolution as the most effective communication medium paved the way for convergent communication services and new business models. The growing incidents of internet service discrimination (1) and service Blockade (2) has once again revived the debate of resolving the old issue of Network neutrality (3). The recent

Khalid Rafique; Chunhui Yuan; Muhammad Saeed

2011-01-01

351

Asymptotic neutrality of diatomic molecules  

Microsoft Academic Search

We use the no-binding theorem of Thomas-Fermi theory to prove that a large diatomic molecule is “almost” neutral. That is to say, that if the total nuclear charge isZ then the numberN of electrons required for the diatomic molecule to be stable satisfies\\u000a

Jan Philip Solovej

1990-01-01

352

Low energy neutral atom imaging  

SciTech Connect

Energetic neutral atom (ENA) and low energy neutral atom (LENA) imaging of space plasmas are emerging new technology which promises to revolutionize the way we view and understand large scale space plasma phenomena and dynamics. ENAs and LENAs are produced in the magnetosphere by charge exchange between energetic and plasma ions and cold geocoronal neutrals. While imaging techniques have been previously developed for observing ENAs, with energies above several tens of keV, most of the ions found in the terrestrial magnetosphere have lower energies. We recently suggested that LENAs could be imaged by first converting the neutrals to ions and then electrostatically analyzing them to reject the UV background. In this paper we extend this work to examine in detail the sensor elements needed to make an LENA imager. These elements are (1) a biased collimator to remove the ambient plasma ions and electrons and set the azimuthal field-of-view; (2) a charge modifier to convert a portion of the incident LENAs to ions; (3) an electrostatic analyzer to reject UV light and set the energy passband; and (4) a coincidence detector to measure converted LENAs while rejecting noise and penetrating radiation. We also examine the issue of LENA imager sensitivity and describe ways of optimizing sensitivity in the various sensor components. Finally, we demonstrate in detail how these general considerations are implemented by describing one relatively straightforward design based on a hemispherical electrostatic analyzer.

McComas, D.J.; Funsten, H.O.; Gosling, J.T.; Moore, K.R.; Thomsen, M.F.

1992-01-01

353

Low energy neutral atom imaging  

SciTech Connect

Energetic neutral atom (ENA) and low energy neutral atom (LENA) imaging of space plasmas are emerging new technology which promises to revolutionize the way we view and understand large scale space plasma phenomena and dynamics. ENAs and LENAs are produced in the magnetosphere by charge exchange between energetic and plasma ions and cold geocoronal neutrals. While imaging techniques have been previously developed for observing ENAs, with energies above several tens of keV, most of the ions found in the terrestrial magnetosphere have lower energies. We recently suggested that LENAs could be imaged by first converting the neutrals to ions and then electrostatically analyzing them to reject the UV background. In this paper we extend this work to examine in detail the sensor elements needed to make an LENA imager. These elements are (1) a biased collimator to remove the ambient plasma ions and electrons and set the azimuthal field-of-view; (2) a charge modifier to convert a portion of the incident LENAs to ions; (3) an electrostatic analyzer to reject UV light and set the energy passband; and (4) a coincidence detector to measure converted LENAs while rejecting noise and penetrating radiation. We also examine the issue of LENA imager sensitivity and describe ways of optimizing sensitivity in the various sensor components. Finally, we demonstrate in detail how these general considerations are implemented by describing one relatively straightforward design based on a hemispherical electrostatic analyzer.

McComas, D.J.; Funsten, H.O.; Gosling, J.T.; Moore, K.R.; Thomsen, M.F.

1992-05-01

354

Neutral Injection Experiments in LITE.  

National Technical Information Service (NTIS)

A series of experiments to study hot ion buildup by neutral beam injection into a small scale mirror device was carried out in the LITE facility using two alternative warm target plasmas, a laser produced LiH plasma and the arc plasma produced by a hydrog...

1978-01-01

355

Neutralization of HIV by antibodies.  

PubMed

Antibodies can neutralize HIV-1 with potency and cross-reactivity that varies widely and is related but not correlated to their antigen-binding affinity. Therefore, in addition to measuring binding affinity, an evaluation of the antibody neutralizing activity in tissue cultures is important for development of antibody-based therapeutics, design of candidate vaccine immunogens, and understanding the mechanisms of virus entry, neutralization, and evasion of immune responses. The development of a standardized assay for measurement of the in vitro neutralizing activities of the antibody has remained a challenging goal in the last two decades. There are two types of widely used assays, which vary in details between different laboratories--assays based on cell line/pseudovirus and assays based on infection of peripheral blood mononuclear cells (PBMCs). Here we describe in detail the PBMC-based assay, which is more laborious but in our opinion represents a closer approximation of the in vivo situation. As with all other in vitro assays the results of such measurements are only an indication of the antibody potency in vivo, and animal studies and ultimately clinical trials are needed for the development of such antibodies as potential prophylactics and therapeutics. PMID:19252841

Prado, Ilia; Fouts, Timothy R; Dimitrov, Antony S

2009-01-01

356

ITER neutral beam injection system  

NASA Astrophysics Data System (ADS)

A Japanese design proposal of the ITER Neutral Beam Injection System (NBS) which is consistent with the ITER common design requirements is described. The injection system is required to deliver a neutral deuterium beam of 75MW at 1.3MeV to the reactor plasma and utilized not only for plasma heating but also for current drive and current profile control. The injection system is composed of 9 modules, each of which is designed so as to inject a 1.3 MeV, 10 MW neutral beam. The most important point in the design is that the injection system is based on the utilization of a cesium-seeded volume negative ion source which can produce an intense negative ion beam with high current density at a low source operating pressure. The design value of the source is based on the experimental values achieved at JAERI. The utilization of the cesium-seeded volume source is essential to the design of an efficient and compact neutral beam injection system which satisfies the ITER common design requirements. The critical components to realize this design are the 1.3MeV, 17A electrostatic accelerator and the high voltage DC acceleration power supply, whose performances must be shown prior to the construction of the ITER NBI system.

Ohara, Yoshihiro; Tanaka, Shigeru; Akiba, Masato

1991-03-01

357

Photodetachment process for beam neutralization  

DOEpatents

A process for neutralization of accelerated ions employing photo-induced charge detachment is disclosed. The process involves directing a laser beam across the path of a negative ion beam such as to effect photodetachment of electrons from the beam ions. The frequency of the laser beam employed is selected to provide the maximum cross-section for the photodetachment process. 2 figs.

Fink, J.H.; Frank, A.M.

1979-02-20

358

Photodetachment process for beam neutralization  

DOEpatents

A process for neutralization of accelerated ions employing photo-induced charge detachment. The process involves directing a laser beam across the path of a negative ion beam such as to effect photodetachment of electrons from the beam ions. The frequency of the laser beam employed is selected to provide the maximum cross-section for the photodetachment process.

Fink, Joel H. (Livermore, CA); Frank, Alan M. (Livermore, CA)

1979-01-01

359

PDX neutral beam reionization losses  

Microsoft Academic Search

Reionization losses for 1.5 MW H ° and 2 MW D ° neutral beams injected into the PDX tokamak were studied using pressure gauges, phototransistors, thermocouples, surface shielding, and surface sample analysis. Considerable outgassing of conventionally prepared 304 SS ducts occurred during initial injections and gradually decreased with the cumulative absorption of beam power. Reionization power losses are presently about

H. W. Kugel; H. F. Dylla; H. P. Eubank; T. A. Kozub; R. Moore; G. Schilling; L. D. Stuart; A. Von Halle; M. D. Williams

1982-01-01

360

Failure of a human immunodeficiency virus (HIV) immune globulin to protect chimpanzees against experimental challenge with HIV.  

PubMed

To assess the possible efficacy of passive immunization against human immunodeficiency virus (HIV) an immune globulin was prepared from plasma of HIV-seropositive donors selected to be among those having the top 12.5% of virus-neutralizing antibody titers. The immune globulin was treated with pepsin to render it intravenously tolerable. The preparation, which we termed HIVIG, neutralized 100 tissue culture 50% infective doses (TCID50) of HIV at an average dilution of 1:1000 in neutralization tests in vitro. During preparation HIVIG was subjected to virus inactivation and removal procedures that in theory resulted in a reduction in HIV infectivity by a factor of 10(25). At a dose of 9-10 ml/kg of body weight both the virus-inactivated source plasma and the final immunoglobulin preparation were noninfective and without adverse effect in two chimpanzees. Two chimpanzees inoculated intravenously with HIVIG at 1 ml/kg and two inoculated with 10 ml/kg were challenged intravenously 1 day later with 400 TCID50 of the same strain of HIV (HTLV-IIIb) used in neutralization assays in vitro. All animals became infected. Incubation periods to virus isolation (by cocultivation with human mononuclear cells) in HIVIG recipients did not differ significantly from the incubation period seen in a control animal that received a normal anti-HIV-free immunoglobulin. These findings may have implications for understanding the failure of experimental vaccines to protect against HIV challenge in chimpanzee experiments. PMID:3413127

Prince, A M; Horowitz, B; Baker, L; Shulman, R W; Ralph, H; Valinsky, J; Cundell, A; Brotman, B; Boehle, W; Rey, F

1988-09-01

361

Failure of a human immunodeficiency virus (HIV) immune globulin to protect chimpanzees against experimental challenge with HIV.  

