The Breadth and Potency of Passively Acquired Human Immunodeficiency Virus Type 1-Specific Neutralizing Antibodies Do Not Correlate with the Risk of Infant Infection

Abstract

Although a major goal of human immunodeficiency virus type 1 (HIV-1) vaccine efforts is to elicit broad and potent neutralizing antibodies (NAbs), there are no data that directly demonstrate a role for such NAbs in protection from HIV-1 infection in exposed humans. The setting of mother-to-child transmission provides an opportunity to examine whether NAbs provide protection from HIV-1 infection because infants acquire passive antibodies from their mothers prior to exposure to HIV-1 through breastfeeding. We evaluated the characteristics of HIV-1-specific NAbs in 100 breast-fed infants of HIV-1-positive mothers who were HIV-1 negative at birth and monitored them until age 2. A panel of eight viruses that included variants representative of those in the study region as well as more diverse strains was used to determine the breadth of the infant NAbs. From their mothers, infants acquired broad and potent NAbs that were capable of recognizing heterologous circulating HIV-1 variants of diverse subtypes, but the presence of NAbs of broad HIV-1 specificity was not associated with transmission risk. There was also no correlation between responses to any particular virus tested, which included a range of diverse variants that demonstrated different neutralization profiles, including recognition by specific antibodies with known epitope targets. The eight viruses tested exhibited neutralization profiles to a variety of monoclonal antibodies (2F5, PG9, and VRC01) similar to those of viruses present in pregnant women in the cohort. These results suggest that the breadth and potency of the heterologous antibody response in exposed infants, measured against a virus panel comprised of variants typical of those circulating in the population, does not predict protection.

The Genetic Bottleneck in Vertical Transmission of Subtype C HIV-1 Is Not Driven by Selection of Especially Neutralization-Resistant Virus from the Maternal Viral Population

“…Although this is in contrast to previous results in subtype Binfected women (12), a recent study has yielded results similar to ours in that the neutralization breadth of maternal antibodies measured in infant samples did not correlate with protection from infection (36). Higher breadth of maternal neutralizing antibodies, at least for women infected with non-B subtypes, has thus shown no correlation with protection from MTCT.…”

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

“…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)(6)(7)(8), yet other studies did not (9)(10)(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.…”

Passively Transmitted gp41 Antibodies in Babies Born from HIV-1 Subtype C-Seropositive Women: Correlation between Fine Specificity and Protection

“…Other recent MTCT studies focused on postnatal transmission and the role of maternal antibodies (18,31). The former one compared Env-specific IgG and IgA in serum and breast milk specimens from 41 HIV-positive women; the IgG fraction from breast milk showed neutralizing and ADCC activities that were 100-fold higher than the IgA ones, and similar differences were observed in serum (15).…”

“…Moreover, the role and extent of other antibody-mediated antiviral activities, such as ADCC, were not addressed in those studies (31). In our study, not only different antibody titers but also different pools of antibodies may exist, with pools being reactive to the MPER or the IDE domains and some of the IgGs displaying virus-neutralizing properties (Fig.…”

“…Other studies, where primary isolates were characterized with monoclonal antibodies, adopted a different system and therefore achieved different results, since polyclonal sera contain many different antibody specificities and could provide neutralization through one or more antibodies, e.g., by targeting overlapping or contiguous epitopes to 2F5 within MPER or by taking advantage of synergic interactions among different antibodies (31). One or more of these hypotheses could provide explanations for the significant neutralization activity associated with the MPER domain that was observed in this cohort, although similar results were not reported in other studies.…”