Immunologic characteristics of HIV-infected individuals who make broadly neutralizing antibodies.

Induction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV-1) is a key, as-yet-unachieved goal of prophylactic HIV-1 vaccine strategies. However, some HIV-infected individuals develop bnAbs after approximately 2-4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4 T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4 (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy-chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4 Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV-1 infection, in particular alterations in CD4 Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV-1 vaccine design.