PubMed Central

To assess the possible efficacy of passive immunization against human immunodeficiency virus (HIV) an immune globulin was prepared from plasma of HIV-seropositive donors selected to be among those having the top 12.5% of virus-neutralizing antibody titers. The immune globulin was treated with pepsin to render it intravenously tolerable. The preparation, which we termed HIVIG, neutralized 100 tissue culture 50% infective doses (TCID50) of HIV at an average dilution of 1:1000 in neutralization tests in vitro. During preparation HIVIG was subjected to virus inactivation and removal procedures that in theory resulted in a reduction in HIV infectivity by a factor of 10(25). At a dose of 9-10 ml/kg of body weight both the virus-inactivated source plasma and the final immunoglobulin preparation were noninfective and without adverse effect in two chimpanzees. Two chimpanzees inoculated intravenously with HIVIG at 1 ml/kg and two inoculated with 10 ml/kg were challenged intravenously 1 day later with 400 TCID50 of the same strain of HIV (HTLV-IIIb) used in neutralization assays in vitro. All animals became infected. Incubation periods to virus isolation (by cocultivation with human mononuclear cells) in HIVIG recipients did not differ significantly from the incubation period seen in a control animal that received a normal anti-HIV-free immunoglobulin. These findings may have implications for understanding the failure of experimental vaccines to protect against HIV challenge in chimpanzee experiments. Images

Prince, A M; Horowitz, B; Baker, L; Shulman, R W; Ralph, H; Valinsky, J; Cundell, A; Brotman, B; Boehle, W; Rey, F

1988-01-01

362

Combined intra- and extracellular immunization against human immunodeficiency virus type 1 infection with a human anti-gp120 antibody.  

PubMed Central

In this study, a human CD4+ T lymphocyte line was transduced to secrete Fab fragments of a broadly neutralizing human monoclonal antibody F105 that reacts with the CD4-binding site of human immunodeficiency virus type 1 (HIV-1) envelope protein. In the transduced cells infected with HIV-1, the nascent Fab fragments bind intracellularly to the HIV-1 envelope protein and inhibit HIV-1 production. The secreted Fab fragments are able to neutralize cell-free HIV-1. In addition, the nascent Fab fragments can inhibit HIV-1 production by binding intracellularly to envelope mutants that escape neutralization by extracellular F105 antibody. The combined intra- and extracellular binding activities of the expressed Fab fragments result in the efficient blocking of cytopathic syncytium formation and infectious virus production. Thus, these antibody-producing T lymphocytes are not only resistant to HIV-1 infection but also can protect surrounding lymphocytes by secreting neutralizing antibodies. This novel strategy of combining intracellular and extracellular immunization may be useful for gene therapy of AIDS and other diseases. Images

Chen, S Y; Khouri, Y; Bagley, J; Marasco, W A

1994-01-01

363

A Prevalence of Posttransplantation Cancers Compared With Cancers in People With Human Immunodeficiency Virus\\/Acquired Immunodeficiency Syndrome After Highly Active Antiretroviral Therapy  

Microsoft Academic Search

BackgroundOrgan transplant recipients and human immunodeficiency virus & acquired Immunodeficiency Syndrome (HIV\\/AIDS) patients have immune deficiencies that are possible mechanisms to develop malignancy. The type of cancers associated with these 2 conditions might elucidate this premise.

N. Srisawat; A. Avihingsanon; K. Praditpornsilpa; W. Jiamjarasrangsi; S. Eiam-Ong; Y. Avihingsanon

2008-01-01

364

Avian Influenza: Potential Impact on Sub-Saharan Military Populations with High Rates of Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome.  

National Technical Information Service (NTIS)

Several sub-Saharan militaries have large percentages of troops with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. With the arrival of avian influenza in Africa, the potential exists that some of those soldiers might also become i...

K. Nickell R. L. Feldman

2007-01-01

365

Variants selected by treatment of human immunodeficiency virus-infected cells with an immunotoxin  

PubMed Central

An immunotoxin has been made by coupling anti-human immunodeficiency virus (HIV) envelope antibody 907 to ricin A chain (907-RAC). 907 recognizes an epitope within the immunodominant PB-1 loop of gp120. Variant cells were selected by cloning persistently infected H9/human T lymphocyte virus IIIB cells in the presence of the immunotoxin. Clones resistant to 907-RAC arose at a frequency of 0.1-1.0%. Seven clones were selected for intensive analysis. When studied, these clones fell into two distinct groups, members of which appeared to be identical, suggesting that the variation arose before the selection process. In contrast to the parent cells, none of the cloned variants produced infectious HIV. The first set of clones, designated the "E" variants, expressed decreased levels of the HIV envelope on the cell surface. However, levels of intracellular HIV antigens and reverse transcriptase were equal to or greater than that of the parental cell line. Radioimmunoprecipitation demonstrated that the gp160 was truncated to 145 kD (gp120 was normal length), capable of binding to CD4, and, unlike normal gp160, was released in its unprocessed form into the cellular supernatant. Sequence analysis demonstrated that a deletion at codon 687 of the envelope gene resulted in the production of this truncated protein. Ultrastructural analysis of E variants demonstrated some budding forms of virus, but also large numbers of HIV within intracellular vesicles. The second set of variants, the "F" series, produced no HIV antigens, reverse transcriptase, nor was there ultrastructural evidence of virus. However, proviral DNA was present. Virus could not be induced with agents known to activate latent HIV. These cells also lacked cell surface CD4 and could not be infected with HIV. These studies demonstrate that variation in HIV can affect the phenotype of the cells carrying the altered virus, allowing for escape from immunologic destruction. The E variants may serve as prototypes for attenuated HIV, which could be used as a vaccine. We have reconstructed the mutation found in the E variants within the infectious HIV clone HXB-2 and demonstrated that the resulting virus retains its noninfectious phenotype.

1990-01-01

366

In vivo Targeting of Human Neutralizing Antibodies against CD55 and CD59 to Lymphoma Cells Increases the Antitumor Activity of Rituximab  

Microsoft Academic Search

An in vivo model of human CD20+ B-lymphoma was established in severe combined immunodeficiency mice to test the ability of human neutralizing miniantibodies to CD55 and CD59(MB55 and MB59) to enhance the therapeutic effect of rituximab. The miniantibodies contained single-chain fragment variables and the hinge-CH2-CH3 domains of human IgG1. LCL2 cells were selected for the in vivo study among six

Paolo Macor; Claudio Tripodo; Sonia Zorzet; Erich Piovan; Fleur Bossi; Roberto Marzari; Alberto Amadori

367

Association of common variable immunodeficiency with vitamin B6 deficiency  

Microsoft Academic Search

Objective:To study the prevalence of vitamin B6 deficiency in common variable immunodeficiency and the impact of vitamin B6 supplementation on immune function in the disorder.Design:Open, non-blinded.Setting:Medical School Hannover, Hannover, Germany.Subjects:Plasma vitamin B6 concentrations were measured in all the 54 common variable immunodeficiency (CVID) patients visiting our outpatients' clinics in 2005.Interventions:The 17 patients with a decreased vitamin B6 concentration were recommended

J Bierwirth; K U Ulbricht; R E Schmidt; T Witte

2008-01-01

368

Severe immunodeficiency disease induced by a defective murine leukaemia virus  

Microsoft Academic Search

DIFFERENT classes of retroviruses have been shown to induce immunodeficiency diseases in various animal species1. These animal models may provide an insight into our understanding of AIDS1-3 but, with the exception of one strain of feline leukaemia virus4, the determinants of pathogenicity have not yet been mapped to these viral genomes. The immunodeficiency-inducing feline leukaemia virus is replication-defective4, harbouring the

Douglas C. Aziz; Zaher Hanna; Paul Jolicoeur

1989-01-01

369

Common variable immunodeficiency syndrome associated with epidermodysplasia verruciformis.  

PubMed

We report the association of common variable immunodeficiency syndrome with epidermodysplasia verruciformis (EV) manifesting as flat warts and squamous cell carcinomas in a 21-year-old Hispanic woman. Human papillomavirus (HPV) typing by polymerase chain reaction using an EV-HPV primer system, cloning, and sequencing detected HPV-8 and HPV-23 DNAs in the biopsy sample. Our case is the second reported case of common variable immunodeficiency syndrome associated with EV. PMID:17902733

Vu, Jenny; Wallace, Genevieve R; Singh, Rajendra; Diwan, Hafeez; Prieto, Victor; Rady, Peter; Tyring, Stephen; Duvic, Madeleine

2007-01-01

370

Progress and prospects: gene therapy for inherited immunodeficiencies  

Microsoft Academic Search

Haematopoietic stem cell transplantation (HSCT) is now widely used to treat primary immunodeficiencies (PID). For patients with specific disorders (severe combined immunodeficiency (SCID)-X1, adenosine deaminase deficiency (ADA)–SCID, X-chronic granulomatous disease (CGD) and Wiskott–Aldrich Syndrome (WAS)) who lack a suitable human leukocyte antigen (HLA)-matched donor, gene therapy has offered an important alternative treatment option. The success of gene therapy can be

W Qasim; H B Gaspar; A J Thrasher

2009-01-01

371

Warts and all: human papillomavirus in primary immunodeficiencies.  

