Humoral Immune Responses in HIV Mother-to-Child Transmission and Disease

Thesis (Ph.D.)--University of Washington, 2015Although significant progress has been made in combating HIV/AIDS, a safe and effective vaccine is still of high priority. Considering that data from HIV vaccine trials are limited, information from other settings can help elucidate what types of immune responses provide protection. Mother-to-child transmission (MTCT) provides one setting in which to study the immune correlates of protection and is unique because infants born to HIV-infected women have HIV-specific antibodies at birth, which may provide protection. This thesis addresses the impact of humoral immune responses on MTCT, with particular focus on antibody-dependent cellular cytotoxicity (ADCC) and neutralizing antibodies (NAbs), which have both been described as potential immune correlates of protection. First, we investigated the role of pre-existing HIV-specific ADCC in infants. We observed that ADCC activity was higher in uninfected infants than infected infants, but the difference was not statistically significant. In infected infants, however, higher pre-existing ADCC activity was associated with decreased mortality, suggesting a therapeutic benefit of ADCC antibodies. As ADCC depends on Fc gamma receptors (FcγRs) on host effector cells, we next examined the influence of FcγR polymorphisms on MTCT. We observed no association between infant or maternal FcγRIIa, or infant FcγRIIIa, polymorphisms and MTCT. Unexpectedly, maternal FcγRIIIa heterozygotes were at increased risk of transmission compared to homozygote mothers. This effect was predominately in the early breastfeeding period, but additional studies need to be done to confirm this association and its mechanism. Finally we examined maternal autologous NAbs and their impact on MTCT. We observed that non-transmitting and transmitting mothers had similar levels of NAbs when tested against individual viruses. Similarly, there was not a significant difference in the number of neutralization resistant viruses in the two groups. These results suggest that maternal autologous NAbs do not significantly contribute to transmission risk during the early breastfeeding period. Overall, these results highlight the roles of humoral immune responses in MTCT and suggest a potential protective influence of ADCC-mediating antibodies in HIV transmission and disease. Future studies should focus on characterizing ADCC antibody epitopes and determining how to best elicit ADCC responses by vaccination