Defining the Role of Maternal Plasma Neutralizing Antibodies in Mother-to-Child Transmission of HIV-1

Defining the Role of Maternal Plasma Neutralizing Antibodies in Mother-to-Child Transmission of HIV-1 . Maxwel Majiwa Omenda Chair of the supervisory Committee: Affiliate Professor Julie Overbaugh Pathobiology & Microbiology Full Member: Division of Human Biology, Fred Hutchinson Cancer Research Center Identifying a vaccine that would elicit neutralizing antibodies (Nabs) that prevent HIV-1 infection of host cells is a priority for the HIV-1 research field. Mother-tochild transmission (MTCT) of HIV-1 offers a natural setting in which to evaluate whether Nabs are correlated with protection in exposed individuals. This topic is the focus of this thesis. Given that Nabs can impact MTCT of HIV-1 by neutralizing viruses within the mother and/or infants, I first evaluated in chapter 2 whether the Env specific Nabs repertoire in the mother correlates with that in their corresponding infants. I compared antibody levels in plasma from 60 mother-infant pairs near the time of birth, including 14 breastfeeding transmission pairs. The Envelope binding titers were strongly correlated (r=0.91, p<0.0001) and similar (1.4-fold greater in maternal plasma) between a mother and her corresponding infant as were the neutralizing antibody (Nab) levels (r ` iv = 0.80, p<0.0001; 1.3-fold higher), suggesting efficient transfer. However, there was no significant difference in heterologous Nab responses between transmitting (TM) and nontransmitting mothers (NTM), although there was a trend for transmitting mothers to have higher HIV-1-specific Nabs. Neutralizing antibody response measured against circulating variants (heterologous Nabs) may not be adequate to measure a protective antibody response; rather Nabs responses specific to the maternal own variants (autologous Nabs) are more relevant to protection against MTCT. Indeed, during MTCT, HIV-1 variants relatively insensitive to maternal autologous Nabs (aNabs) are transmitted, suggesting protective effect of such antibodies against sensitive variants. In chapter 3 of this dissertation, I explore the hypothesis that if aNabs are protective against MTCT then NTM, particularly those at high risk of MTCT (high viral load & breastfeeding), may have few neutralization resistant viruses. We tested maternal Env variants that represent each woman’s quasispecies against autologous plasma obtained near transmission, and compared the inhibitory concentration (IC50s) of TM to NTM. I found that there was no association between postpartum MTCT risk and IC50 (Odds Ratio = 1.0; p = 0.201). To examine whether sample timing may yield a different conclusion regarding aNab escape, maternal and infant variants obtained near the time of MTCT were tested against contemporaneous maternal plasma (early plasma) versus maternal plasma obtained ~6 months after transmission (later plasma) and compared using GEE (chapter 4). IC50 values against early plasma among maternal variants were 10-fold greater than for infant variants (p<0.0001). However, there was no significant difference in IC50 ` v values of maternal versus infant variants when tested against later plasma (maternal/infant IC50 ratio =1.3; p=0.69) because the infant variants were more sensitive to later aNabs in the mother (late/early IC50 ratio = 6.3; p<0.0001). Our findings suggest that although maternal aNab induced in natural infection may limit MTCT of sensitive variants, as defined by studies of aNabs near the transmission event, they are not sufficient to explain protection among high-risk NTM. Overall, maternal Nabs induced in natural HIV-1 infection are present both in the mother and her infant, but the level of these antibodies are insufficient to protect against HIV-1 transmission. However, maternal Nabs present around the time when MTCT, may provide protection against neutralization sensitive variants. ` i Table of