The Cellular and Molecular Biology of HIV-1 Broadly Neutralizing Antibodies

Induction of neutralizing antibodies capable of protecting against human immunodeficiency virus 1 (HIV-1) infection is a key goal of HIV-1 vaccine development. The target of neutralizing antibodies is the HIV-1 envelope (Env) protein on the virion surface. Although HIV-1 is extraordinarily diverse, some antibodies can recognize highly conserved sites on Env and neutralize diverse viral strains. Such broadly neutralizing antibodies (bnAbs) arise in ~20% of infected individuals, usually several years after infection. Antibody responses to these conserved epitopes are disfavored and subdominant, and to date, no vaccines have induced bnAbs. Recent data have demonstrated that bnAbs often exhibit unusual characteristics, including long heavy chain complementarity determinant region 3, high levels of somatic mutation, and recognition of self-antigens, or autoreactivity-traits that render them prone to elimination by clonal deletion and limit their abundance in the B cell repertoire. These challenges have necessitated an in depth understanding of the maturation pathways of bnAbs and their immunoregulatory controls so that novel strategies can be designed to induce them by vaccination.