Journal
IMMUNOLOGICAL REVIEWS
Volume 275, Issue 1, Pages 62-78Publisher
WILEY
DOI: 10.1111/imr.12504
Keywords
autoantibody; broadly neutralizing antibody; CD4(+) T follicular helper cell; CD4(+) T follicular regulatory cell; human immunodeficiency virus; regulatory T cell
Categories
Funding
- NIH, NIAID, Division of AIDS [AI100645]
- MRC [MR/K012037]
- MRC [MR/K012037/1] Funding Source: UKRI
- Medical Research Council [MR/K012037/1] Funding Source: researchfish
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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 2-4years 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.
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