Sustained Delivery of a Broadly Neutralizing Antibody in Nonhuman Primates Confers Long-Term Protection against Simian/Human Immunodeficiency Virus Infection

ABSTRACTPathogen-specific neutralizing antibodies protect against many viral infections and can potentially prevent human immunodeficiency virus (HIV) transmission in humans. However, neutralizing antibodies have so far only been shown to protect nonhuman primates (NHP) against lentiviral infection when given shortly before challenge. Thus, the clinical utility and feasibility of passive antibody transfer to confer long-term protection against HIV-1 are still debated. Here, we investigate the potential of a broadly neutralizing HIV-1 antibody to provide long-term protection in a NHP model of HIV-1 infection. A human antibody was simianized to avoid immune rejection and used to sustain therapeutic levels for ∼5 months. Two months after the final antibody administration, animals were completely protected against viral challenge. These findings demonstrate the feasibility and potential of long-term passive antibody for protection against HIV-1 in humans and provide a model to test antibody therapies for other diseases in NHP.IMPORTANCEAntibodies against HIV are potential drugs that may be able to prevent HIV infection in humans. However, the long-term protective capacity of antibodies against HIV has not been assessed. Here, we repetitively administered a macaque version of a human anti-HIV antibody to monkeys, after which the antibody persisted in the blood for >5 months. Moreover, the antibody could be sustained at protective levels for 108 days, conferring protection 52 days after the last dose in a monkey model of HIV infection. Thus, passive antibody transfer can provide durable protection against infection by viruses that cause AIDS in primates.

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Late diagnosis of human immunodeficiency virus infections in high-risk groups in Karachi, Pakistan

International Journal of STD & AIDS ◽

10.1177/0956462418785264 ◽

2018 ◽

Vol 29 (14) ◽

pp. 1400-1406

Author(s):

Zahra Hasan ◽

Sharaf Shah ◽

Rumina Hasan ◽

Shoaib Rao ◽

Manzoor Ahmed ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

High Risk ◽

Early Diagnosis ◽

Hiv Infection ◽

Hiv Infections ◽

Risk Groups ◽

Newly Diagnosed ◽

Immunodeficiency Virus ◽

Hiv 1

Human immunodeficiency virus (HIV) infection prevalence in Pakistan has been increasing in high-risk groups, including people who inject drugs (PWID) and transgender hijra sex workers (TG-HSWs) nationwide. Effective control of HIV requires early diagnosis of the infection. We investigated recency of HIV infections in newly-diagnosed cases in PWID and TG-HSWs. This was an observational study with convenience sampling. Overall, 210 HIV-positive subjects comprising an equal number of PWID and TG-HSWs were included. Antibody avidity was tested using the Maxim HIV-1 Limiting Antigen Avidity (LAg) EIA (Maxim Biomedical, Inc. Rockville, Maryland, USA). The mean age of study subjects was 29.5 years: PWID, 28.5 years and TG-HSWs, 30.4 years. Study subjects were married, 27%, or unmarried. Eighteen percent of individuals had recently-acquired HIV infections: 19% of PWID and 17% of TG-HSWs. Eighty-two percent of individuals had long-term HIV infections: 81% of PWID and 83% of TG-HSWs. This is the first study identification of recent HIV-1 infections in Pakistan. We show that most newly-diagnosed HIV patients in the high-risk groups studied had long-term infections. There is an urgent need for intervention in these groups to facilitate early diagnosis and treatment of HIV infection to reduce transmission in Pakistan.

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Serum Levels of Human Immunodeficiency Virus Type 1 (HIV‐1) RNA after Seroconversion: A Predictor of Long‐Term Mortality in HIV Infection

The Journal of Infectious Diseases ◽

10.1086/517305 ◽

1997 ◽

Vol 176 (3) ◽

pp. 798-800 ◽

Cited By ~ 23

Author(s):

Kevin J. P. Craib ◽

Steffanie A. Strathdee ◽

Robert S. Hogg ◽

Barbara Leung ◽

Julio S. G. Montaner ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Hiv Infection ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Serum Levels ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Long Term Mortality

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Neutralization Synergy of Human Immunodeficiency Virus Type 1 Primary Isolates by Cocktails of Broadly Neutralizing Antibodies

Journal of Virology ◽

10.1128/jvi.75.24.12198-12208.2001 ◽

2001 ◽

Vol 75 (24) ◽

pp. 12198-12208 ◽

Cited By ~ 128

Author(s):

Michael B. Zwick ◽

Meng Wang ◽

Pascal Poignard ◽

Gabriela Stiegler ◽

Hermann Katinger ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Fixed Ratio ◽