PubMed

Infection with human papillomavirus (HPV) is almost universal and eventually asymptomatic, but pathologic infection with HPV is severe, recurrent, and recalcitrant to therapy. It is also an underappreciated manifestation of primary immunodeficiency. Mutations in EVER1, EVER2, GATA2, CXCR4, and dedicator of cytokinesis 8 (DOCK8) are typically associated with extensive HPV infections, whereas several other primary immune defects result in severe HPV much less frequently. We review immunodeficiencies with severe HPV infections and the mechanisms underlying them. PMID:23036745

Leiding, Jennifer W; Holland, Steven M

2012-10-01

372

Acquired immunodeficiency syndrome and the blood-brain barrier  

Microsoft Academic Search

The blood-brain barrier (BBB) plays a critical role in normal physiology of the central nervous system by regulating what\\u000a reaches the brain from the periphery. The BBB also plays a major role in neurologic disease including neuropathologic sequelae\\u000a associated with infection by human immunodeficiency virus (HIV) in humans and the closely related simian immunodeficiency\\u000a virus (SIV) in macaques. In this

Nathan S. Ivey; Andrew G. MacLean; Andrew A. Lackner

2009-01-01

373

Measurement of plasma production and neutralization in gas neutralizers  

SciTech Connect

In order to satisfy the need of experimental data for the designing of gas neutralizers we have started a project aimed at measuring all relevant cross sections for the charge exchange of H/sup -/, H/sup 0/ and H/sup +/ projectiles, as well as the cross sections for the production of ions in the target. The expected results of these latter measurements are shown schematically.

Maor, D.; Meron, M.; Johnson, B.; Jones, K.; Agagu, A.; Hu, B.

1986-06-17

374

Amygdala activation in the processing of neutral faces in social anxiety disorder: Is neutral really neutral?  

Microsoft Academic Search

Previous research has suggested that Social Anxiety Disorder (SAD) is associated with a tendency to interpret ambiguous social stimuli in a threatening manner. The present study used event-related functional magnetic resonance imaging to examine patterns of neural activation in response to the processing of neutral facial expressions in individuals diagnosed with SAD and healthy controls (CTLs). The SAD participants exhibited

Rebecca E. Cooney; Lauren Y. Atlas; Jutta Joormann; Fanny Eugène; Ian H. Gotlib

2006-01-01

375

Gp120-induced Bob/GPR15 activation: a possible cause of human immunodeficiency virus enteropathy.  

PubMed

Human immunodeficiency virus (HIV)-infected patients often develop malabsorption and increased intestinal permeability with diarrhea, called HIV enteropathy, even without enteric opportunistic infections. HIV gp120-induced calcium signaling, microtubule loss, and physiological changes resembling HIV enteropathy were previously found in the HT-29 intestinal cell line. How gp120 caused these changes was unclear. We show that the HIV co-receptor Bob/GPR15, unlike CCR5 and CXCR4, is abundant at the basal surface of small intestinal epithelium. The gp120-induced effects on HT-29 cells were inhibited by anti-Bob neutralizing antibodies, the selective G protein inhibitor pertussis toxin, and the phospholipase inhibitor U73122, but not neutralizing antibodies to CXCR4. Gp120 strains that induced signaling in HT-29 cells also induced calcium fluxes in Bob-transfected Ghost (3) cells, whereas gp120 strains not activating HT-29 cells also did not activate Bob-transfected cells. Bob is the first HIV co-receptor shown to be abundantly expressed on the basolateral surface of intestinal epithelium. Although Bob is an inefficient infection-inducing co-receptor, it mediates viral strain-specific gp120-induced calcium signaling at low, physiologically reasonable gp120 concentrations, up to 10,000-fold lower gp120 concentrations than the principal co-receptors. Gp120-induced Bob activation is a plausible cause of HIV enteropathy. PMID:11696454

Clayton, F; Kotler, D P; Kuwada, S K; Morgan, T; Stepan, C; Kuang, J; Le, J; Fantini, J

2001-11-01

376

Role of a Putative gp41 Dimerization Domain in Human Immunodeficiency Virus Type 1 Membrane Fusion?  

PubMed Central

The entry of human immunodeficiency virus type 1 (HIV-1) into a target cell entails a series of conformational changes in the gp41 transmembrane glycoprotein that mediates the fusion of the viral and target cell membranes. A trimer-of-hairpins structure formed by the association of two heptad repeat (HR) regions of the gp41 ectodomain has been implicated in a late step of the fusion pathway. Earlier native and intermediate states of the protein are postulated to mediate the antiviral activity of the fusion inhibitor enfuvirtide and of broadly neutralizing monoclonal antibodies (NAbs), but the details of these structures remain unknown. Here, we report the identification and crystal structure of a dimerization domain in the C-terminal ectodomain of gp41 (residues 630 to 683, or C54). Two C54 monomers associate to form an asymmetric, antiparallel coiled coil with two distinct C-terminal ?-helical overhangs. This dimer structure is conferred largely by interactions within a central core that corresponds to the sequence of enfuvirtide. The mutagenic alteration of the dimer interface severely impairs the infectivity of Env-pseudotyped viruses. Moreover, the C54 structure binds tightly to both the 2F5 and 4E10 NAbs and likely represents a potential intermediate conformation of gp41. These results should enhance our understanding of the molecular basis of the gp41 fusogenic structural transitions and thereby guide rational, structure-based efforts to design new fusion inhibitors and vaccine candidates intended to induce broadly neutralizing antibodies.

Liu, Jie; Deng, Yiqun; Li, Qunnu; Dey, Antu K.; Moore, John P.; Lu, Min

2010-01-01

377

Novel mutation (K70E) in human immunodeficiency virus type 1 reverse transcriptase confers decreased susceptibility to 9-[2-(phosphonomethoxy)ethyl]adenine in vitro.  

PubMed Central

9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), an acyclic nucleoside phosphonate analog, is active against several retroviruses and herpesviruses and has shown anti-human immunodeficiency virus (HIV) activity in clinical trials. Serial passage of HIV type 1 (strain IIIb, in MT2 cells in increasing concentrations of PMEA resulted in viruses with > 12-fold increases in their 50% inhibitory concentrations of PMEA compared with that for strain IIIb. Sequence analyses of these PMEA-selected viruses demonstrated the presence of a novel lysine-to-glutamic acid mutation at amino acid 70 (K70E) in HIV reverse transcriptase. A recombinant virus carrying the K70E mutation was constructed and showed a 10-fold increase in its 50% inhibitory concentrations of PMEA and 2',3'-dideoxy-3'-thiacytidine but showed wild-type susceptibility levels to 2',3'-dideoxycytosine, 2',3'-dideoxyinosine,2',3'-didehydro-2'3'-dideoxythymidine, 3'-azido-3'-deoxythymidine, foscarnet, and two additional phosphonates, 9-[(R)-2-(phosphonomethoxy)propyl]adenine and 9-[2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]adenine. Additionally, the K70E recombinant showed a minor reduction in growth kinetics compared with those of the wild-type virus in vitro.

Cherrington, J M; Mulato, A S; Fuller, M D; Chen, M S

1996-01-01

378

Inhibition of human immunodeficiency virus type 1 (HIV-1) nuclear import via Vpr-Importin {alpha} interactions as a novel HIV-1 therapy  

SciTech Connect

The development of multidrug-resistant viruses compromises the efficacy of anti-human immunodeficiency virus (HIV) therapy and limits treatment options. Therefore, new targets that can be used to develop novel antiviral agents need to be identified. One such target is the interaction between Vpr, one of the accessory gene products of HIV-1 and Importin {alpha}, which is crucial, not only for the nuclear import of Vpr, but also for HIV-1 replication in macrophages. We have identified a potential parent compound, hematoxylin, which suppresses Vpr-Importin {alpha} interaction, thereby inhibiting HIV-1 replication in a Vpr-dependent manner. Analysis by real-time PCR demonstrated that hematoxylin specifically inhibited nuclear import step of pre-integration complex. Thus, hematoxylin is a new anti-HIV-1 inhibitor that targets the nuclear import of HIV-1 via the Vpr-Importin {alpha} interaction, suggesting that a specific inhibitor of the interaction between viral protein and the cellular factor may provide a new strategy for HIV-1 therapy.

Suzuki, Tatsunori [Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); Yamamoto, Norio [Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); Department of General Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Nonaka, Mizuho; Hashimoto, Yoshie; Matsuda, Go; Takeshima, Shin-nosuke [Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); Matsuyama, Megumi; Igarashi, Tatsuhiko; Miura, Tomoyuki [Institute for Virus Research, Kyoto University, Kyoto 606-8507 (Japan); Tanaka, Rie; Kato, Shingo [Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582 (Japan); Aida, Yoko [Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)], E-mail: aida@riken.jp

2009-03-20

379

Isolation and molecular characterization of a nelfinavir (NFV)-resistant human immunodeficiency virus type 1 that exhibits NFV-dependent enhancement of replication.  

