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Despite the wide availability of antiretroviral drugs, more than 250,000 infants are vertically infected with HIV-1 annually, emphasizing the need for additional interventions to eliminate pediatric HIV-1 infections. Here, we aimed to define humoral immune correlates of risk of mother-to-child transmission (MTCT) of HIV-1, including responses associated with protection in the RV144 vaccine trial. Eighty-three untreated, HIV-1-transmitting mothers and 165 propensity score-matched nontransmitting mothers were selected from the Women and Infants Transmission Study (WITS) of US nonbreastfeeding, HIV-1-infected mothers. In a multivariable logistic regression model, the magnitude of the maternal IgG responses specific for the third variable loop (V3) of the HIV-1 envelope was predictive of a reduced risk of MTCT. Neutralizing Ab responses against easy-to-neutralize (tier 1) HIV-1 strains also predicted a reduced risk of peripartum transmission in secondary analyses. Moreover, recombinant maternal V3-specific IgG mAbs mediated neutralization of autologous HIV-1 isolates. Thus, common V3-specific Ab responses in maternal plasma predicted a reduced risk of MTCT and mediated autologous virus neutralization, suggesting that boosting these maternal Ab responses may further reduce HIV-1 MTCT.
Introduction
Antiretroviral (ARV) treatment can significantly reduce the risk of mother-to-child transmission (MTCT), yet implementation barriers, adherence challenges, infant toxicities, and ARV-resistant HIV-1 strains will impede the achievement of an HIV-1-free generation. MTCT is a unique setting in which to investigate humoral immune correlates of transmission, whereby recipients are passively immunized with maternal Abs. High levels of maternal IgG Abs directed against the envelope (Env) gp120 protein, including the variable region 3 (V3) loop, have been correlated with protection against MTCT (1). However, not all studies established this association (2, 3). Several studies reported more potent HIV-1-neutralizing Ab responses in nontransmitting mothers compared with those in transmitting mothers (4) as well as transmission of neutralization escape variants (5-8), yet other studies did not (9-11). These disparate results may be due to small cohort sizes, distinct timing of infant HIV-1 diagnosis, and inadequate control of major nonimmune risk modifiers of transmission. It is also of interest to determine whether the humoral immune correlates of risk of HIV-1 acquisition identified in vaccinees in the RV144 adult HIV-1 vaccine trial (12, 13) play a role in MTCT.
We studied a cohort of U.S. nonbreastfeeding, HIV-1-infected mother-infant pairs enrolled in the pre-ARV era Women...