Human Antibody ◽

Human Mabs ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Several reports have described the existence of synergy between neutralizing monoclonal antibodies (MAbs) against human immunodeficiency virus type 1 (HIV-1). Synergy between human MAbs b12, 2G12, 2F5, and 4E10 in neutralization of primary isolates is of particular interest. Neutralization synergy of these MAbs, however, has not been studied extensively, and the mechanism of synergy remains unclear. We investigated neutralization synergy among this human antibody set by using the classical approach of titrating antibodies mixed at a fixed ratio as well as by an alternative, variable ratio approach in which the neutralization curve of one MAb is assessed in the presence and absence of a fixed, weakly neutralizing concentration of a second antibody. The advantage of this second approach is that it does not require mathematical analysis to establish synergy. No neutralization enhancement of any of the MAb combinations tested was detected for the T-cell-line-adapted molecular HIV-1 clone HxB2 using both assay formats. Studies of primary isolates (89.6, SF162, and JR-CSF) showed neutralization synergy which was relatively weak, with a maximum of two- to fourfold enhancement between antibody pairs, thereby increasing neutralization titers about 10-fold in triple and quadruple antibody combinations. Analysis of b12 and 2G12 binding to oligomeric envelope glycoprotein by using flow cytometry failed to demonstrate cooperativity in binding between these two antibodies. The mechanism by which these antibodies synergize is, therefore, not yet understood. The results lend some support to the notion that an HIV-1 vaccine that elicits moderate neutralizing antibodies to multiple epitopes may be more effective than hereto supposed, although considerable caution in extrapolating to a vaccine situation is required.

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Development of Antibodies with Broad Neutralization Specificities against HIV-1 after Long Term SHIV Infection in Macaques

Viruses ◽

10.3390/v12020163 ◽

2020 ◽

Vol 12 (2) ◽

pp. 163 ◽

Cited By ~ 3

Author(s):

Nan Gao ◽

Yanxin Gai ◽

Lina Meng ◽

Chu Wang ◽

Xin Zhang ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Neutralizing Antibodies ◽

Plasma Samples ◽

Broadly Neutralizing Antibodies ◽

Immunodeficiency Virus ◽

Longitudinal Plasma ◽

Protection Efficacy ◽

Shiv Infection ◽

Hiv 1

Non-human primates (NHP) are the only animal model suitable to evaluate the protection efficacy of HIV-1 vaccines. It is important to understand how and when neutralizing antibodies (nAbs) with specificities similar to those of human broadly neutralizing antibodies (bnAbs) develop in NHPs. To address these questions, we determined plasma neutralization specificities in two macaques which developed neutralization breadth after long-term simian/human immunodeficiency virus (SHIV) infection and identified neutralization escape mutations by analyzing the env sequences from longitudinal plasma samples. Neutralization activities targeting V2, CD4bs, V3 and gp120-gp41 interface only became detectable in week 350 plasma from macaques G1015R and G1020R using 25710 env mutants. When mapped with CAP45 env mutants, only V2 specificity was detected at week 217 and persisted until week 350 in G1015R. Neutralization escape mutations were found in CD4bs and V2 regions. However, all of them were different from those resistant mutations identified for human bnAbs. These results show that nAbs with specificities similar to human bnAbs are only detectable after long-term SHIV infection and that neutralization escape mutations in macaques are different from those found in HIV-1-infected individuals. These findings can have important implications in the best utilization of the NHP model to evaluate HIV-1 vaccines.

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Effector Function Activities of a Panel of Mutants of a Broadly Neutralizing Antibody against Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.75.24.12161-12168.2001 ◽

2001 ◽

Vol 75 (24) ◽

pp. 12161-12168 ◽

Cited By ~ 151

Author(s):

Marjan Hezareh ◽

Ann J. Hessell ◽

Richard C. Jensen ◽

Jan G. J. van de Winkel ◽

Paul W. H. I. Parren

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Human Antibody ◽

Immunodeficiency Virus ◽

Infected Cells ◽

Human Igg1 ◽

Hiv 1

ABSTRACT The human antibody immunoglobulin G1 (IgG1) b12 neutralizes a broad range of human immunodeficiency virus-type 1 (HIV-1) isolates in vitro and is able to protect against viral challenge in animal models. Neutralization of free virus, which is an antiviral activity of antibody that generally does not require the antibody Fc fragment, likely plays an important role in the protection observed. The role of Fc-mediated effector functions, which may reduce infection by inducing phagocytosis and lysis of virions and infected cells, however, is less clear. To investigate this role, we constructed a panel of IgG1 b12 mutants with point mutations in the second domain of the antibody heavy chain constant region (CH2). These mutations, as expected, did not affect gp120 binding or HIV-1 neutralization. IgG1 b12 mediated strong antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of HIV-1-infected cells, but these activities were reduced or abrogated for the antibody mutants. Two mutants were of particular interest. K322A showed a twofold reduction in FcγR binding affinity and ADCC, while C1q binding and CDC were abolished. A double mutant (L234A, L235A) did not bind either FcγR or C1q, and both ADCC and CDC functions were abolished. In this study, we confirmed that K322 forms part of the C1q binding site in human IgG1 and plays an important role in the molecular interactions leading to complement activation. Less expectedly, we demonstrate that the lower hinge region in human IgG1 has a strong modulating effect on C1q binding and CDC. The b12 mutants K322A and L234A, L235A are useful tools for dissecting the in vivo roles of ADCC and CDC in the anti-HIV-1 activity of neutralizing antibodies.