PubMed

During the use of a phenotypic anti-human immunodeficiency virus type 1 (HIV-1) drug resistance assay in a large set of clinical virus isolates, we found a unique variant (CL-4) that exhibited a high level of nelfinavir (NFV) resistance and rather enhanced replication under subinhibitory concentrations of NFV (0.001 to 0.1 micro M). Comparison of gag-pol sequences of the CL-4 variant and its predecessor virus isolates showed a stepwise accumulation of a total of 19 amino acid substitutions in protease (PR) and Gag p17 during 32-month NFV-containing antiretroviral therapy, while other Gag regions including the cleavage sites of the p55 precursor remained highly conserved. To understand the relationship between the genetic and phenotypic changes in CL-4, we constructed chimeric viruses using pNL4-3, replacing the PR, p24PR, or p17PR gene segment of CL-4 or its predecessor. A series of tissue culture infections with the chimeras in the absence or presence of increasing concentrations of NFV demonstrated that only the p17PR segment of CL-4 could confer the NFV-dependent replication enhancement phenotype on NL4-3. Our data suggest a novel adaptation mechanism of HIV-1 to NFV, in which coevolution of Gag and PR genes generates a variant that replicates more efficiently in the cellular environment in the presence of NFV than without the drug. PMID:12477837

Matsuoka-Aizawa, Saori; Sato, Hironori; Hachiya, Atsuko; Tsuchiya, Kiyoto; Takebe, Yutaka; Gatanaga, Hiroyuki; Kimura, Satoshi; Oka, Shinichi

2003-01-01

380

Mutation analysis in primary immunodeficiency diseases: case studies  

PubMed Central

Purpose of review The application of mutation analysis is becoming an integral part of the complete evaluation of patients with primary immunodeficiencies, and as such, clinicians caring for these patients must develop a better understanding of the utility and challenges of this important laboratory technology. Recent findings Genomic DNA sequencing is currently the standard approach used to characterize a possible gene mutation causing a specific primary immunodeficiency. There are clinical situations in which this approach is revealing of a genetic defect and other circumstances in which this generates a false-positive or false-negative result. One case study is presented that reviews a straightforward analysis that clarifies the genetic basis of a primary immunodeficiency, and four cases are presented that required additional studies to clarify the underlying basis of the immunodeficiency. In the latter circumstances, the rationale for additional studies is outlined and the outcome of these is presented. Summary The identification of a gene mutation as the underlying basis of a primary immunodeficiency begins with the evaluation of the clinical presentation focusing on the infection history so as to develop a differential diagnosis including potential genetic causes. The next step is to obtain specific laboratory studies, including immunologic function evaluation, and, based on these findings, to proceed with DNA sequencing of one or several selected candidate genes. Genomic DNA sequencing has certain limitations, and alternative follow-up approaches may be necessary to establish the molecular basis of the primary immunodeficiency in a given patient.

Hsu, Amy P.; Fleisher, Thomas A.; Niemela, Julie E.

2009-01-01

381

Magnitude and Breadth of the Neutralizing Antibody Response in the RV144 and Vax003 HIV-1 Vaccine Efficacy Trials  

PubMed Central

Background.?A recombinant canarypox vector expressing human immunodeficiency virus type 1 (HIV-1) Gag, Pro, and membrane-linked gp120 (vCP1521), combined with a bivalent gp120 protein boost (AIDSVAX B/E), provided modest protection against HIV-1 infection in a community-based population in Thailand (RV144 trial). No protection was observed in Thai injection drug users who received AIDSVAX B/E alone (Vax003 trial). We compared the neutralizing antibody response in these 2 trials. Methods.?Neutralization was assessed with tier 1 and tier 2 strains of virus in TZM-bl and A3R5 cells. Results.?Neutralization of several tier 1 viruses was detected in both RV144 and Vax003. Peak titers were higher in Vax003 and waned rapidly in both trials. The response in RV144 was targeted in part to V3 of gp120.vCP1521 priming plus 2 boosts with gp120 protein was superior to 2 gp120 protein inoculations alone, confirming a priming effect for vCP1521. Sporadic weak neutralization of tier 2 viruses was detected only in Vax003 and A3R5 cells. Conclusion.?The results suggest either that weak neutralizing antibody responses can be partially protective against HIV-1 in low-risk heterosexual populations or that the modest efficacy seen in RV144 was mediated by other immune responses, either alone or in combination with neutralizing antibodies.

Montefiori, David C.; Karnasuta, Chitraporn; Huang, Ying; Ahmed, Hasan; Gilbert, Peter; de Souza, Mark S.; McLinden, Robert; Tovanabutra, Sodsai; Laurence-Chenine, Agnes; Sanders-Buell, Eric; Moody, M. Anthony; Bonsignori, Mattia; Ochsenbauer, Christina; Kappes, John; Tang, Haili; Greene, Kelli; Gao, Hongmei; LaBranche, Celia C.; Andrews, Charla; Polonis, Victoria R.; Rerks-Ngarm, Supachai; Pitisuttithum, Punnee; Nitayaphan, Sorachai; Kaewkungwal, Jaranit; Self, Steve G.; Berman, Phillip W.; Francis, Donald; Sinangil, Faruk; Lee, Carter; Tartaglia, Jim; Robb, Merlin L.; Haynes, Barton F.; Michael, Nelson L.; Kim, Jerome H.

2012-01-01

382

A Pathogenic Threshold of Virus Load Defined in Simian Immunodeficiency Virus or Simian-Human Immunodeficiency VirusInfected Macaques  

Microsoft Academic Search

To determine if a specific pathogenic threshold of plasma viral RNA could be defined irrespective of virus strain, RNA levels in the plasma of more than 50 infected rhesus macaques (Macaca mulatta) were measured. Animals were inoculated intravenously with either simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) strains of known pathogenic potential (SIV8980, SIVsmm-3, SIVmac32H\\/J5, SIVmac32H\\/1XC, reverse transcriptase-SHIV,

PETER TEN HAAFT; BABS VERSTREPEN; KLAUS UBERLA; BRIGITTE ROSENWIRTH; JONATHAN HEENEY

1998-01-01

383

Frequency and Clinical Manifestations of Patients with Primary Immunodeficiency Disorders in Iran: Update from the Iranian Primary Immunodeficiency Registry  

Microsoft Academic Search

Primary immunodeficiency disorders (PID) are a heterogeneous group of diseases, characterized by an increased susceptibility to infections. A total of 930 patients (573 males and 357 females) are registered in Iranian PID Registry (IPIDR) during three decades. Predominantly antibody deficiencies were the most common (38.4%), followed by congenital defects of phagocyte number and\\/or function (28.3%), other well-defined immunodeficiency syndromes (17.7%),

NIMA REZAEI; ASGHAR AGHAMOHAMMADI; MOSTAFA MOIN; ZAHRA POURPAK; MASOUD MOVAHEDI; MOHAMMAD GHARAGOZLOU; LIDA ATAROD; BAHRAM MIRSAEID GHAZI; ANNA ISAEIAN; MARYAM MAHMOUDI; KAMRAN ABOLMAALI; DAVOUD MANSOURI; SABA ARSHI; NASER JAVAHER TARASH; ROYA SHERKAT; HEDAYAT AKBARI; REZA AMIN; ABDOLVAHAB ALBORZI; SARA KASHEF; REZA FARID; IRAJ MOHAMMADZADEH; MEHRNAZ SADEGHI SHABESTARI; MOHAMMAD NABAVI; ABOLHASSAN FARHOUDI

2006-01-01

384

Gamma\\/Delta T-Cell Functional Responses Differ after Pathogenic Human Immunodeficiency Virus and Nonpathogenic Simian Immunodeficiency Virus Infections  

Microsoft Academic Search

The objective of this study was to functionally assess gamma\\/delta () T cells following pathogenic human immunodeficiency virus (HIV) infection of humans and nonpathogenic simian immunodeficiency virus (SIV) infection of sooty mangabeys. T cells were obtained from peripheral blood samples from patients and sooty mangabeys that exhibited either a CD4-healthy (>200 CD4 T cells\\/l blood) or CD4-low (<200 CD4 cells\\/l

David A. Kosub; Ginger Lehrman; Jeffrey M. Milush; Dejiang Zhou; Elizabeth Chacko; Amanda Leone; Shari Gordon; Guido Silvestri; James G. Else; Philip Keiser; Mamta K. Jain; Donald L. Sodora

2008-01-01

385

Accuracy of Self-Reports of Acquired Immunodeficiency Syndrome and Acquired Immunodeficiency Syndrome-related Conditions in Women  

Microsoft Academic Search

To investigate the validity of self-reported acquired immunodeficiency syndrome (AIDS) among women enrolled in a prospective study of human immunodeficiency virus (HIV) infection, the authors compared the self- reported occurrence of AIDS-specific diagnoses with AIDS diagnoses documented by county AIDS surveillance registries. Also examined was the association between participant characteristics and the validity of self-reports. Among the 339 HIV-infected participants

Nancy A. Hessol; Sandra Schwarcz; Niloufar Ameli; Gary Oliver; Ruth M. Greenblatt

386

Characterization of Simian Immunodeficiency Virus SIVSM\\/Human Immunodeficiency Virus Type 2 Vpx Function in Human Myeloid Cells  

Microsoft Academic Search

Human immunodeficiency virus type 2 (HIV-2)\\/simian immunodeficiency virus SIVSM Vpx is incorporated into virion particles and is thus present during the early steps of infection, when it has been reported to influence the nuclear import of viral DNA. We recently reported that Vpx promoted the accumulation of full-length viral DNA following the infection of human monocyte-derived dendritic cells (DCs). This

Caroline Goujon; Vanessa Arfi; Thomas Pertel; Jeremy Luban; Julia Lienard; Dominique Rigal; Jean-Luc Darlix; Andrea Cimarelli

2008-01-01

387

Protective Immune Responses Induced by Secretion of a Chimeric Soluble Protein from a Recombinant Mycobacterium bovis Bacillus Calmette-Guerin Vector Candidate Vaccine for Human Immunodeficiency Virus Type 1 in Small Animals  

Microsoft Academic Search

A recombinant Mycobacterium bovis bacillus Calmette-Guacute{e}rin (BCG) vector-based vaccine that secretes the V3 principal neutralizing epitope of human immunodeficiency virus (HIV) could induce immune response to the epitope and prevent the viral infection. By using the Japanese consensus sequence of HIV-1, we successfully constructed chimeric protein secretion vectors by selecting an appropriate insertion site of a carrier protein and established

