Human Immunodeficiency Virus Type 1 Superinfection Occurs despite Relatively Robust Neutralizing Antibody Responses

ABSTRACT Superinfection by a second human immunodeficiency virus type 1 (HIV-1) strain indicates that gaps in protective immunity occur during natural infection. To define the role of HIV-1-specific neutralizing antibodies (NAbs) in this setting, we examined NAb responses in 6 women who became superinfected between ∼1 to 5 years following initial infection compared to 18 women with similar risk factors who did not. Although superinfected individuals had less NAb breadth than matched controls at ∼1 year postinfection, no significant differences in the breadth or potency of NAb responses were observed just prior to the second infection. In fact, four of the six subjects had relatively broad and potent NAb responses prior to infection by the second strain. To more specifically examine the specificity of the NAbs against the superinfecting virus, these variants were cloned from five of the six individuals. The superinfecting variants did not appear to be inherently neutralization resistant, as measured against a pool of plasma from unrelated HIV-infected individuals. Moreover, the superinfected individuals were able to mount autologous NAb responses to these variants following reinfection. In addition, most superinfected individuals had NAbs that could neutralize their second viral strains prior to their reinfection, suggesting that the level of NAbs elicited during natural infection was not sufficient to block infection. These data indicate that preventing infection by vaccination will likely require broader and more potent NAb responses than those found in HIV-1-infected individuals.

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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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Viral Phenotypes and Antibody Responses in Long-Term Survivors Infected with Attenuated Human Immunodeficiency Virus Type 1 Containing Deletions in the nef and Long Terminal Repeat Regions

Journal of Virology ◽

10.1128/jvi.00650-07 ◽

2007 ◽

Vol 81 (17) ◽

pp. 9268-9278 ◽

Cited By ~ 14

Author(s):

Erin E. Verity ◽

Dimitra Zotos ◽

Kim Wilson ◽

Catherine Chatfield ◽

Victoria A. Lawson ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Wild Type Virus ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The Sydney Blood Bank Cohort (SBBC) consists of eight blood transfusion recipients infected with nef-attenuated human immunodeficiency virus type 1 (HIV-1) acquired from a single donor. Here, we show that viral phenotypes and antibody responses differ considerably between individual cohort members, despite the single source of infection. Replication of isolated virus varied from barely detectable to similar to that of the wild-type virus, and virus isolated from five SBBC members showed coreceptor usage signatures unique to each individual. Higher viral loads and stronger neutralizing antibody responses were associated with better-replicating viral strains, and detectable viral replication was essential for the development of strong and sustained humoral immune responses. Despite the presence of strong neutralizing antibodies in a number of SBBC members, disease progression was not prevented, and each cohort member studied displayed a unique outcome of infection with nef-attenuated HIV-1.

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Human Immunodeficiency Virus Type 1 Escape from Cyclotriazadisulfonamide-Induced CD4-Targeted Entry Inhibition Is Associated with Increased Neutralizing Antibody Susceptibility

Journal of Virology ◽

10.1128/jvi.00648-09 ◽

2009 ◽

Vol 83 (18) ◽

pp. 9577-9583 ◽

Cited By ~ 7

Author(s):

Kurt Vermeire ◽

Kristel Van Laethem ◽

Wouter Janssens ◽

Thomas W. Bell ◽

Dominique Schols

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Receptor Expression ◽

Antibody Treatment ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Continuous specific downmodulation of CD4 receptor expression in T lymphocytes by the small molecule cyclotriazadisulfonamide (CADA) selected for the CADA-resistant human immunodeficiency virus type 1 (HIV-1) NL4.3 virus containing unique mutations in the C4 and V5 regions of gp120, likely stabilizing the CD4-binding conformation. The amino acid changes in Env were associated with decreased susceptibility to anti-CD4 monoclonal antibody treatment of the cells and with higher susceptibility of the virus to soluble CD4. In addition, the acquired ability of a CADA-resistant virus to infect cells with low CD4 expression was associated with an increased susceptibility of the virus to neutralizing antibodies from sera of several HIV-1-infected patients.

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Vaccine-Elicited V3 Loop-Specific Antibodies in Rhesus Monkeys and Control of a Simian-Human Immunodeficiency Virus Expressing a Primary Patient Human Immunodeficiency Virus Type 1 Isolate Envelope

Journal of Virology ◽

10.1128/jvi.75.9.4165-4175.2001 ◽

2001 ◽

Vol 75 (9) ◽

pp. 4165-4175 ◽

Cited By ~ 43

Author(s):

Norman L. Letvin ◽

Suzanne Robinson ◽

Daniela Rohne ◽

Michael K. Axthelm ◽

John W. Fanton ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Peptide Vaccine ◽

Neutralizing Antibody ◽

V3 Loop ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Vaccine-elicited antibodies specific for the third hypervariable domain of the surface gp120 of human immunodeficiency virus type 1 (HIV-1) (V3 loop) were assessed for their contribution to protection against infection in the simian-human immunodeficiency virus (SHIV)/rhesus monkey model. Peptide vaccine-elicited anti-V3 loop antibody responses were examined for their ability to contain replication of SHIV-89.6, a nonpathogenic SHIV expressing a primary patient isolate HIV-1 envelope, as well as SHIV-89.6P, a pathogenic variant of that virus. Low-titer neutralizing antibodies to SHIV-89.6 that provided partial protection against viremia following SHIV-89.6 infection were generated. A similarly low-titer neutralizing antibody response to SHIV-89.6P that did not contain viremia after infection with SHIV-89.6P was generated, but a trend toward protection against CD4+ T-lymphocyte loss was seen in these infected monkeys. These observations suggest that the V3 loop on some primary patient HIV-1 isolates may be a partially effective target for neutralizing antibodies induced by peptide immunogens.

