Maternal Humoral Immune Correlates of Peripartum Transmission of Clade C HIV-1 in the Setting of Peripartum Antiretrovirals

Abstract

Despite the widespread use of antiretrovirals (ARV), more than 150,000 pediatric HIV-1 infections continue to occur annually. Supplemental strategies are necessary to eliminate pediatric HIV infections. We previously reported that maternal HIV envelope-specific anti-V3 IgG and CD4 binding site-directed antibodies, as well as tier 1 virus neutralization, predicted a reduced risk of mother-to-child transmission (MTCT) of HIV-1 in the pre-ARV era U.S.-based Women and Infants Transmission Study (WITS) cohort. As the majority of ongoing pediatric HIV infections occur in subSaharan Africa, we sought to determine if the same maternal humoral immune correlates predicted MTCT in a subset of the Malawian Breastfeeding, Antiretrovirals, and Nutrition (BAN) cohort of HIV-infected mothers (n ϭ 88, with 45 transmitting and 43 nontransmitting). Women and infants received ARV at delivery; thus, the majority of MTCT was in utero (91%). In a multivariable logistic regression model, neither maternal anti-V3 IgG nor clade C tier 1 virus neutralization was associated with MTCT. Unexpectedly, maternal CD4 binding-site antibodies and anti-variable loop 1 and 2 (V1V2) IgG were associated with increased MTCT, independent of maternal viral load. Neither infant envelope (Env)-specific IgG levels nor maternal IgG transplacental transfer efficiency was associated with transmission. Distinct humoral immune correlates of MTCT in the BAN and WITS cohorts could be due to differences between transmission modes, virus clades, or maternal antiretroviral use. The association between specific maternal antibody responses and in utero transmission, which is distinct from potentially protective maternal antibodies in the WITS cohort, underlines the importance of investigating additional cohorts with well-defined transmission modes to understand the role of antibodies during HIV-1 MTCT.

Diversity and function of maternal HIV-1-specific antibodies at the time of vertical transmission

“…There is some evidence that V3 nAbs play a role in MTCT, although the results are not consistent across studies and cohorts. V3-specificity was associated with protection in the clade B Women and Infant Transmission Study (7, 8), but not in the clade C Breastfeeding and Nutrition study (11). Based on evidence suggesting that V3-targeting antibodies can select virus escape mutants and drive neutralization resistance in the autologous virus reservoir (30), it has been proposed that maternal V3 nAbs could drive selection of neutralization-resistant transmitted viruses in MTCT (6).…”

“…Relatedly, there is also inconsistency in studies that sought to define properties of Env-specific maternal antibodies that are associated with reduced risk of mother-to-child transmission (MTCT) (6). Some studies suggest that protection is associated with antibodies that target specific epitopes such as variable loop region 3 (V3) (7–9) or gp41 (10), while another study found no association between nAb properties and MTCT risk (11) and still others have found antibody specificities that are associated with increased infection risk (12).…”

Optimized Mucosal Modified Vaccinia Virus Ankara Prime/Soluble gp120 Boost HIV Vaccination Regimen Induces Antibody Responses Similar to Those of an Intramuscular Regimen

“…Protein vaccines and adjuvants. The antigen used for booster immunizations consisted of either C.1086 delta7gp120K160N (gp120) (47,76) or a fusion protein between C.1086 delta7gp120K160N and the Ad2F adhesin (gp120-Ad2F) using a method described previously (26). Briefly, the C-terminal region of Ad2F, from G378 to E582, was used as the transporter/targeting domain.…”

Optimized Mucosal MVA Prime/ Soluble gp120 Boost Vaccination Regimen Induces Similar Antibody Responses as an Intramuscular Regimen

“…The antigen used for booster immunizations consisted of either C.1086 delta7gp120K160N (gp120) (45, 46) or a fusion protein between C.1086 delta7gp120K160N and the Ad2F adhesin (gp120-Ad2F) using the method to that previously described (26). Briefly, the C-terminal region of the Ad2F, starting from G378 to E582, was used as the transporter/targeting domain.…”