Mitsuo Honda; Kazuhiro Matsuo; Tadashi Nakasone; Yukari Okamoto; Hitomi Yoshizaki; Katsuhiko Kitamura; Wataru Sugiura; Kuhomi Watanabe; Yoshiko Fukushima; Shinji Haga; Yoshimoto Katsura; Hiromichi Tasaka; Katsutoshi Komuro; Takeshi Yamada; Toshihiko Asano; Akihiro Yamazak; Shudo Yamazaki

1995-01-01

388

A Novel Antibody-Dependent Cellular Cytotoxicity Epitope in gp120 Is Identified by Two Monoclonal Antibodies Isolated from a Long-Term Survivor of Human Immunodeficiency Virus Type 1 Infection  

Microsoft Academic Search

Two monoclonal antibodies (MAbs), 42F and 43F, were isolated some 14 months apart from a single long-term survivor of human immunodeficiency virus type 1 (HIV-1) infection. These MAbs were found to be indistinguishable in terms of their isotypes, specificities, affinities, and biological activities. Both 42F and 43F directedsubstantialantibody-dependentcellularcytotoxicity(ADCC)againstcellsinfectedwithfourdivergent lab-adapted strains of HIV-1, but no neutralizing activity against these strains was

OSAMA ALSMADI; RUTH HERZ; ELLEN MURPHY; ABRAHAM PINTER; ANDSHERMAINE A. TILLEY

1997-01-01

389

Radiative lifetimes of neutral gadolinium  

NASA Astrophysics Data System (ADS)

The current work is part of an ongoing study of radiative properties of rare earth neutral atoms motivated by research needs in several disparate fields including astrophysics, laser chemistry and lighting technology. Time-resolved laser-induced fluorescence on a slow atomic beam has been used to measure radiative lifetimes, accurate to ±5%, for 136 levels of neutral gadolinium. Of the 136 levels, 6 are odd parity ranging in energy from 32 929 to 36 654 cm-1, and the remaining 130 are even parity ranging from 17 750 to 34 175 cm-1. This set of Gd i lifetimes represents a significant extension to the available published data, with 93 of the 136 level lifetimes measured for the first time. These lifetimes will provide the absolute normalization for a large set of measured Gd i transition probabilities.

Den Hartog, E. A.; Bilty, K. A.; Lawler, J. E.

2011-03-01

390

Radiative lifetimes of neutral samarium  

NASA Astrophysics Data System (ADS)

Radiative lifetimes of 120 odd-parity levels of neutral samarium, ranging in energy from 17?190 to 33?507 cm?1, are measured using the technique of time-resolved laser-induced fluorescence on a slow atomic beam. This work is part of an ongoing study of radiative properties of rare earth neutral atoms, and is motivated by research needs in astrophysics and lighting technology. This set of Sm i lifetimes substantially increases the available published lifetime data, with 49 of the 120 level lifetimes measured for the first time. These data, most of which are accurate to ±5%, will be combined with branching fractions determined from Fourier transform spectroscopy to produce a large set of measured Sm i transition probabilities.

Den Hartog, E. A.; Lawler, J. E.

2013-09-01

391

The beam driven plasma neutralizer  

NASA Astrophysics Data System (ADS)

The improvement of the efficiency of neutral beam systems to be compatible with the economic requirements of fusion power plants is a key theme in the European research programme. A novel plasma neutralizer, in which the negative ion beam itself is the source of the plasma, is described. Its success depends on the confinement of the free electrons generated by stripping from the beam and their generation of additional plasma. The device requires no additional power in contrast to the photoneutralizer, presently the main device of research interest. Although the efficiency of the plasma device is not as high as the photoneutralizer it is essentially of a low technological risk, inherently reliable and will not require a significant R&D programme to demonstrate.

Surrey, E.; Holmes, A.

2013-02-01

392

A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies.  

PubMed

A desirable but as yet unachieved property of a human immunodeficiency virus type 1 (HIV-1) vaccine candidate is the ability to induce broadly neutralizing antibodies (bNAbs). One approach to the problem is to create trimeric mimics of the native envelope glycoprotein (Env) spike that expose as many bNAb epitopes as possible, while occluding those for non-neutralizing antibodies (non-NAbs). Here, we describe the design and properties of soluble, cleaved SOSIP.664 gp140 trimers based on the subtype A transmitted/founder strain, BG505. These trimers are highly stable, more so even than the corresponding gp120 monomer, as judged by differential scanning calorimetry. They are also homogenous and closely resemble native virus spikes when visualized by negative stain electron microscopy (EM). We used several techniques, including ELISA and surface plasmon resonance (SPR), to determine the relationship between the ability of monoclonal antibodies (MAbs) to bind the soluble trimers and neutralize the corresponding virus. In general, the concordance was excellent, in that virtually all bNAbs against multiple neutralizing epitopes on HIV-1 Env were highly reactive with the BG505 SOSIP.664 gp140 trimers, including quaternary epitopes (CH01, PG9, PG16 and PGT145). Conversely, non-NAbs to the CD4-binding site, CD4-induced epitopes or gp41ECTO did not react with the trimers, even when their epitopes were present on simpler forms of Env (e.g. gp120 monomers or dissociated gp41 subunits). Three non-neutralizing MAbs to V3 epitopes did, however, react strongly with the trimers but only by ELISA, and not at all by SPR and to only a limited extent by EM. These new soluble trimers are useful for structural studies and are being assessed for their performance as immunogens. PMID:24068931

Sanders, Rogier W; Derking, Ronald; Cupo, Albert; Julien, Jean-Philippe; Yasmeen, Anila; de Val, Natalia; Kim, Helen J; Blattner, Claudia; de la Peña, Alba Torrents; Korzun, Jacob; Golabek, Michael; de Los Reyes, Kevin; Ketas, Thomas J; van Gils, Marit J; King, C Richter; Wilson, Ian A; Ward, Andrew B; Klasse, P J; Moore, John P

2013-09-19

393

A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies  

PubMed Central

A desirable but as yet unachieved property of a human immunodeficiency virus type 1 (HIV-1) vaccine candidate is the ability to induce broadly neutralizing antibodies (bNAbs). One approach to the problem is to create trimeric mimics of the native envelope glycoprotein (Env) spike that expose as many bNAb epitopes as possible, while occluding those for non-neutralizing antibodies (non-NAbs). Here, we describe the design and properties of soluble, cleaved SOSIP.664 gp140 trimers based on the subtype A transmitted/founder strain, BG505. These trimers are highly stable, more so even than the corresponding gp120 monomer, as judged by differential scanning calorimetry. They are also homogenous and closely resemble native virus spikes when visualized by negative stain electron microscopy (EM). We used several techniques, including ELISA and surface plasmon resonance (SPR), to determine the relationship between the ability of monoclonal antibodies (MAbs) to bind the soluble trimers and neutralize the corresponding virus. In general, the concordance was excellent, in that virtually all bNAbs against multiple neutralizing epitopes on HIV-1 Env were highly reactive with the BG505 SOSIP.664 gp140 trimers, including quaternary epitopes (CH01, PG9, PG16 and PGT145). Conversely, non-NAbs to the CD4-binding site, CD4-induced epitopes or gp41ECTO did not react with the trimers, even when their epitopes were present on simpler forms of Env (e.g. gp120 monomers or dissociated gp41 subunits). Three non-neutralizing MAbs to V3 epitopes did, however, react strongly with the trimers but only by ELISA, and not at all by SPR and to only a limited extent by EM. These new soluble trimers are useful for structural studies and are being assessed for their performance as immunogens.

Sanders, Rogier W.; Derking, Ronald; Cupo, Albert; Julien, Jean-Philippe; Yasmeen, Anila; de Val, Natalia; Kim, Helen J.; Blattner, Claudia; de la Pena, Alba Torrents; Korzun, Jacob; Golabek, Michael; de los Reyes, Kevin; Ketas, Thomas J.; van Gils, Marit J.; King, C. Richter; Wilson, Ian A.; Ward, Andrew B.; Klasse, P. J.; Moore, John P.

2013-01-01

394

Theoretical investigation of neutral francium  

Microsoft Academic Search

Energy levels of neutral francium are investigated in the Ritz formalism along the Rydberg series up to n = 30. Transition probabilities are calculated for the s-p and p-d transitions. Core-polarization effects are included in the model adopted. The validity of the approach has been tested by comparison with the laser lifetime measurements available for the 70953-4075\\/31\\/24\\/012\\/img7 and 70953-4075\\/31\\/24\\/012\\/img8 states

E. Biémont; P. Quinet; V. Van Renterghem

1998-01-01

395

A “tongue” of neutral composition  

Microsoft Academic Search

Both the thermosphere and the ionosphere react to forcing from the magnetospherically imposed ion convection pattern. A twin-celled, neutral convection pattern is set up that normally follows the ion convection pattern; however, unlike the ionosphere, the thermosphere takes a considerable time to react to geomagnetic forcing. In solar maximum conditions this reaction time can take 1–3h. The close relationship between

A. G. Burns; W. Wang; T. L. Killeen; S. C. Solomon

2004-01-01

396

The Neutralized Drift Compression Experiment  

NASA Astrophysics Data System (ADS)

The most recent, and highly innovative, proposal for a next, integrated beam experiment in the U.S. Heavy Ion Fusion Virtual National Laboratory (HIF-VNL) is the Neutralized Drift Compression Experiment (NDCX). NDCX will develop novel, still unexplored beam manipulation techniques in order to establish the physics limits on compression of heavy ion beams for creating high energy density matter and fusion ignition conditions. As a major advance for the HIF-VNL, NDCX could also provide significant beam pulse energy on target (10^11 J/m^3). The main components of NDCX are discussed, in particular a new injector concept, the load-and-fire injector, and the neutralized drift compression section. NDCX will compress the beam within neutralizing plasma, therefore significantly extending the transportable beam current into high-intensity regimes not reachable in the absence of background plasma. To validate these essential components experimentally NDCX will be built in several phases, which are described in more detail.

