Escape of maternal plasma broadly neutralizing antibody as a mechanism of mother to child HIV transmission

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Abstract Over 150,000 HIV-1 infants are infected via mother to child transmission (MTCT) each year, accounting for nearly 10% of the global annual HIV-1 infections. Even implementation of highly effective antiretroviral therapy (ART) cannot prevent up to 5% of HIV-1 infected women from transmitting the virus to their infants. Thus, approaches that synergize with ART will be needed to eliminate MTCT. The most promising interventions in under clinical development to prevent HIV infection includes passive administration or active induction of broadly-neutralizing antibodies (bnAbs). Yet, paradoxically, broad neutralization activity in maternal plasma has been associated with risk of infant transmission, raising concerns about the safety of these approaches in pregnancy. Thus, a better understanding of the role of maternal neutralizing activity and MTCT risk is needed to develop effective bnAb-based interventions, which together with ART can more effectively block MTCT. HIV MTCT is a unique transmission route that occurs in the setting of preexisting antibody raised against autologous viruses. We previously found that transmitted/founder (T/F) viruses in infants were more resistant to neutralization by paired maternal plasma than non-transmitted maternal viruses. Moreover, we established that bnAb activity in maternal plasma can drive the development of circulating viral escape variants that become infant T/F viruses. We hypothesize that multispecificity of maternal plasma bnAb activity is associated with reduced risk of MTCT and autologous virus escape from these functional responses by infant T/F viruses is a risk factor for transmission. Moreover, identifying bnAb escape variants that are fit for transmission is important to designing combination bnAb approaches that can effectively prevent virus transmission. We will use the following three Specific Aims to test our hypotheses: (1) Compare the specificity and polyfunctionality of plasma bnAb activity from transmitting and non-transmitting mothers to assess the role of maternal bnAb activity in vertical virus transmission risk. (2) Determine if infant T/F viruses and circulating viruses of transmitting mothers are more resistant to plasma neutralizing activity compared to that of non-transmitted maternal variants from transmitting and non-transmitting mothers. (3) Define genetic signatures responsible for escape from the maternal Env-specific B cell repertoire among transmitted infant Env variants using a panel of native Env trimer-specific mAbs isolated from transmitting mothers. Defining the specificity and function of pre-existing maternal neutralizing antibodies that can reduce virus escape and impede transmission will be critical to design novel passive and active vaccine approaches that can eliminate HIV transmission from mothers to infants, and is a tool to define the population impact of the future use of bnAb- based prophylaxis on HIV transmission dynamics.