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Neutralizing Antibodies from the Sera of Human Immunodeficiency Virus Type 1-Infected Individuals Bind to Monomeric gp120 and Oligomeric gp140

Journal of Virology ◽

10.1128/jvi.72.12.9656-9667.1998 ◽

1998 ◽

Vol 72 (12) ◽

pp. 9656-9667 ◽

Cited By ~ 28

Author(s):

Nicholas M. Stamatos ◽

John R. Mascola ◽

Vaniambadi S. Kalyanaraman ◽

Mark K. Louder ◽

Lynn M. Frampton ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Immunodeficiency Virus ◽

Monomeric Gp120 ◽

Antibody Specificities ◽

Hiv 1

ABSTRACT Antibodies that neutralize primary isolates of human immunodeficiency virus type 1 (HIV-1) appear during HIV-1 infection but are difficult to elicit by immunization with current vaccine products comprised of monomeric forms of HIV-1 envelope glycoprotein gp120. The limited neutralizing antibody response generated by gp120 vaccine products could be due to the absence or inaccessibility of the relevant epitopes. To determine whether neutralizing antibodies from HIV-1-infected patients bind to epitopes accessible on monomeric gp120 and/or oligomeric gp140 (ogp140), purified total immunoglobulin from the sera of two HIV-1-infected patients as well as pooled HIV immune globulin were selectively depleted of antibodies which bound to immobilized gp120 or ogp140. After passage of each immunoglobulin preparation through the respective columns, antibody titers against gp120 and ogp140 were specifically reduced at least 128-fold. The gp120- and gp140-depleted antibody fraction from each serum displayed reduced neutralization activity against three primary and two T-cell line-adapted (TCLA) HIV-1 isolates. Significant residual neutralizing activity, however, persisted in the depleted sera, indicating additional neutralizing antibody specificities. gp120- and ogp140-specific antibodies eluted from each column neutralized both primary and TCLA viruses. These data demonstrate the presence and accessibility of epitopes on both monomeric gp120 and ogp140 that are specific for antibodies that are capable of neutralizing primary isolates of HIV-1. Thus, the difficulties associated with eliciting neutralizing antibodies by using current monomeric gp120 subunit vaccines may be related less to improper protein structure and more to ineffective immunogen formulation and/or presentation.

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Neutralizing Antibodies Associated with Viremia Control in a Subset of Individuals after Treatment of Acute Human Immunodeficiency Virus Type 1 Infection

Journal of Virology ◽

10.1128/jvi.75.21.10200-10207.2001 ◽

2001 ◽

Vol 75 (21) ◽

pp. 10200-10207 ◽

Cited By ~ 70

Author(s):

David C. Montefiori ◽

Tanya S. Hill ◽

Ha T. T. Vo ◽

Bruce D. Walker ◽

Eric S. Rosenberg

Keyword(s):

Human Immunodeficiency Virus ◽

B Cell ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Treatment Interruption ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Immediate treatment of acute human immunodeficiency virus type 1 (HIV-1) infection has been associated with subsequent control of viremia in a subset of patients after therapy cessation, but the immune responses contributing to control have not been fully defined. Here we examined neutralizing antibodies as a correlate of viremia control following treatment interruption in HIV-1-infected individuals in whom highly active antiretriviral therapy (HAART) was initiated during early seroconversion and who remained on therapy for 1 to 3 years. Immediately following treatment interruption, neutralizing antibodies were undetectable with T-cell-line adapted strains and the autologous primary HIV-1 isolate in seven of nine subjects. Env- and Gag-specific antibodies as measured by enzyme-linked immunosorbent assay were also low or undetectable at this time. Despite this apparent poor maturation of the virus-specific B-cell response during HAART, autologous neutralizing antibodies emerged rapidly and correlated with a spontaneous downregulation in rebound viremia following treatment interruption in three subjects. Control of rebound viremia was seen in other subjects in the absence of detectable neutralizing antibodies. The results indicate that virus-specific B-cell priming occurs despite the early institution of HAART, allowing rapid secondary neutralizing-antibody production following treatment interruption in a subset of individuals. Since early HAART limits viral diversification, we hypothesize that potent neutralizing-antibody responses to autologous virus are able to mature and that in some persons these responses contribute to the control of plasma viremia after treatment cessation.