Leitner, M. A.; Anders, A.; Bieniosek, F. M.; Eylon, S.; Greenway, W. G.; Henestroza, E.; Logan, B. G.; Roy, P. K.; Shuman, D. B.; Vanecek, D. L.; Waldron, W. L.; Yu, S. S.; Rose, D. V.; Thoma, C.; Welch, D. R.; Davidson, R. C.; Efthimion, P. C.; Gilson, E. P.; Kaganovich, I.; Sefkow, A. B.; Barnard, J. J.; Sharp, W. M.

2004-11-01

397

Absence of cytotoxic antibody to human immunodeficiency virus-infected cells in humans and its induction in animals after infection or immunization with purified envelope glycoprotein gp120  

SciTech Connect

The presence of antibody-dependent complement-mediated cytotoxicity (ACC) was assessed in humans and chimpanzees, which are capable of infection with human immunodeficiency virus isolate HTLV-IIIb, and examined in the goat after immunization with the major viral glycoprotein (gp120) of HTLV-IIIb. In infected humans no antibody mediating ACC was observed regardless of the status of disease. Even healthy individuals with high-titer, broadly reactive, neutralizing antibodies has no ACC. In contrast, chimpanzees infected with HTLV-IIIb, from whom virus could be isolated, not only had neutralizing antibody but also antibodies broadly reactive in ACC, even against distantly related human immunodeficiency virus isolates, as well as against their own reisolated virus. In the goat, the gp120 of HTLV-IIIb induced a highly type-specific response as measured by both ACC and flow cytofluorometry of live infected H9 cells. Normal human cells were not subject to ACC by animal anti-HTLV-III gp120-specific sera. Induction of ACC and neutralizing antibody were closely correlated in the animal experimental models but not in humans. The presence of ACC in gp120-inoculated goats and HTLV-III-infected chimpanzees represent a qualitative difference that may be important in the quest for the elicitation of a protective immunity in humans.

Nara, P.L.; Robey, W.G.; Gonda, M.A.; Carter, S.G.; Fischinger, P.J.

1987-06-01

398

Tiered Categorization of a Diverse Panel of HIV-1 Env Pseudoviruses for Assessment of Neutralizing Antibodies ?  

PubMed Central

The restricted neutralization breadth of vaccine-elicited antibodies is a major limitation of current human immunodeficiency virus-1 (HIV-1) candidate vaccines. In order to permit the efficient identification of vaccines with enhanced capacity for eliciting cross-reactive neutralizing antibodies (NAbs) and to assess the overall breadth and potency of vaccine-elicited NAb reactivity, we assembled a panel of 109 molecularly cloned HIV-1 Env pseudoviruses representing a broad range of genetic and geographic diversity. Viral isolates from all major circulating genetic subtypes were included, as were viruses derived shortly after transmission and during the early and chronic stages of infection. We assembled a panel of genetically diverse HIV-1-positive (HIV-1+) plasma pools to assess the neutralization sensitivities of the entire virus panel. When the viruses were rank ordered according to the average sensitivity to neutralization by the HIV-1+ plasmas, a continuum of average sensitivity was observed. Clustering analysis of the patterns of sensitivity defined four subgroups of viruses: those having very high (tier 1A), above-average (tier 1B), moderate (tier 2), or low (tier 3) sensitivity to antibody-mediated neutralization. We also investigated potential associations between characteristics of the viral isolates (clade, stage of infection, and source of virus) and sensitivity to NAb. In particular, higher levels of NAb activity were observed when the virus and plasma pool were matched in clade. These data provide the first systematic assessment of the overall neutralization sensitivities of a genetically and geographically diverse panel of circulating HIV-1 strains. These reference viruses can facilitate the systematic characterization of NAb responses elicited by candidate vaccine immunogens.

Seaman, Michael S.; Janes, Holly; Hawkins, Natalie; Grandpre, Lauren E.; Devoy, Colleen; Giri, Ayush; Coffey, Rory T.; Harris, Linda; Wood, Blake; Daniels, Marcus G.; Bhattacharya, Tanmoy; Lapedes, Alan; Polonis, Victoria R.; McCutchan, Francine E.; Gilbert, Peter B.; Self, Steve G.; Korber, Bette T.; Montefiori, David C.; Mascola, John R.

2010-01-01

399

The Net Neutrality Debate: The Basics  

ERIC Educational Resources Information Center

|Rich Greenfield examines the basics of today's net neutrality debate that is likely to be an ongoing issue for society. Greenfield states the problems inherent in the definition of "net neutrality" used by Common Cause: "Network neutrality is the principle that Internet users should be able to access any web content they choose and use any…

Greenfield, Rich

2006-01-01

400

Ion-beam Plasma Neutralization Interaction Images  

SciTech Connect

Neutralization of the ion beam charge and current is an important scientific issue for many practical applications. The process of ion beam charge and current neutralization is complex because the excitation of nonlinear plasma waves may occur. Computer simulation images of plasma neutralization of the ion beam pulse are presented.

Igor D. Kaganovich; Edward Startsev; S. Klasky; Ronald C. Davidson

2002-04-09

401

Neutral beamline with improved ion energy recovery  

DOEpatents

A neutral beamline employing direct energy recovery of unneutralized residual ions is provided which enhances the energy recovery of the full energy ion component of the beam exiting the neutralizer cell, and thus improves the overall neutral beamline efficiency. The unneutralized full energy ions exiting the neutralizer are deflected from the beam path and the electrons in the cell are blocked by a magnetic field applied transverse to the beam direction in the neutral izer exit region. The ions which are generated at essentially ground potential and accelerated through the neutralizer cell by a negative acceleration voltage are collected at ground potential. A neutralizer cell exit end region is provided which allows the magnetic and electric fields acting on the exiting ions to be loosely coupled. As a result, the fractional energy ions exiting the cell are reflected onto and collected at an interior wall of the neutralizer formed by the modified end geometry, and thus do not detract from the energy recovery efficiency of full energy ions exiting the cell. Electrons within the neutralizer are prevented from exiting the neutralizer end opening by the action of crossed fields drift (ExB) and are terminated to a collector collar around the downstream opening of the neutralizer. The correct combination of the extended neutralizer end structure and the magnet region is designed so as to maximize the exit of full energy ions and to contain the fractional energy ions.

Kim, Jinchoon (San Diego, CA)

1984-01-01

402

Perspectives of neutral beam injection techniques  

Microsoft Academic Search

A description is presented of some of the problems associated with the design of a high-energy neutral injector. Apart from the use of clusters, energetic neutral atoms are produced by electron capture by positive ions, electron stripping of negative ions, or dissociation of molecular ions. Attention is given to the specification of the parameters of a neutral injector, the design

E. Thompson

1976-01-01

403

The 33 MW TFTR neutral beams  

Microsoft Academic Search

The TFTR (Tokamak Fusion Test Reactor) neutral beam injection system (NBIS) has performed injection experiments on TFTR since 1984. During the 1990 run period the NBIS exceeded previous levels, reaching a record 48 MJ (24 MW for 2 s) of neutral injected energy and, at a later date, a record neutral power of 33 MW, which produced a record plasma

T. Stevenson; J. Kamperschroer; L. Dudek; L. Grisham; R. Newman; T. O'Connor; A. von Halle; M. D. Williams

1991-01-01

404

Immunodeficiency and laser magnetic therapy in urology  

NASA Astrophysics Data System (ADS)

The importance of immunodeficiency problem has increased last time not only due to AIDS appearance, but also to a great extent as a result of the development and active practical use of the methods of immunology parameters investigations. Al great pharmaceutical firms are organizing the process of creating the drugs, influencing on the different phases of immunity, but unfortunately, the problem of their adverse effect and connected complications is till today a milestone. A great number of investigations, proving a good effect of laser-magnetic therapy concerning immune system have been done today. There is, in particular, changing of blood counts and immunologic tests after intravenous laser irradiation of blood. Intravenous laser irradiation of blood results in increasing of lymphocytes, T-immuno stimulation, stabilization of t-lymphocyte subpopulation, increasing of t-lymphocyte helper activity and decreasing of suppressor one.Under this laser action number of circulating immune complexes is decreased, and blood serum bactericide activity and lisozyme number are increased.

Maati, Moufagued; Rozanov, Vladimir V.; Avdoshin, V. P.

1996-11-01

405

Gastrointestinal Manifestations of the Acquired Immunodeficiency Syndrome  

PubMed Central

In addition to abnormalities in systemic immune function, patients with the acquired immunodeficiency syndrome (AIDS) and the pre-AIDS syndromes have significant abnormalities in the distribution of T-cell subsets in the intestinal tract. Such immune deficits predispose such patients to opportunistic infections and tumors, many of which involve the gastrointestinal tract. For example, Candida albicans often causes stomatitis and esophagitis. Intestinal infections with parasites (Cryptosporidium, Isospora belli, Microsporidia) or bacteria (Mycobacterium avium-intracellulare) are associated with severe diarrhea and malabsorption, whereas viruses like cytomegalovirus and herpes simplex virus cause mucosal ulcerations. Clinically debilitating chronic diarrhea develops in many AIDS patients for which no clear cause can be identified. Enteric pathogens like Salmonella and Campylobacter can be associated with bacteremias. Kaposi's sarcoma and lymphoma involving the intestinal tract are now well-recognized complications of AIDS. Although AIDS is not associated with a pathognomonic liver lesion, opportunistic infections and Kaposi's sarcoma or lymphoma may involve the liver. ImagesFigure 3.Figure 4.Figure 5.Figure 6.Figure 7.

