Maternal HIV-1 envelope-specific antibody responses and reduced risk of perinatal transmission

Abstract

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.

Figure 2. Heatmap of neutralization sensitivity (IC₅₀) to autologous V3–specific IgG mAbs of env pseudoviruses isolated from the plasma of a nontransmitting mother.

env pseudoviruses (5426.1–5426.47) were divided into 2 groups by their neutralization sensitivity to the autologous V3–specific mAbs (DH290-299) on the basis of hierarchical clustering of neutralization sensitivity (A). Insertion of mutations V200I and N188S into an env pseudovirus from the resistant group (5426.31; Supplemental Figure 5) conferred sensitivity to autologous V3–specific mAbs (DH290–299) (B). Darker color indicates greater neutralization sensitivity (lower IC₅₀).

Figure 1. Comparison of humoral immune responses measured in HIV-1–infected transmitting and nontransmitting mothers.

MTCT risk was not predicted by maternal MN gp120–specific IgG binding (A), MN gp41–specific IgG binding (B), or IgA binding (C) responses; however, the maternal IgG V3 binding score predicted a reduced risk of MTCT (D). The magnitude of the tier 1 neutralization (B.MN, E ) and plasma sCD4–blocking response (against B.JFRL, F) was associated with reduced MTCT risk in exploratory analyses. Maternal plasma sCD4 blocking of B.JFRL Env, neutralization potency of B.SF162, and B.V3 IgG binding were highly correlated (G). Nontransmitting women are indicated in blue, and transmitting women are indicated in red. In(FI), natural log MFI; ln(titer), natural log ID₅₀.