Characterization of HIV-1 Neutralizing Antibody Responses in Rhesus Macaques
Open AccessHIV-1/AIDS remains one of the largest public health crises in the world. An effective vaccine that prevents HIV-1 infection would likely be the most useful tool in curbing the ongoing pandemic. Many HIV-1 vaccines are designed to elicit neutralizing antibodies, and pre-clinical testing is often carried out in rhesus macaques (RMs). To contribute to the knowledge base used in future vaccine design, here we show a three-part work closely examining RM antibody responses to HIV-1 and SHIV. First, we adapt a method of B cell immortalization for use with RM B cells in which cells are transduced with Bcl-6 and Bcl-xL. Importantly, RM B cells from lymph nodes are more effectively immortalized by this method than B cells from PBMC. We suggest the discrepancy between these two tissues is due to increased expression of CD40 on RM lymph node B cells. We further show the characterization of this system and its application for the isolation of HIV-1 neutralizing antibodies from a SHIV.CH505-infected animal, both with and without antigen probe. Overall, we show that Bcl-6/xL immortalization is a valuable and flexible tool for antibody discovery in RMs. Second, we study the effect of early heterologous bNAb treatment on downstream autologous neutralizing antibody responses. In this study, RMs were challenged with SHIV and either left untreated, treated with bNAbs, or treated with bNAbs with enhanced affinity for Fcγ receptors. Interestingly, at the later time points of 64 and 116 weeks, we did not see any effect of bNAb treatment on autologous neutralizing antibody responses. We then leveraged this robust dataset to identify correlates of strong neutralizing antibody responses. We found that viral load correlates positively with neutralization potency and breadth, and frequencies of CD4 T cells and dendritic cells correlate negatively. The strongest positive correlations were in GC TFH cells, particularly the CXCR5 MFI on GC TFH cells. In the third study, we characterized antibody responses in RMs vaccinated with germline targeting immunogen GT1.1. Animals were vaccinated beginning with prime immunogens of either GT1.1 or HIV Envs without GT1.1 modifications. GT1.1-primed animals show more evidence of VRC01-like CD4bs neutralization. Here, we cultured B cells from GT1.1-primed animals followed by a microneutralization assay to identify neutralizing B cell clones. When monoclonal B cells were studied in detail, we found several notable shared features with previously-identified bNAbs, including significant global neutralization breath (50%) as well as shared binding mechanisms. Taken together, we have provided a detailed look into antibody responses in RM models of infection and vaccination toward the goal of informing the design of more effective vaccines with real world efficacy in prevention of HIV-1 infection.
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