Defining neutralizing antibody specificities that target diverse HIV-1 transmitted strains

Abstract

Studies in animal models have shown that pre-existing neutralizing antibodies (NAbs), which target the human immunodeficiency virus type 1 (HIV-1) envelope (Env) to prevent entry into host cells, can block infection. A limitation of these models is that typically only one challenge virus is used. Given the diversity of HIV-1 in real world settings, a NAb-based vaccine must have broad and potent activity against multiple strains. This thesis describes NAb specificities that target diverse HIV-1 transmitted variants in natural infection within a high-risk population of exposed infants and women. First, we investigated how transmitted viruses `escape' NAbs by comparing neutralization-resistant viruses in infants to neutralization-sensitive maternal variants near the time of transmission in 2 mother-infant pairs. Although the molecular determinants of escape were distinct, NAb escape involved conformational masking of distal epitopes in both pairs. This strategy may allow HIV-1 Env to utilize limited changes to simultaneously evade multiple NAb specificities while preserving the ability to infect a new host. Next, we determined the activity of 7 broadly neutralizing antibodies (bNAbs) against 45 heterosexually transmitted viruses obtained from Kenyan women. NIH45-46W, which targets the CD4 binding site, was most broad, neutralizing 91% of viruses. Viruses resistant to NIH45-46W were neutralized by PGT128, which targets variable loop 3 of Env, suggesting that combining bNAbs with distinct specificities would provide optimal coverage of HIV-1 variants. Finally, we explored the ability of the early immune system to develop bNAbs by screening 28 infant plasma samples against heterologous viruses. Remarkably, as early as 2.5 years of life and of HIV infection, some infants generated NAbs of similar breadth and potency to those found in adults identified as having very broad responses after approximately 5 years of infection. This finding implies that there is sufficient B-cell functionality in early life to generate broad and potent responses against HIV-1. Overall, these studies suggest that for a preventative vaccine, bNAbs targeting distinct conserved epitopes may be required to overcome HIV-1 diversity, and that characterizing the early development of bNAbs in infants may provide insight into how to elicit such NAb responses.