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Combined Genotypes of CCR5, CCR2, SDF1, and HLA Genes Can Predict the Long-Term Nonprogressor Status in Human Immunodeficiency Virus-1–Infected Individuals

Blood ◽

10.1182/blood.v93.3.936 ◽

1999 ◽

Vol 93 (3) ◽

pp. 936-941 ◽

Cited By ~ 151

Author(s):

Magdalena Magierowska ◽

Ioannis Theodorou ◽

Patrice Debré ◽

Françoise Sanson ◽

Brigitte Autran ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Chemokine Receptor ◽

Multivariate Logistic Regression Model ◽

Hla B27 ◽

Hla Alleles ◽

Immunodeficiency Virus ◽

Combined Genotypes ◽

Hiv 1

Abstract Human immunodeficiency virus (HIV)-1–infected long-term nonprogressors (LT-NP) represent less than 5% of HIV-1–infected patients. In this work, we tried to understand whether combined genotypes of CCR5-▵32, CCR2-64I, SDF1-3′A and HLA alleles can predict the LT-NP status. Among the chemokine receptor genotypes, only the frequency of the CCR5-▵32 allele was significantly higher in LT-NP compared with the group of standard progressors. The predominant HLA alleles in LT-NP were HLA-A3, HLA-B14, HLA-B17, HLA-B27, HLA-DR6, and HLA-DR7. A combination of both HLA and chemokine receptor genotypes integrated in a multivariate logistic regression model showed that if a subject is heterozygous for CCR5-▵32 and homozygous for SDF1 wild type, his odds of being LT-NP are increased by 16-fold, by 47-fold when a HLA-B27 allele is present with HLA-DR6 absent, and by 47-fold also if at least three of the following alleles are present: HLA-A3, HLA-B14, HLA-B17, HLA-DR7. This model allowed a correct classification of 70% of LT-NPs and 81% of progressors, suggesting that the host’s genetic background plays an important role in the evolution of HIV-1. The chemokine receptor and chemokine genes along with the HLA genotype can serve as predictors of HIV-1 outcome for classification of HIV-1–infected subjects as LT-NPs or progressors.

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Human immunodeficiency virus 1. Predominance of a group-specific neutralizing epitope that persists despite genetic variation.

Journal of Experimental Medicine ◽

10.1084/jem.170.5.1681 ◽

1989 ◽

Vol 170 (5) ◽

pp. 1681-1695 ◽

Cited By ~ 27

Author(s):

I Berkower ◽

G E Smith ◽

C Giri ◽

D Murphy

Keyword(s):

Genetic Diversity ◽

Human Immunodeficiency Virus ◽

Neutralizing Antibodies ◽

Neutralizing Epitope ◽

Vaccine Strategy ◽

Disease Pathogenesis ◽

Immunodeficiency Virus ◽

High Degree ◽

Hiv 1 ◽

Human Immunodeficiency Virus 1

HIV-1 is known to show a high degree of genetic diversity, which may have major implications for disease pathogenesis and prevention. If every divergent isolate represented a distinct serotype, then effective vaccination might be impossible. However, using a sensitive new plaque-forming assay for HIV-1, we have found that most infected patients make neutralizing antibodies, predominantly to a group-specific epitope shared among three highly divergent isolates. This epitope persists among divergent isolates and rarely mutates, despite the rapid overall mutation rate of HIV-1, suggesting that it may participate in an essential viral function. These findings, plus the rarity of reinfections among these patients, suggest that HIV-1 may be more susceptible to a vaccine strategy based on a group-specific neutralizing epitope than was previously suspected.

