Antibodies with High Avidity to the gp120 Envelope Protein in Protection from Simian Immunodeficiency Virus SIV _mac251 Acquisition in an Immunization Regimen That Mimics the RV-144 Thai Trial

Abstract

The recombinant canarypox vector, ALVAC-HIV, together with human immunodeficiency virus (HIV) gp120 envelope glycoprotein, has protected 31.2% of Thai individuals from HIV acquisition in the RV144 HIV vaccine trial. This outcome was unexpected, given the limited ability of the vaccine components to induce CD8 ؉ T-cell responses or broadly neutralizing antibodies. We vaccinated macaques with an immunization regimen intended to mimic the RV144 trial and exposed them intrarectally to a dose of the simian immunodeficiency virus SIV mac251 that transmits few virus variants, similar to HIV transmission to humans. Vaccination induced anti-envelope antibodies in all vaccinees and CD4؉ and CD8 ؉ T-cell responses. Three of the 11 macaques vaccinated with ALVAC-SIV/gp120 were protected from SIV mac251 acquisition, but the result was not significant. The remaining vaccinees were infected and progressed to disease. The magnitudes of vaccine-induced SIV mac251 -specific T-cell responses and binding antibodies were not significantly different between protected and infected animals. However, sera from protected animals had higher avidity antibodies to gp120, recognized the variable envelope regions V1/V2, and reduced SIV mac251 infectivity in cells that express high levels of ␣ 4 ␤ 7 integrins, suggesting a functional role of antibodies to V2. The current results emphasize the utility of determining the titer of repeated mucosal challenge in the preclinical evaluation of HIV vaccines.

Enhanced Fusion and Virion Incorporation for HIV-1 Subtype C Envelope Glycoproteins with Compact V1/V2 Domains

“…In the RV144 Thai vaccine trial, the levels of antibodies directed against V1/V2 inversely correlated with infection risk (57,58). Consistent with these findings, macaques immunized with a similar regimen and challenged with repeated low doses of simian immunodeficiency virus mac251 mounted a statistically significant antibody response to V1/V2 that was inversely correlated with infection (59). In superinfection studies, anti-V1/V2 antibodies to the primary virus were associated with a decreased risk of superinfection by a second virus of the same subtype (60).…”

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

“…Extensive analyses have been carried out seeking correlations between immune responses and reduced risk of infection (25,26,28,29,54,(74)(75)(76). The strongest correlation with reduced risk of infection was binding antibodies to the V1/ V2 region of gp120 (25,26,29,76).…”

Derivation and Characterization of Pathogenic Transmitted/Founder Molecular Clones from Simian Immunodeficiency Virus SIVsmE660 and SIVmac251 following Mucosal Infection

“…We have additionally used SGA analysis of viral envelope sequences to show that the titer of mucosal inoculation of SIV in rhesus macaques (Macaca mulatta) can be determined in order to recapitulate the number of T/F genomes observed in mucosal transmission of HIV-1 (18)(19)(20)(21). Mucosal challenges whose titers have been determined and subsequent SGA-based T/F variant quantification have more recently been used to examine vaccine efficacy in preclinical NHP vaccine trials, where a reduction in the number of T/F viruses in vaccinated macaques mucosally inoculated with SIV has been proposed as a parameter to help evaluate partial vaccine efficacy in preclinical studies (22)(23)(24)(25)(26)(27)(28). Although sequencing the Env gene is typically sufficient for quantifying the T/F viruses and analyzing Env-based phenotypes, the same approach can also be used to identify and clone full-length T/F genome sequences for biological analyses (3,29,30).…”