Maternal Neutralization-Resistant Virus Variants Do Not Predict Infant HIV Infection Risk

Abstract

Mother-to-child transmission (MTCT) of HIV provides a setting for studying immune correlates of protection. Neutralizing antibodies (NAbs) are suggested to contribute to a viral bottleneck during MTCT, but their role in blocking transmission is unclear, as studies comparing the NAb sensitivities of maternal viruses have yielded disparate results. We sought to determine whether transmitting mothers differ from nontransmitting mothers in the ability to neutralize individual autologous virus variants present at transmission. Ten transmitting and 10 nontransmitting HIV-infected mothers at high risk of MTCT were included in this study. Full-length HIV envelope genes (n = 100) were cloned from peripheral blood mononuclear cells obtained near transmission from transmitting mothers and at similar time points from nontransmitting mothers. Envelope clones were tested as pseudoviruses against contemporaneous, autologous maternal plasma in neutralization assays. The association between transmission and the log2 50% inhibitory concentration (IC50) for multiple virus variants per mother was estimated by using logistic regression with clustered standard errors. t tests were used to compare proportions of neutralization-resistant viruses. Overall, transmitting mothers had a median IC50 of 317 (interquartile range [IQR], 202 to 521), and nontransmitting mothers had a median IC50 of 243 (IQR, 95 to 594). Transmission risk was not significantly associated with autologous NAb activity (odds ratio, 1.25; P = 0.3). Compared to nontransmitting mothers, transmitting mothers had similar numbers of or fewer neutralization-resistant virus variants, depending on the IC50 neutralization resistance cutoff. In conclusion, HIV-infected mothers harbor mostly neutralization-sensitive viruses, although resistant variants were detected in both transmitting and nontransmitting mothers. These results suggest that MTCT during the breastfeeding period is not driven solely by the presence of maternal neutralization escape variants.

HIV-1 Neutralizing Antibodies with Limited Hypermutation from an Infant

“…Full-length envs were cloned from DNA isolated from uncultured PBMCs for the BF520 14-week (3.8 month) time-point as previously described (Milligan et al, 2016). For the 6-month time-point, envs were cloned total RNA that was extracted from 50 μL of plasma as described in (Palmer et al, 2005).…”

“…For the 6-month time-point, envs were cloned total RNA that was extracted from 50 μL of plasma as described in (Palmer et al, 2005). cDNA synthesis and nested PCR of full-length env was performed as previously described with minor modifications to the primers, which are available upon request (Milligan et al, 2016; Wu et al, 2006). …”

“…Maternal (Milligan et al, 2016) and infant env sequences were aligned using MacClade version 4.01. A maximum likelihood phylogenetic tree was constructed using the HIV LANL HIV tools database PHYML interface (Guindon et al, 2010) http://www.hiv.lanl.gov/content/sequence/PHYML/interface.html.…”

The Role of Maternal HIV Envelope-Specific Antibodies and Mother-to-Child Transmission Risk

“…Env-specific IgG responses can mediate immune pressure on autologous circulating viruses and therefore could contribute to the selection of infant T/F viruses (Figure 1 B). While some studies have suggested that viruses transmitted from mother to infant may be resistant to neutralization by maternal antibodies ( 10 , 21 , 22 ), other studies have not confirmed these observations ( 13 , 23 ). The reported increased resistance of infant T/F viruses to maternal NAbs may be explained by genetic differences compared to maternal non-transmitted viruses at key sites including Env glycan motifs.…”

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

“…The specific role of maternal autologous virus-neutralizing IgG responses in driving the selection of infant transmitted founder viruses is both controversial and complex. Some studies, including the larger studies on this topic, report that viruses transmitted from mother to infant are more resistant to neutralization by maternal antibodies than the overall maternal viral population, implying maternal antibodies may select against transmission of the most neutralization sensitive variants (1–3), but this has not been consistently observed in all studies (4, 5). 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).…”