ROLE OF NEUTRALIZING ANTIBODIES IN TRANSMISSION OF SHIV

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The role of maternal neutralizing antibodies (NAbs) in determining whether an infant becomes infected during Mother to Child Transmission (MTCT) of HIV-1 is unclear. Higher levels of both autologous and heterologous NAbs are associated with non- transmission, and NAb-resistant isolates are transmitted. This topic is timely and important, as there is increasing interest in testing vaccines or immunotherapies during the early breastfeeding period, when postpartum transmission risk is highest and drug therapy can select resistant isolates. Would the augmentation of the passively transferred maternal NAbs with human monoclonals (mAbs) be effective in this setting? To address some of these questions experimentally outside the clinic, we have established a perinatal SHIV transmission model in M. nemestrina and in M. mulatta. In this model, we have observed durable plasma virus control in newborn macaques infected orally with SHIV- SF162P3 in the presence of sub-sterilizing levels of IgG that neutralized the challenge virus. We have shown that passively transferred NAbs can accelerate de novo anti-SHIV NAbs, similar to experiments in the SIV model. In this renewal, we propose to shift the focus toward understanding the mechanisms behind these observations. WIn AIM 1, we plan to comprehensively evaluate the anti- SHIV T- and B-cell responses in SHIV-IgG-treated and control adult macaques for magnitude, timing, avidity, specificity, conformation-dependence, and breadth. In AIM 2, we plan to characterize the development of specific B cell responses in macaques with accelerated versus normal neutralizing responses by cloning antibody variable regions from individual antibody-secreting B cells (ASCs) and reconstructing them as human IgG1 antibodies. By this method, we can capture the diversity of the early IgG response and characterize the Env-specific mAbs for antiviral activity including neutralization and ADCVI. In AIM 3, we will test the effectiveness of new HIV Env- specific broadly neutralizing mAbs in complementing maternal SHIV-IgG as a more effective passive immunotherapy in newborns. We propose that these experiments will yield valuable information about the mechanisms of antibodies in controlling HIV in vivo and may inform potential immunotherapies to limit MTCT in the clinic.