Identification of human immunodeficiency virus subtypes with distinct patterns of sensitivity to serum neutralization.

Cheng‐Mayer, Cecilia; Homsy, Jacques; Evans, Louise; Levy, Jay A.

doi:10.1073/pnas.85.8.2815

Cited by 131 publications

(79 citation statements)

References 35 publications

(33 reference statements)

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“…However, it was reported shortly thereafter that HIV-1-neutralizing antibodies were strain specific, posing a substantial obstacle to protecting against genetically diverse HIV-1 strains (82,83). Another significant early observation was that vaccine-induced antibodies typically could neutralize Fig.…”

Section: Discussionmentioning

confidence: 99%

Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope

Kilgore

Murphy

Burton

et al. 2015

J Virol

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Antibodies that can neutralize diverse viral strains are likely to be an important component of a protective human immunodeficiency virus type 1 (HIV-1) vaccine. To this end, preclinical simian immunodeficiency virus (SIV)-based nonhuman primate immunization regimens have been designed to evaluate and enhance antibody-mediated protection. However, these trials often rely on a limited selection of SIV strains with extreme neutralization phenotypes to assess vaccine-elicited antibody activity. To mirror the viral panels used to assess HIV-1 antibody breadth, we created and characterized a novel panel of 14 genetically and phenotypically diverse SIVsm envelope (Env) glycoproteins. To assess the utility of this panel, we characterized the neutralizing activity elicited by four SIVmac239 envelope-expressing DNA/modified vaccinia virus Ankara vector-and protein-based vaccination regimens that included the immunomodulatory adjuvants granulocyte-macrophage colony-stimulating factor, Toll-like receptor (TLR) ligands, and CD40 ligand. The SIVsm Env panel exhibited a spectrum of neutralization sensitivity to SIV-infected plasma pools and monoclonal antibodies, allowing categorization into three tiers. Pooled sera from 91 rhesus macaques immunized in the four trials consistently neutralized only the highly sensitive tier 1a SIVsm Envs, regardless of the immunization regimen. The inability of vaccine-mediated antibodies to neutralize the moderately resistant tier 1b and tier 2 SIVsm Envs defined here suggests that those antibodies were directed toward epitopes that are not accessible on most SIVsm Envs. To achieve a broader and more effective neutralization profile in preclinical vaccine studies that is relevant to known features of HIV-1 neutralization, more emphasis should be placed on optimizing the Env immunogen, as the neutralization profile achieved by the addition of adjuvants does not appear to supersede the neutralizing antibody profile determined by the immunogen. IMPORTANCEMany in the HIV/AIDS vaccine field believe that the ability to elicit broadly neutralizing antibodies capable of blocking genetically diverse HIV-1 variants is a critical component of a protective vaccine. Various SIV-based nonhuman primate vaccine studies have investigated ways to improve antibody-mediated protection against a heterologous SIV challenge, including administering adjuvants that might stimulate a greater neutralization breadth. Using a novel SIV neutralization panel and samples from four rhesus macaque vaccine trials designed for cross comparison, we show that different regimens expressing the same SIV envelope immunogen consistently elicit antibodies that neutralize only the very sensitive tier 1a SIV variants. The results argue that the neutralizing antibody profile elicited by a vaccine is primarily determined by the envelope immunogen and is not substantially broadened by including adjuvants, resulting in the conclusion that the envelope immunogen itself should be the primary consideration in efforts to elicit antibodi...

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Section: Discussionmentioning

confidence: 99%

Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope

Kilgore

Murphy

Burton

et al. 2015

J Virol

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“…Some HIV strains can infect B-cell lines and even B lymphocytes in culture, particularly if EBV is present (218,455,800). Likewise, viruses can be distinguished by their ability to grow in bowel-and brain-derived cell lines as well as in primary cells from fetal and adult organs (47,155,298,1031,1066) (see also Section VI A). Some investigators have used these and other properties to classify HIV strains into subgroups (38,298,1228) or to designate their degree of virulence (38,163,298,668,1170,1172) (Table 15).…”

Section: Clinical Latencymentioning

confidence: 99%

Pathogenesis of Human Immunodeficiency Virus Infection

Levy¹

1989

Annals of the New York Academy of Sciences

222

290

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“…Most seropositive individuals produce anti-HIV neutralizing antibodies [1,2] and antibodies capable of mediating antibody-dependent cellular cytotoxicity (ADCC) [3][4][5] and complement-dependent lysis of viral particles and infected cells [6,7]. Natural killer (NK) activity [8,9] and antigen-specific CD8^ cytotoxic T lymphocytes have also been demonstrated in HIV-infected individuals [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of HIV replication by CD8+ T cells correlates with CD4 counts and clinical stage of disease

Gómez

Smaill

Rosenthal

1994

Clinical and Experimental Immunology

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SUMMARY We sought to evaluate the relationship of CD8+ T cell‐mediated inhibition of autologous HIV replication in vitro to disease stage in HIV+ individuals. Depletion of CD8+ T cells from peripheral blood lymphocytes of 16 HIV+ subjects increased the percentage of virus‐producing cultures from 56% to 81%. CD4+ T cells were purified from 52 HIV+ individuals and cultured alone or in the presence of autologous CD8+ T cells. In 13 (25%) subjects HIV replication was only detected in the absence of CD8+ T cells (inhibition positive); in 26 (50%) viral replication occurred both in the absence and presence of CD8+ cells (inhibition negative). In the remaining 13 (25%) subjects, CD8+ T cell‐mediated inhibitory activity could not be evaluated because stimulation of their purified CD4+ T cells did not result in p24 production. In some virus culture‐negative individuals, the inability to demonstrate HIV replication was due to the presence of low numbers of CD8+ T cells that co‐purified with CD4+ T cells. Detection of inhibitory CD8+ T cells was associated with significantly higher CD4 counts and better clinical status compared with inhibition‐negative subjects. These results demonstrate that CD8+ T cell‐mediated inhibition of HIV replication correlates with disease stage, and thus may play a role in preventing disease progression. CD8+ T cells did not inhibit autologous HIV replication across a semipermeable membrane. Further, the ability of CD8+ T cells to prevent HIV replication did not correlate with lysis of autologous CD4+ T cells. Thus, CD8+ T cells inhibited autologous HIV replication in vitro through a contact mediated non‐lytic mechanism.

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Identification of human immunodeficiency virus subtypes with distinct patterns of sensitivity to serum neutralization.

Abstract: The human immunodeficiency virus (HIV) type 1 displays a high degree of genetic variation, especially in

Cited by 131 publications

References 35 publications

Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope

Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope

Pathogenesis of Human Immunodeficiency Virus Infection

Inhibition of HIV replication by CD8+ T cells correlates with CD4 counts and clinical stage of disease

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