Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 129, Issue 11, Pages 4838-4849Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI126391
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Funding
- NIAID US Public Health Service [UM1 AI068614, UM1 AI068618, UM1 AI068635]
- NIH/NIAID [P01 AI120756]
- NIH/NIAID Duke Center for AIDS Research [AI064518]
- Bill and Melinda Gates Foundation
- NIH NIAID
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HVTN 505 is a preventative vaccine efficacy trial testing DNA followed by recombinant adenovirus serotype 5 (rAd5) in circumcised, Ads-seronegative men and transgendered persons who have sex with men in the United States. Identified immune correlates of lower HIV-1 risk and a virus sieve analysis revealed that, despite lacking overall efficacy, vaccine-elicited responses exerted pressure on infecting HIV-1 viruses. To interrogate the mechanism of the antibody correlate of HIV-1 risk, we examined antigen-specific antibody recruitment of Fc gamma receptors (Fc gamma Rs), antibody-dependent cellular phagocytosis (ADCP), and the role of anti-envelope (anti-Env) IgG3. In a prespecified immune correlates analysis, antibody-dependent monocyte phagocytosis and antibody binding to Fc gamma RIIa correlated with decreased HIV-1 risk. Follow-up analyses revealed that anti-Env IgG3 breadth correlated with reduced HIV-1 risk, anti-Env IgA negatively modified infection risk by Fc effector functions, and that vaccine recipients with a specific Fc gamma RIIa single-nucleotide polymorphism locus had a stronger correlation with decreased HIV-1 risk when ADCP, Env-Fc gamma RIIa, and IgG3 binding were high. Additionally, Fc gamma RIIa engagement correlated with decreased viral load setpoint in vaccine recipients who acquired HIV-1. These data support a role for vaccine-elicited anti-HIV-1 Env IgG3, antibody engagement of FcRs, and phagocytosis as potential mechanisms for HIV-1 prevention.
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