Rodgers, Vance D.; Kagnoff, Martin F.

1987-01-01

406

A Stiffness Switch in Human Immunodeficiency Virus  

PubMed Central

After budding from the cell, human immunodeficiency virus (HIV) and other retrovirus particles undergo a maturation process that is required for their infectivity. During maturation, HIV particles undergo a significant internal morphological reorganization, changing from a roughly spherically symmetric immature particle with a thick protein shell to a mature particle with a thin protein shell and conical core. However, the physical principles underlying viral particle production, maturation, and entry into cells remain poorly understood. Here, using nanoindentation experiments conducted by an atomic force microscope (AFM), we report the mechanical measurements of HIV particles. We find that immature particles are more than 14-fold stiffer than mature particles and that this large difference is primarily mediated by the HIV envelope cytoplasmic tail domain. Finite element simulation shows that for immature virions the average Young's modulus drops more than eightfold when the cytoplasmic tail domain is deleted (930 vs. 115 MPa). We also find a striking correlation between the softening of viruses during maturation and their ability to enter cells, providing the first evidence, to our knowledge, for a prominent role for virus mechanical properties in the infection process. These results show that HIV regulates its mechanical properties at different stages of its life cycle (i.e., stiff during viral budding versus soft during entry) and that this regulation may be important for efficient infectivity. Our report of this maturation-induced “stiffness switch” in HIV establishes the groundwork for mechanistic studies of how retroviral particles can regulate their mechanical properties to affect biological function.

Kol, Nitzan; Shi, Yu; Tsvitov, Marianna; Barlam, David; Shneck, Roni Z.; Kay, Michael S.; Rousso, Itay

2007-01-01

407

Envelope-modified single-cycle simian immunodeficiency virus selectively enhances antibody responses and partially protects against repeated, low-dose vaginal challenge.  

PubMed

Immunization of rhesus macaques with strains of simian immunodeficiency virus (SIV) that are limited to a single cycle of infection elicits T-cell responses to multiple viral gene products and antibodies capable of neutralizing lab-adapted SIV, but not neutralization-resistant primary isolates of SIV. In an effort to improve upon the antibody responses, we immunized rhesus macaques with three strains of single-cycle SIV (scSIV) that express envelope glycoproteins modified to lack structural features thought to interfere with the development of neutralizing antibodies. These envelope-modified strains of scSIV lacked either five potential N-linked glycosylation sites in gp120, three potential N-linked glycosylation sites in gp41, or 100 amino acids in the V1V2 region of gp120. Three doses consisting of a mixture of the three envelope-modified strains of scSIV were administered on weeks 0, 6, and 12, followed by two booster inoculations with vesicular stomatitis virus (VSV) G trans-complemented scSIV on weeks 18 and 24. Although this immunization regimen did not elicit antibodies capable of detectably neutralizing SIV(mac)239 or SIV(mac)251(UCD), neutralizing antibody titers to the envelope-modified strains were selectively enhanced. Virus-specific antibodies and T cells were observed in the vaginal mucosa. After 20 weeks of repeated, low-dose vaginal challenge with SIV(mac)251(UCD), six of eight immunized animals versus six of six naïve controls became infected. Although immunization did not significantly reduce the likelihood of acquiring immunodeficiency virus infection, statistically significant reductions in peak and set point viral loads were observed in the immunized animals relative to the naïve control animals. PMID:20702641

Alpert, Michael D; Rahmberg, Andrew R; Neidermyer, William; Ng, Sharon K; Carville, Angela; Camp, Jeremy V; Wilson, Robert L; Piatak, Michael; Mansfield, Keith G; Li, Wenjun; Miller, Christopher J; Lifson, Jeffrey D; Kozlowski, Pamela A; Evans, David T

2010-08-11

408

Association of non-acquired immunodeficiency syndrome-defining cancers with human immunodeficiency virus infection.  

PubMed

Kaposi's sarcoma and non-Hodgkin's lymphoma were among the earliest recognized manifestations of the acquired immunodeficiency syndrome (AIDS) epidemic. Excluding these two tumors, the overall risk of all other cancers in human immunodeficiency virus (HIV)-infected individuals is similar to that of the general population. However, varying levels of evidence link several additional neoplasms to HIV infection. The evidence is strongest for an association with Hodgkin's disease, with lower relative and absolute risks than for non-Hodgkin's lymphoma. Anogenital intraepithelial neoplasia also appears to be HIV associated, but increases of invasive disease are still uncertain for both cervical and anal cancers. Various studies have suggested associations with testicular seminoma, multiple myeloma, oral cancer, and melanoma, but the data are inconsistent. Leiomyosarcoma and benign leiomyomas have increased in incidence in HIV-infected children but are unusual in HIV-infected adults. Conjunctival carcinoma is seen in HIV-infected individuals in sub-Saharan Africa but it is uncommon in Western countries. Most other cancers do not seem to have increased incidences in HIV infection. The etiologic mechanisms of HIV-related cancer likely differ among these diverse cancers and do not globally increase cancer risk. PMID:9709298

Rabkin, C S

1998-01-01

409

Prevention and treatment of human immunodeficiency virus/acquired immunodeficiency syndrome in resource-limited settings.  

PubMed Central

Strategies for confronting the epidemic of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) have included a range of different approaches that focus on prevention and treatment. However, debate persists over what levels of emphasis are appropriate for the different components of the global response. This paper presents an overview of this debate and briefly summarizes the evidence on a range of interventions designed to prevent the spread of HIV infection, paying particular attention to voluntary counselling and testing, treatment for sexually transmitted infections and prevention of mother-to-child transmission. We also review the experience with antiretroviral therapy to date in terms of response rates and survival rates, adherence, drug resistance, behavioural change and epidemiological impact. Although various studies have identified strategies with proven effectiveness in reducing the risks of HIV infection and AIDS mortality, considerable uncertainties remain. Successful integration of treatment and prevention of HIV/AIDS will require a balanced approach and rigorous monitoring of the impact of programmes in terms of both individual and population outcomes.

Hogan, Daniel R.; Salomon, Joshua A.

2005-01-01

410

Intravenous immunoglobulins in immunodeficiencies: more than mere replacement therapy.  

PubMed

Intravenous immunoglobulin (IVIG) is a therapeutic compound prepared from pools of plasma obtained from several thousand healthy blood donors. For more than 20 years, IVIG has been used in the treatment of a wide range of primary and secondary immunodeficiencies. IVIG now represents a standard therapeutic option for most antibody deficiencies. Routinely, IVIG is used in patients with X-linked agammaglobulinaemia (XLA), common variable immunodeficiency (CVID), X-linked hyper-IgM, severe combined immunodeficiency, Wiskott-Aldrich syndrome, and selective IgG class deficiency. In addition, IVIG is used extensively in the treatment of a wide variety of autoimmune disorders. IVIG is administered at distinct doses in the two clinical settings: whereas immunodeficient patients are treated with replacement levels of IVIG, patients with autoimmune and inflammatory diseases are administered with very high doses of IVIG. Several lines of experimental evidence gathered in the recent years suggest that the therapeutic beneficial effect of IVIG in immunodeficiencies reflects an active role for IVIG, rather than a mere passive transfer of antibodies. PMID:21466545

Kaveri, S V; Maddur, M S; Hegde, P; Lacroix-Desmazes, S; Bayry, J

2011-06-01

411

Neutral gas dynamics in fireballs  

SciTech Connect

Fireballs are local discharge phenomena on positively biased electrodes in partially ionized plasmas. Electrons, energized at a double layer, heat neutral gas which expands. The gas pressure exceeds the plasma pressure, hence becomes important to the stability and transport in fireballs. The flow of gas moves the electrode and sensors similar to a mica pendulum. Flow speed and directions are measured. A fireball gun has been developed to partially collimate the flow of hot gas and heat objects in its path. New applications of fireballs are suggested.

Stenzel, R. L. [Department of Physics and Astronomy, University of California, Los Angeles, California 90095-1547 (United States); Ionita, C.; Schrittwieser, R. [University of Innsbruck, Department for Ion Physics and Applied Physics, A-6020 Innsbruck (Austria)

2011-06-01

412

Human immunodeficiency virus–related lymphoma: relation between clinical features and histologic subtypes  

Microsoft Academic Search

PurposeNon-Hodgkin’s lymphoma occurs frequently in patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). We determined the association between the clinical and histologic features of HIV-related lymphoma.

