Development and Characteristics of the Earliest Cross-Neutralizing Antibody Response to HIV-1

Abstract

A neutralizing antibody response of sufficient potency, magnitude and duration is considered an important part of a successful HIV vaccine. A better understanding of the factors associated with the development of broadly neutralizing antibody responses (effective against a wide range of clinical isolates), and the epitopes they target, will aid in our understanding of how to elicit such responses by vaccination. Cross-sectional studies of chronic HIV-1 infection have demonstrated that approximately 15% of HIV-1-infected subjects develop such responses. We characterized the development and epitope specificities of the earliest serum cross-reactive neutralizing antibody responses in an acute/early HIV infection cohort. We demonstrate that 29% of subjects in that cohort develop such responses within 2-3 years of infection. Our epitope-mapping results indicate that the earliest cross-neutralizing antibody responses target a limited number of regions on the HIV Envelope, often involving the highly conserved CD4-binding site on the HIV Envelope. In a case study of an HIV-1-infected individual we aimed to understand the emergence and evolution of the earliest cross-neutralizing antibody responses, and identified two distinct epitope specificities. Antibodies that targeted the CD4-BS became detectable at around 3 years post infection, and were responsible for the neutralization of most cross-clade viral isolates tested. Another specificity became apparent over a year later, which was due to broadly neutralizing antibodies specific to a carbohydrate at position 160 on the HIV Env. Our findings supports vaccine design efforts that aim to elicit multiple antibody specificities.