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Interleukin 7 Increases Human Immunodeficiency Virus Type 1 LAI-Mediated Fas-Induced T-Cell Death

Journal of Virology ◽

10.1128/jvi.79.5.3195-3199.2005 ◽

2005 ◽

Vol 79 (5) ◽

pp. 3195-3199 ◽

Cited By ~ 15

Author(s):

Jean-Daniel Lelièvre ◽

Frédéric Petit ◽

Damien Arnoult ◽

Jean-Claude Ameisen ◽

Jérôme Estaquier

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Cell Death ◽

T Cell ◽

Hiv Infection ◽

Cell Infection ◽

Interleukin 7 ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Fas-mediated T-cell death is known to occur during human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 LAI (HIV-1LAI) primes CD8+ T cells from healthy donors for apoptosis, which occurs after Fas ligation. This effect is counteracted by a broad caspase inhibitor (zVAD-fmk). Fas-mediated cell death does not depend on CD8+ T-cell infection, because it occurred in the presence of reverse transcriptase inhibitors. However, purified CD8+ T cells are sensitive to Fas only in the presence of soluble CD4. Finally, we found that interleukin 7 (IL-7) increases Fas-mediated CD4+ and CD8+ T-cell death induced by HIV-1LAI. Since high levels of IL-7 are a marker of poor prognosis during HIV infection, our data suggest that enhancement of Fas-mediated T-cell death by HIV-1LAI and IL-7 is one of the mechanisms involved in progression to AIDS.

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Grossly Defective nef Gene Sequences in a Human Immunodeficiency Virus Type 1-Seropositive Long-Term Nonprogressor

Journal of Virology ◽

10.1128/jvi.72.5.3646-3657.1998 ◽

1998 ◽

Vol 72 (5) ◽

pp. 3646-3657 ◽

Cited By ~ 121

Author(s):

Roberto Salvi ◽

Anna Rosa Garbuglia ◽

Antonino Di Caro ◽

Simonetta Pulciani ◽

Francesco Montella ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Length Polymorphism ◽

Mononuclear Cells ◽

Polymorphism Analysis ◽

Immunodeficiency Virus ◽

Peripheral Mononuclear Cells ◽

Hiv 1

ABSTRACT We have been investigating a long-term nonprogressor who was found to be human immunodeficiency virus type 1 (HIV-1) seropositive in 1985 and has survived with stable CD4+ T-cell counts (>1,000 CD4 cells/μl) without any AIDS-related illness. We have previously reported that repeated attempts to measure HIV-1 RNA in the peripheral mononuclear cells obtained from this subject have invariably failed. In the present study, we have analyzed the molecular nature of the HIV-1 quasispecies infecting this patient by PCR amplification of two proviral regions, the 5′ long terminal repeat (5′LTR)/gagleader and the nef gene, directly from fresh uncultured peripheral mononuclear cells, followed by length polymorphism analysis (with 1994, 1995, and 1996 samples) and sequencing (with a 1996 sample). Only proviral forms with nef deletions were revealed by length polymorphism analysis in samples from all three time points. Sequence analysis of the nef gene from the 1996 sample confirmed the presence of similar proviral quasispecies characterized by the presence of several deletions located in thenef-alone and the nef/U3 overlapping regions. Length polymorphism analysis of the 5′LTR/gag leader region suggested the existence of two major quasispecies populations, one characterized by the presence of forms carrying deletions in the U3 region and the other showing a completely intact, full-length 5′LTR. Evidence of the role of nef gene defects in long-term survival of HIV-1-infected patients has been provided so far in two independent investigations involving patients infected with HIV through blood transfusion. Here we show the existence of a similar condition in a subject who acquired HIV-1 seropositivity through the sexual route.

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Neutralizing Antibody Responses in Acute Human Immunodeficiency Virus Type 1 Subtype C Infection

Journal of Virology ◽

10.1128/jvi.00239-07 ◽

2007 ◽

Vol 81 (12) ◽

pp. 6187-6196 ◽

Cited By ~ 209

Author(s):

E. S. Gray ◽

P. L. Moore ◽

I. A. Choge ◽

J. M. Decker ◽

F. Bibollet-Ruche ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Subtype C ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The study of the evolution and specificities of neutralizing antibodies during the course of human immunodeficiency virus type 1 (HIV-1) infection may be important in the discovery of possible targets for vaccine design. In this study, we assessed the autologous and heterologous neutralization responses of 14 HIV-1 subtype C-infected individuals, using envelope clones obtained within the first 2 months postinfection. Our data show that potent but relatively strain-specific neutralizing antibodies develop within 3 to 12 months of HIV-1 infection. The magnitude of this response was associated with shorter V1-to-V5 envelope lengths and fewer glycosylation sites, particularly in the V1-V2 region. Anti-MPER antibodies were detected in 4 of 14 individuals within a year of infection, while antibodies to CD4-induced (CD4i) epitopes developed to high titers in 12 participants, in most cases before the development of autologous neutralizing antibodies. However, neither anti-MPER nor anti-CD4i antibody specificity conferred neutralization breadth. These data provide insights into the kinetics, potency, breadth, and epitope specificity of neutralizing antibody responses in acute HIV-1 subtype C infection.

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