Vaccination against Heterologous R5 Clade C SHIV: Prevention of Infection and Correlates of Protection

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cIdentifying immune correlates of protection is important to develop vaccines against infectious diseases. We designed a novel, universally applicable strategy to profile the antibody (Ab) repertoire of protected vaccine recipients, using recombinant phages encoding random peptide libraries. The new approach, termed "protection-linked (PL) biopanning," probes the Ab paratopes of protected vaccinees versus those with vaccine failure. As proof of concept, we screened plasma samples from vaccinated rhesus macaques (RMs) that had completely resisted multiple mucosal challenges with R5-tropic simian-human immunodeficiency viruses (SHIVs). The animals had been immunized with a multicomponent vaccine (multimeric HIV-1 gp160, HIV-1 Tat, and SIV Gag-Pol particles). After PL biopanning, we analyzed the phagotopes selected for amino acid homologies; in addition to the expected Env mimotopes, one recurring motif reflected the neutralizing Ab epitope at the N terminus (NT) of HIV-1 Tat. Subsequent binding and functional assays indicated that anti-Tat NT Abs were present only in completely or partially protected RMs; peak viremia of the latter was inversely correlated with anti-Tat NT Ab titers. In contrast, highly viremic, unvaccinated controls did not develop detectable Abs against the same epitope. Based upon the protective effect observed in vivo, we suggest that Tat should be included in multicomponent HIV-1 vaccines. Our data highlight the power of the new PL-biopanning strategy to identify Ab responses with significant association to vaccine protection, regardless of the mechanism(s) or targets of the protective Abs. PL biopanning is also unbiased with regard to pathogens or disease model, making it a universal tool.T he design of a safe, effective vaccine is desirable to control the AIDS pandemic. In order to improve future vaccine candidates, it is important to understand the protective mechanism(s) leading to reduced virus acquisition (1). Thus, correlates of infection risk for the recent RV144 vaccine efficacy trial (2) are the subject of intense study (3,4). However, additional information can be gained by dissecting immune responses in biologically relevant animal models where immunization induced complete protection from immunodeficiency virus challenge(s) (5, 6).Recent results of active (7,8) and passive (9) immunization trials in humans and in nonhuman primates suggested that antihuman immunodeficiency virus type 1 (HIV-1) Env antibodies (Abs) can have protective roles even in the absence of virus neutralization, implying that other Ab-mediated mechanisms may be involved in preventing mucosal virus acquisition. Thus, the ability to profile Ab epitopes associated with protection might help to identify potential targets for future HIV-1 vaccines.Random peptide phage display has been used to dissect Ab responses in the context of primate immunodeficiency virus infections, and several studies have identified HIV-1 or simian-human immunodeficiency virus (SHIV)-specific peptides (10-14). We developed a novel epitope...

Section: Animalsmentioning

confidence: 99%

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confidence: 92%

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confidence: 96%

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Novel Biopanning Strategy To Identify Epitopes Associated with Vaccine Protection

Bachler

Humbert

Palikuqi

et al. 2013

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“…Encouragingly, new SHIV strains (10)(11)(12)(13)(14)(15)39) have been developed in recent years that are R5-tropic, that are of the tier 2 neutralization phenotype that is common for most circulating strains of HIV-1, and that can exhibit pathogenesis after mucosal exposure. The SIV system has the advantage of having relatively well characterized, with consistent challenge models available, and thus has been used widely in vaccine studies (16)(17)(18)(19)(20)(21). However, significant differences exist between the SIV and HIV-1 genomes and pathogenesis characteristics (22)(23)(24).…”

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confidence: 99%

Vaccine-Induced Linear Epitope-Specific Antibodies to Simian Immunodeficiency Virus SIVmac239 Envelope Are Distinct from Those Induced to the Human Immunodeficiency Virus Type 1 Envelope in Nonhuman Primates

Shen

Duffy

Howington

et al. 2015

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To evaluate antibody specificities induced by simian immunodeficiency virus (SIV) versus human immunodeficiency virus type 1 (HIV-1) envelope antigens in nonhuman primate (NHP), we profiled binding antibody responses to linear epitopes in NHP studies with HIV-1 or SIV immunogens. We found that, overall, HIV-1 Env IgG responses were dominated by V3, with the notable exception of the responses to the vaccine strain A244 Env that were dominated by V2, whereas the anti-SIVmac239 Env responses were dominated by V2 regardless of the vaccine regimen.

“…Two R5-tropic clade C SHIVs (SHIV-Cs) that carry env related to a pediatric HIV clade C (HIV-C) isolate, HIV1157i, have been developed by our laboratory and used in challenge studies (9,10,23). SHIV-1157ipEL-p carries the recently transmitted env and has a tier 1 neutralization profile (20).…”

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confidence: 99%

Efficiency of Neutralizing Antibodies Targeting the CD4-Binding Site: Influence of Conformational Masking by the V2 Loop in R5-Tropic Clade C Simian-Human Immunodeficiency Virus

Watkins

Diaz-Rodriguez

Siddappa

et al. 2011

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In R5-tropic clade C simian-human immunodeficiency viruses (SHIV-Cs), we identified a 3-asparagine (3N) deletion mutation in the V2 loop stem of gp120 as the major determinant of neutralization escape of the anti-CD4-binding site (anti-CD4-bs) neutralizing monoclonal antibody (nMAb) b12. However, the more potent anti-CD4-bs nMAbs VRC01 and VRC03 were not sensitive to this mutation. Using isogenic tier 1 or tier 2 proviruses differing only in the 3N mutation, we showed that this mutation might result in selective conformational b12 epitope masking. Therefore, human immunodeficiency virus (HIV) Env immunogens targeting the CD4-bs and designed to neutralize tier 2 viruses should take conformational masking by the V2 loop into account.