The role of neutralizing antibodies in prevention of HIV-1 infection: what can we learn from the mother-to-child transmission context?

Abstract

In most viral infections, protection through existing vaccines is linked to the presence of vaccine-induced neutralizing antibodies (NAbs). However, more than 30 years after the identification of AIDS, the design of an immunogen able to induce antibodies that would neutralize the highly diverse HIV-1 variants remains one of the most puzzling challenges of the human microbiology. The role of antibodies in protection against HIV-1 can be studied in a natural situation that is the mother-to-child transmission (MTCT) context. Indeed, at least at the end of pregnancy, maternal antibodies of the IgG class are passively transferred to the fetus protecting the neonate from new infections during the first weeks or months of life. During the last few years, strong data, presented in this review, have suggested that some NAbs might confer protection toward neonatal HIV-1 infection. In cases of transmission, it has been shown that the viral population that is transmitted from the mother to the infant is usually homogeneous, genetically restricted and resistant to the maternal HIV-1-specific antibodies. Although the breath of neutralization was not associated with protection, it has not been excluded that NAbs toward specific HIV-1 strains might be associated with a lower rate of MTCT. A better identification of the antibody specificities that could mediate protection toward MTCT of HIV-1 would provide important insights into the antibody responses that would be useful for vaccine development. The most convincing data suggesting that NAbs might confer protection against HIV-1 infection have been obtained by experiments of passive immunization of newborn macaques with the first generation of human monoclonal broadly neutralizing antibodies (HuMoNAbs). However, these studies, which included only a few selected subtype B challenge viruses, provide data limited to protection against a very restricted number of isolates and therefore have limitations in addressing the hypervariability of HIV-1. The recent identification of highly potent second-generation cross-clade HuMoNAbs provides a new opportunity to evaluate the efficacy of passive immunization to prevent MTCT of HIV-1.

Figure 1

Infant antibody levels over the three possible stages (in utero, perinatally or postpartum) of mother-to-child transmission of HIV-1. During pregnancy, maternal IgG are transmitted to the fetus across the placenta, reaching normal or somewhat exceeding adult levels at term. After birth, the IgG transferred from the mother disappear progressively, while the amount of IgG being produced by the infant continues to increase. In contrast, the placenta is relatively impermeable to Ig of other classes, levels of which are therefore very low in the newborn.

Figure 2

Selective transmission of HIV-1. A. The quasispecies of the chronically infected donor is usually composed of a major viral population (dark blue virions), as well as numerous other minor variants. One of these minor variants (yellow virion) successfully crosses the mucosal barrier to generate the infection of the recipient. B. The neighbor-joining trees of HIV-1 env gp120 nucleotide sequences issued from two mother-infant pairs show the transmission of a single maternal viral variant [85]. Bootstrap values are expressed as percentages per 1000 replicates. Only bootstrap values >50% are indicated. Horizontal branch lengths are drawn to scale, with the black bar denoting 1% divergence. Each symbol denotes a single env sequence; □, maternal sequence; ●, infant sequence.

Figure 3

A model of the HIV-1 Env spike with selected HuMoNAbs Fabs bound to their conserved epitopes. Adapted with permission from AAAS - Burton et al.[118]. The names of selected HuMoNAbs are underlined. The locations of their targeted epitopes are indicated in bold and italic. The name of other HuMoNabs targeting similar epitopes is included [96,115-117,152,153].

Figure 4

Studies of passive immunization in newborn macaques. A. Passive administration of high concentrations of various combinations of the first-generation HuMoNAbs (b12, 2G12, 2F5, 4E10, F105) (white arrow) before or simultaneously with intravenous or oral challenge with SHIVs (green arrow) protected neonatal rhesus macaques against infection: there was no infection [4,149,150]. B. There was no protection when the first-generation HuMoNAbs (white arrow) were administered more than 12 hours post-virus inoculation (green arrow) [151]. C. New second-generation HuMoNAbs (PG-, PGT-, VRC-series) that are 10- to 100-fold more potent in vitro than the first-generation HuMoNAbs have been identified [96,115-117,152,153]. It would be interesting to re-evaluate the potential protective potency of NAbs in newborn macaques when administered either before or after (white arrow) viral exposure (green arrow).