Neutralizing Antibody Responses to Human Immunodeficiency Virus Type 1 in Primary Infection and Long‐Term‐Nonprogressive Infection

Pilgrim, Alice K.; Pantaleo, Giuseppe; Cohen, Oren J.; Fink, Lisa M.; Zhou, Ji; Zhou, Jian‐Liang; Bolognesi, Dani P.; Fauci, Anthony S.; Montefiori, David C.

doi:10.1086/516508

Cited by 293 publications

(230 citation statements)

References 37 publications

(4 reference statements)

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“…Consistent with other studies (60)(61)(62)(63), our study population exhibited wide variation in the ability to neutralize early autologous isolates. The rate of evolution in terms of amino acid substitutions, averaged over the whole viral envelope, correlated well with the rate of phenotypic escape, but we failed to demonstrate a correlation between the rate of escape from neutralizing antibodies and the rate of evolution of N-linked glycosylation sites and insertions and deletions.…”

Section: Discussionsupporting

confidence: 90%

Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection

Frost

Wrin

Smith

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

317

316

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HIV type 1 (HIV-1) can rapidly escape from neutralizing antibody responses. The genetic basis of this escape in vivo is poorly understood. We compared the pattern of evolution of the HIV-1 env gene between individuals with recent HIV infection whose virus exhibited either a low or a high rate of escape from neutralizing antibody responses. We demonstrate that the rate of viral escape at a phenotypic level is highly variable among individuals, and is strongly correlated with the rate of amino acid substitutions. We show that dramatic escape from neutralizing antibodies can occur in the relative absence of changes in glycosylation or insertions and deletions (''indels'') in the envelope; conversely, changes in glycosylation and indels occur even in the absence of neutralizing antibody responses. Comparison of our data with the predictions of a mathematical model support a mechanism in which escape from neutralizing antibodies occurs via many amino acid substitutions, with low cross-neutralization between closely related viral strains. Our results suggest that autologous neutralizing antibody responses may play a pivotal role in the diversification of HIV-1 envelope during the early stages of infection.selection ͉ glycosylation

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Section: Discussionsupporting

confidence: 90%

Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection

Frost

Wrin

Smith

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

317

316

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“…These NAbs inhibit viral entry by blocking virion attachment to its receptors or membrane fusion [1]. During natural infection the effect of the autologous neutralization response appears to be limited, since the virus rapidly escapes the immune pressure in most individuals [2][3][4][5][6]. Therefore, eliciting robust neutralizing antibody responses against diverse HIV strains remains a major obstacle for vaccine development.…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity of recombinant human immunodeficiency virus type 1-like particles expressing gp41 derivatives in a pre-fusion state

Kim

Qiao

et al. 2007

Vaccine

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The conserved membrane proximal external region (MPER) of the ectodomain of human immunodeficiency virus type 1 (HIV-1) gp41 is the target of two broadly neutralizing antibodies, 2F5 and 4E10. However, no neutralizing antibodies have been elicited against immunogens bearing these epitopes. Given that structural and biochemical studies suggest that the lipid membrane of the virion is involved in their proper configuration, HIV-1 gp41 derivatives in a pre-fusion state were expressed on the surface of immature virus like particles (VLP) derived from Sf9 cells. Guinea pigs were immunized with three doses of VLPs or Sf9 cells presenting gp41 derivatives with or without E. coli heat-labile enterotoxin (LT) as an adjuvant. While immune sera contained high titer anti-VLP antibodies, the specific anti-gp41 antibody responses were low with no neutralizing antibodies detected. An explanation for this absence may be the low level of gp41 expression relative to the many other proteins derived from host cells which are incorporated onto the VLP surface. In addition, the anti-gp41 immune response was preferentially directed to the C-helical domain, away from the MPER. Future vaccine design needs to contend with the complexity of epitope display as well as immunodominance.

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“…It now appears clear that CD8 ϩ T cells are an important component to restriction of virus replication induced by chronic virus infections in each of these model systems and likely play a similar role in the restriction of HIV replication in humans. For this reason, considerable attention has been focused on the HIV-specific CD8 ϩ T cell responses of patients who are felt to have immune system-mediated restriction of virus replication (5)(6)(7)(8)(9)(10)(11)(12). Although patients with normal CD4 ϩ T cell counts and low levels of plasma virus are a heterogeneous group, a small subgroup of patients with truly nonprogressive HIV infection and restriction of virus replication likely hold important clues to the basis of an effective immune response to HIV.…”

mentioning

confidence: 99%

Maintenance of Large Numbers of Virus-Specific CD8+ T Cells in HIV-Infected Progressors and Long-Term Nonprogressors

Gea-Banacloche

Migueles

Martino

et al. 2000

The Journal of Immunology

247

192

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The virus-specific CD8+ T cell responses of 21 HIV-infected patients were studied including a unique cohort of long-term nonprogressors with low levels of plasma viral RNA and strong proliferative responses to HIV Ags. HIV-specific CD8+ T cell responses were studied by a combination of standard cytotoxic T cell (CTL) assays, MHC tetramers, and TCR repertoire analysis. The frequencies of CD8+ T cells specific to the majority of HIV gene products were measured by flow cytometric detection of intracellular IFN-γ in response to HIV-vaccinia recombinant-infected autologous B cells. Very high frequencies (0.8–18.0%) of circulating CD8+ T cells were found to be HIV specific. High frequencies of HIV-specific CD8+ T cells were not limited to long-tern nonprogressors with restriction of plasma virus. No correlation was found between the frequency of HIV-specific CD8+ T cells and levels of plasma viremia. In each case, the vast majority of cells (up to 17.2%) responded to gag-pol. Repertoire analysis showed these large numbers of Ag-specific cells were scattered throughout the repertoire and in the majority of cases not contained within large monoclonal expansions. These data demonstrate that high numbers of HIV-specific CD8+ T cells exist even in patients with high-level viremia and progressive disease. Further, they suggest that other qualitative parameters of the CD8+ T cell response may differentiate some patients with very low levels of plasma virus and nonprogressive disease.

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Neutralizing Antibody Responses to Human Immunodeficiency Virus Type 1 in Primary Infection and Long‐Term‐Nonprogressive Infection

Cited by 293 publications

References 37 publications

Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection

Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection

Immunogenicity of recombinant human immunodeficiency virus type 1-like particles expressing gp41 derivatives in a pre-fusion state

Maintenance of Large Numbers of Virus-Specific CD8+ T Cells in HIV-Infected Progressors and Long-Term Nonprogressors

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