Immune exposure to a specific sequence of antibody escape variants could program long-term potential for neutralization breadth in subtype A HIV-1 infection (P6161)

Abstract

Abstract Approximately one quarter of HIV-1 infected individuals will generate broadly neutralizing antibodies, but the exact mechanisms for triggering and maturation of these responses are presently undefined. We consequently investigated the roots of neutralization breadth. In a subtype A HIV-1 infected Rwandan seroconverter, we pinpointed the primary neutralizing antibody target and the successive routes of viral escape using envelope glycoproteins from the transmitted/founder virus and longitudinal escape variants along with autologous plasma and monoclonal antibodies. Initially, a single mutation at one of three clustered residues proximal to gp120’s third hypervariable loop conferred viral escape. This putative epitope subsequently elicited at least two somatically related monoclonal antibodies, which bound and neutralized the established escape mutations. Resistance to this secondary wave of immune pressure then arose in later viral envelopes through introduction of two glycans that obscured this consistently targeted space. At 16-months post-infection, what had been a narrow, regional response evolved to force recognition and neutralization of distinct envelope portions, which resulted in moderate cross-clade humoral breadth. Our data suggest that unveiling a certain chain of envelope mutations could drive B cells toward the production of broadly neutralizing antibodies. Appreciating this knowledge during immunogen construction could positively impact HIV-1 vaccine design.