Abstract
Each year, >180,000 infants become infected via mother-to-child transmission (MTCT) of HIV despite the availability of effective maternal antiretroviral treatments, underlining the need for a maternal HIV vaccine. We characterized 224 maternal HIV envelope (Env)-specific IgG monoclonal antibodies (MAbs) from seven nontransmitting and transmitting HIV-infected U.S. and Malawian mothers and examined their neutralization activities against nontransmitted autologous circulating viruses and infant-transmitted founder (infant-T/F) viruses. Only a small subset of maternal viruses, 3 of 72 (4%), were weakly neutralized by maternal linear V3 epitope-specific IgG MAbs, whereas 6 out of 6 (100%) infant-T/F viruses were neutralization resistant to these V3-specific IgG MAbs. We also show that maternal-plasma broadly neutralizing antibody (bNAb) responses targeting the V3 glycan supersite in a transmitting woman may have selected for an N332 V3 glycan neutralization-resistant infant-T/F virus. These data have important implications for bNAb-eliciting vaccines and passively administered bNAbs in the setting of MTCT.IMPORTANCE Efforts to eliminate MTCT of HIV with antiretroviral therapy (ART) have met little success, with >180,000 infant infections each year worldwide. It is therefore likely that additional immunologic strategies that can synergize with ART will be required to eliminate MTCT of HIV. To this end, understanding the role of maternal HIV Env-specific IgG antibodies in the setting of MTCT is crucial. In this study, we found that maternal-plasma broadly neutralizing antibody (bNAb) responses can select for T/F viruses that initiate infection in infants. We propose that clinical trials testing the efficacy of single bNAb specificities should not include HIV-infected pregnant women, as a single bNAb might select for neutralization-resistant infant-T/F viruses.
Highlights
Each year, Ͼ180,000 infants become infected via mother-to-child transmission (MTCT) of HIV despite the availability of effective maternal antiretroviral treatments, underlining the need for a maternal HIV vaccine
We previously defined maternal humoral correlates of protection against MTCT of HIV and demonstrated that maternal linear variable loop 3 (V3) epitope-specific IgG binding and tier 1 virus-neutralizing responses were associated with a reduced risk of MTCT [17]
The mapping of maternal V3-specific binding and neutralizing responses to the same region within the V3 loop led us to hypothesize that the potential mechanism of these protective responses was mediated through autologous-virus neutralization by weakly neutralizing antibodies directed against the linear portion of the V3 loop
Summary
Ͼ180,000 infants become infected via mother-to-child transmission (MTCT) of HIV despite the availability of effective maternal antiretroviral treatments, underlining the need for a maternal HIV vaccine. To this end, understanding the role of maternal HIV Env-specific IgG antibodies in the setting of MTCT is crucial. Several studies suggest that nontransmitting HIV-infected women have Env-specific IgG responses that are associated with protection compared to those of transmitting mothers [15,16,17,18]. A separate study of chronically HIV-infected adults reported that linear V3-specific IgG responses in plasma strongly neutralized a large proportion of circulating autologous viruses in plasma and selected for neutralization-resistant variants that repopulated the virus pool, suggesting that linear V3-specific IgG responses can exert strong immune pressure on autologous plasma variants [22]. A better understanding of the evolution dynamics of maternal neutralizing antibodies and maternal autologous viruses, which is the precursor pool of the infant-T/F viruses,
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