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Reduced cell-associated DNA and improved viral control in macaques following passive transfer of a single anti-V2 monoclonal antibody and repeated SHIV challenges.
Journal of Virology 2018 March 8
A high level of V1V2-specific IgG antibodies in vaccinees' sera was the only independent variable that correlated with a reduced risk of HIV acquisition in the RV144 clinical trial. In contrast, IgG avidity, antibody neutralization, and antibody-dependent cellular cytotoxicity each failed as independent correlates of infection. Extended analyses of RV144 samples demonstrated antiviral activity of V1V2-specific vaccine-induced antibodies. V2-specific antibodies have also been associated with protection from SIV, and the V2i-specific subset of human monoclonal antibodies (mAbs), while poor neutralizers, mediate Fc-dependent antiviral functions in vitro The objective of this study was to determine the protective efficacy of a V2i-specific human mAb 830A against mucosal SHIV challenge. V2i mAb binding sites overlap the integrin binding site in the V2 region and are similar to the epitopes bound by antibodies associated with reduced HIV infection rate in RV144. Because the IgG3 subclass was a correlate of reduced infection rate in RV144, we compared passive protection by both IgG1 and IgG3 subclasses of V2i mAb 830A. This experiment represents the first in vivo test of the hypothesis emanating from RV144 and SIV studies that V2i Abs can reduce infection risk. The results show that passive transfer with a single V2i mAb, IgG1 830A, reduced plasma and PBMC virus levels and decreased viral DNA in lymphoid tissues compared to controls, but too few animals remained uninfected to achieve significance in reducing infection risk. Based on these findings, we conclude that V2i antibodies can impede viral seeding following mucosal challenge, resulting in improved viral control. IMPORTANCE Since the results of the HIV RV144 clinical trial were reported, there has been significant interest in understanding how protection was mediated. Antibodies directed to a subregion of the Envelope protein called V1V2 were directly correlated with reduced risk, and surprisingly low virus neutralization was observed. To determine whether these antibodies alone could mediate protection, we used a human monoclonal antibody directed to V2 with properties similar to those elicited in the vaccine trial for passive infusions in rhesus macaques and challenge with SHIV. The single V2 antibody at the dose given did not significantly reduce the number of infections, but there was a significant reduction in seeding of virus to the lymph nodes and a decrease in plasma viremia in the HIV antibody-infused macaques compared with the control antibody-infused animals. This finding shows that V2 antibodies mediate antiviral activities in vivo that could contribute to a protective HIV vaccine.
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