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Lack of Autologous Neutralizing Antibody to Human Immunodeficiency Virus Type 1 (HIV‐1) and Macrophage Tropism Are Associated with Mother‐to‐Infant Transmission

The Journal of Infectious Diseases ◽

10.1086/314886 ◽

1999 ◽

Vol 180 (2) ◽

pp. 344-350 ◽

Cited By ~ 45

Author(s):

Janet L. Lathey ◽

Jeff Tsou ◽

Karen Brinker ◽

Karen Hsia ◽

William A. Meyer III ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibody ◽

Macrophage Tropism ◽

Immunodeficiency Virus ◽

Hiv 1

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Removal of a Single N-Linked Glycan in Human Immunodeficiency Virus Type 1 gp120 Results in an Enhanced Ability To Induce Neutralizing Antibody Responses

Journal of Virology ◽

10.1128/jvi.01691-07 ◽

2007 ◽

Vol 82 (2) ◽

pp. 638-651 ◽

Cited By ~ 127

Author(s):

Yun Li ◽

Bradley Cleveland ◽

Igor Klots ◽

Bruce Travis ◽

Barbra A. Richardson ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Pronounced Increase ◽

Enhanced Sensitivity ◽

Subtype B ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Glycans on human immunodeficiency virus (HIV) envelope protein play an important role in infection and evasion from host immune responses. To examine the role of specific glycans, we introduced single or multiple mutations into potential N-linked glycosylation sites in hypervariable regions (V1 to V3) of the env gene of HIV type 1 (HIV-1) 89.6. Three mutants tested showed enhanced sensitivity to soluble CD4. Mutant N7 (N197Q) in the carboxy-terminal stem of the V2 loop showed the most pronounced increase in sensitivity to broadly neutralizing antibodies (NtAbs), including those targeting the CD4-binding site (IgG1b12) and the V3 loop (447-52D). This mutant is also sensitive to CD4-induced NtAb 17b in the absence of CD4. Unlike the wild-type (WT) Env, mutant N7 mediates CD4-independent infection in U87-CXCR4 cells. To study the immunogenicity of mutant Env, we immunized pig-tailed macaques with recombinant vaccinia viruses, one expressing SIVmac239 Gag-Pol and the other expressing HIV-1 89.6 Env gp160 in WT or mutant forms. Animals were boosted 14 to 16 months later with simian immunodeficiency virus gag DNA and the cognate gp140 protein before intrarectal challenge with SHIV89.6P-MN. Day-of-challenge sera from animals immunized with mutant N7 Env had significantly higher and broader neutralizing activities than sera from WT Env-immunized animals. Neutralizing activity was observed against SHIV89.6, SHIV89.6P-MN, HIV-1 SF162, and a panel of subtype B primary isolates. Compared to control animals, immunized animals showed significant reduction of plasma viral load and increased survival after challenge, which correlated with prechallenge NtAb titers. These results indicate the potential advantages for glycan modification in vaccine design, although the role of specific glycans requires further examination.

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Induction of Primary Virus-Cross-Reactive Human Immunodeficiency Virus Type 1-Neutralizing Antibodies in Small Animals by Using an Alphavirus-Derived In Vivo Expression System

Journal of Virology ◽

10.1128/jvi.77.5.3119-3130.2003 ◽

2003 ◽

Vol 77 (5) ◽

pp. 3119-3130 ◽

Cited By ~ 40

Author(s):

Ming Dong ◽

Peng Fei Zhang ◽

Franziska Grieder ◽

James Lee ◽

Govindaraj Krishnamurthy ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Neutralizing Activity ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Primary Virus

ABSTRACT We have studied the induction of neutralizing antibodies by in vivo expression of the human immunodeficiency virus type 1 (HIV-1) envelope by using a Venezuelan equine encephalitis virus (VEE) replicon system with mice and rabbits. The HIV-1 envelope, clone R2, has broad sensitivity to cross-reactive neutralization and was obtained from a donor with broadly cross-reactive, primary virus-neutralizing antibodies (donor of reference serum, HIV-1-neutralizing serum 2 [HNS2]). It was expressed as gp160, as secreted gp140, and as gp160ΔCT with the cytoplasmic tail deleted. gp140 was expressed in vitro at a high level and was predominantly uncleaved oligomer. gp160ΔCT was released by cells in the form of membrane-bound vesicles. gp160ΔCT induced stronger neutralizing responses than the other forms. Use of a helper plasmid for replicon particle packaging, in which the VEE envelope gene comprised a wild-type rather than a host range-adapted sequence, also enhanced immunogenicity. Neutralizing activity fractionated with immunoglobulin G. This activity was cross-reactive among a panel of five nonhomologous primary clade B strains and a Chinese clade C strain and minimally reactive against a Chinese clade E (circulating recombinant form 1) strain. The comparative neutralization of these strains by immune mouse sera was similar to the relative neutralizing effects of HNS2, and responses induced in rabbits were similar to those induced in mice. Together, these results demonstrate that neutralizing antibody responses can be induced in mice within 2 to 3 months that are similar in potency and cross-reactivity to those found in the chronically infected, long-term nonprogressive donor of HNS2. These findings support the expectation that induction of highly cross-reactive HIV-1 primary virus-neutralizing activity by vaccination may be realized.

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