Jean Gabarre; Martine Raphael; Eric Lepage; Antoine Martin; Eric Oksenhendler; Luc Xerri; Micheline Tulliez; Josée Audouin; Régis Costello; Jean Baptiste Golfier; Daniel Schlaifer; Olivier Hequet; Nabih Azar; Christine Katlama; Christian Gisselbrecht

2001-01-01

413

Increased titers of neutralizing antibodies after immunization with both envelope proteins of the porcine endogenous retroviruses (PERVs)  

PubMed Central

Despite enormous difficulties to induce antibodies neutralizing HIV-1, especially broadly neutralizing antibodies directed against the conserved membrane proximal external region (MPER) of the transmembrane envelope protein, such antibodies can be easily induced in the case of gammaretroviruses, among them the porcine endogenous retroviruses (PERVs). In addition to neutralizing antibodies directed against the transmembrane envelope protein p15E, neutralizing antibodies were also induced by immunization with the surface envelope protein gp70. PERVs represent a special risk for xenotransplantation using pig tissues or organs since they are integrated in the genome of all pigs and infect human cells and a vaccine may protect from transmission to the recipient. To investigate the effect of simultaneous immunization with both proteins in detail, a study was performed in hamsters. Gp70 and p15E of PERV were produced in E. coli, purified and used for immunization. All animals developed binding antibodies against the antigens used for immunization. Sera from animals immunized with p15E recognized epitopes in the MPER and the fusion peptide proximal region (FPPR) of p15E. One MPER epitope showed a sequence homology to an epitope in the MPER of gp41 of HIV-1 recognized by broadly neutralizing antibodies found in HIV infected individuals. Neutralizing antibodies were detected in all sera. Most importantly, sera from animals immunized with gp70 had a higher neutralizing activity when compared with the sera from animals immunized with p15E and sera from animals immunized with gp70 together with p15E had a higher neutralizing activity compared with sera from animals immunized with each antigen alone. These immunization studies are important for the development of vaccines against other retroviruses including the human immunodeficiency virus HIV-1.

2012-01-01

414

Differences in the antibody response to human immunodeficiency virus-1 envelope glycoprotein (gp160) in infected laboratory workers and vaccinees.  

PubMed Central

Studies of the immune response to the human immunodeficiency virus (HIV) have been hampered by the antigenic diversity of the HIV envelope protein. In an effort to predict the efficacy of vaccination we have compared the systemic anti-envelope antibody response in seronegative volunteers immunized with recombinant gp160 (either in vaccinia or as soluble protein produced in baculovirus) derived from the HTLV-IIIB strain of HIV-1 and in two laboratory workers accidentally infected with the same strain. 11 of 14 vaccinees responded to immunization by producing anti-gp160 of similar titer and the same isotype as that seen in the laboratory workers. Four vaccinees also had antibody to the principal neutralizing domain (V3 loop) that was comparable in titer with that seen in the laboratory workers, but the fine specificity of anti-V3 antibody was qualitatively different in the two groups. Antibody that can block the interaction between CD4 and gp120 was present at comparable levels in three vaccines and the lab workers. Neutralizing antibody titers were markedly lower in the vaccinees than in the laboratory workers. In seven of the vaccinees, an immunodominant epitope was at amino acid 720-740. Analyses of monoclonal antibodies to this region indicate that they do not neutralize, bind to infected cells, nor function as immunotoxins. Although the anti-gp160 antibody response was of similar magnitude in both infected and vaccinated individuals, there were important qualitative differences.

Pincus, S H; Messer, K G; Schwartz, D H; Lewis, G K; Graham, B S; Blattner, W A; Fisher, G

1993-01-01

415

Human papillomavirus, human immunodeficiency virus and immunosuppression.  

PubMed

The vast majority of women infected with human immunodeficiency virus (HIV) will be co-infected with human papillomavirus (HPV). The interaction between the two sexually transmitted infections appears to be related to the alteration in cell-mediated immunity in HIV infected persons, increased susceptibility, and possibly reactivation of latent HPV infection. Linkage studies of HIV/AIDs and Cancer registries have indicated a 2- to 22-fold increase in cervical cancer in HIV-positive women compared to HIV-negative women. Data on the prevalence of HPV types in invasive cervical carcinoma (ICC) suggest that the proportion of infection with types HPV16/18 (responsible for over 70% of all cervical cancers) is similar in HIV-negative and HIV-positive women. The biological interaction between HIV and HPV needs further elucidation, although there is some evidence that the presence of HPV infection may be associated with increased HIV transmission. Adolescents perinatally infected by HIV are known to have higher rates of HPV infection and also have been shown to seroconvert in response to HPV vaccination with the quadrivalent vaccine, albeit to lower titers than HIV-negative individuals. Anal cancer incidence is greatly increased in HIV-positive individuals, particularly in HIV-positive men who have sex with men. Screening for anal cancer precursors is feasible and effective; however, the impact on reduction of anal cancer remains to be demonstrated. There are ongoing studies on the safety, immunogenicity, and efficacy of current HPV vaccines in HIV-positive individuals and mature data are awaited. Male circumcision may be another approach to prevention of HPV transmission, which also requires further study. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012. PMID:23199960

Denny, Lynette A; Franceschi, Silvia; de Sanjosé, Silvia; Heard, Isabelle; Moscicki, Anna Barbara; Palefsky, Joel

2012-11-20

416

Bioengineering Human Microvascular Networks in Immunodeficient Mice  

PubMed Central

The future of tissue engineering and cell-based therapies for tissue regeneration will likely rely on our ability to generate functional vascular networks in vivo. In this regard, the search for experimental models to build blood vessel networks in vivo is of utmost importance 1. The feasibility of bioengineering microvascular networks in vivo was first shown using human tissue-derived mature endothelial cells (ECs) 2-4; however, such autologous endothelial cells present problems for wide clinical use, because they are difficult to obtain in sufficient quantities and require harvesting from existing vasculature. These limitations have instigated the search for other sources of ECs. The identification of endothelial colony-forming cells (ECFCs) in blood presented an opportunity to non-invasively obtain ECs 5-7. We and other authors have shown that adult and cord blood-derived ECFCs have the capacity to form functional vascular networks in vivo7-11. Importantly, these studies have also shown that to obtain stable and durable vascular networks, ECFCs require co-implantation with perivascular cells. The assay we describe here illustrates this concept: we show how human cord blood-derived ECFCs can be combined with bone marrow-derived mesenchymal stem cells (MSCs) as a single cell suspension in a collagen/fibronectin/fibrinogen gel to form a functional human vascular network within 7 days after implantation into an immunodeficient mouse. The presence of human ECFC-lined lumens containing host erythrocytes can be seen throughout the implants indicating not only the formation (de novo) of a vascular network, but also the development of functional anastomoses with the host circulatory system. This murine model of bioengineered human vascular network is ideally suited for studies on the cellular and molecular mechanisms of human vascular network formation and for the development of strategies to vascularize engineered tissues.

Lin, Ruei-Zeng; Melero-Martin, Juan M.

2011-01-01

417

Medical management of human immunodeficiency virus infection  

PubMed Central

The human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome (AIDS) pandemic has pervasive effects on culture, economics, policy, and human development. All organs can be affected by complications of HIV/AIDS, including the eye. When sufficient resources are available and widespread antiretroviral resistance does not exist, the four available classes of antiretroviral agents - nucleoside/ nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors - can be combined to provide highly active antiretroviral therapy (HAART). For many (not all) patients, HAART converts an inexorably fatal disease into a chronic disease with a fairly good prognosis. Use of HAART often induces partial immune recovery, which has predominantly beneficial effects on ocular complications of AIDS. However, HAART-induced immune recovery sometimes results in immune recovery inflammatory syndromes, such as immune recovery uveitis. Use of HAART is the single most useful intervention for most patients with ocular complications of AIDS. However, specific ocular therapy is also critical to avoid blindness in the early months before immune recovery can occur, or if HAART is unavailable. Increasing availability of HAART worldwide shows great promise to alleviate one of the world?s greatest plagues. However, predictable secular trends in the AIDS epidemic make it likely that the number of cases of ocular complications of AIDS will increase substantially before they decrease. Ophthalmologists worldwide should be familiar with the diagnosis and management of cytomegalovirus retinitis - the most common ocular complication of AIDS - and should establish partnerships with physicians who are able to provide HAART. Research is needed to determine the optimal approach for managing cytomegalovirus retinitis in resource- constrained settings.

2008-01-01

418

Instabilities in Neutral and Non-Neutral Plasmas.  

NASA Astrophysics Data System (ADS)

The objective of the research reported herein was to develop theories and conduct numerical investigations of some specific plasma instabilities. This thesis consists of two distinct parts--parametric instabilities in non -neutral plasma (the first part) and drift instabilities in neutral plasmas (the second part). Chapter I presents a discussion of the historical background in experiments and theoretical development of non-neutral plasmas related to the free electron laser (a new, powerful and coherent source of electromagnetic radiation). In Chapter II, an analysis of the parametric excitation of fast and slow space-charge waves in a cylindrical metallic waveguide filled with relativistic beam electrons is presented. The pump wave in the laboratory reference frame consists of a static, spatially periodic axial electric field. Formulas are derived for the temporal growth rate and frequency of the backscattered fast space-charge wave in both the laboratory and beam frames. The effects of a uniform axial magnetic field of arbitrary magnitude on the amplitude gain and frequency enhancement are studied. In Chapter III, parametric decay of a longitudinal electrostatic pump wave into two space-charge waves in a cylindrical metallic waveguide partially filled with relativistic beam electrons is analyzed. The dependence of the amplitude gain factor and frequency enhancement on the ratio of beam radius to waveguide radius is studied numerically. In Chapter IV, theoretical determination of the dispersion curve and electrostatic potential for drift waves in a quadrupole plasma is carried out. Linear theory is employed to derive and solve numerically an equation for the eigenvalue (frequency omega) and the eigenfunction (electrostatic potential) as a function of the distance along a magnetic field line for each given value of the axial wave number k_{ rm z}. Chapter V presents the general theory of Landau resonances which will permit calculation of the growth or damping rate of electrostatic waves in the magnetic quadrupole. In Chapter VI, electrostatic drift waves with frequency small compared to the ion cyclotron frequency in a plasma confined by a magnetic quadrupole are considered. An