Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Abstract

SummaryInduction 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.

Pregnancy favors circulating IL‐21–secreting TFH‐like cell recovery in ARV‐treated HIV‐1–infected women

“…There is a possibility that the reduction in IL-6 production associated with an elevated IL-10 release in pregnant patients may contribute to attenuating the expansion of dysfunctional Tfh-like cells. The frequency of this T FH -cell subset during acute HIV-1 infection correlates negatively with set point viral load and positively with anti-p24 IgG titers 41. Although we did not investigate this relationship, better virological response to ARV therapy was observed among our PW.More interestingly, pregnancy affects the efficiency of ARV therapy in elevating different circulating cytokine-secreting T FH -cell subsets.…”

“…11 The frequency of this T FH -cell subset during acute HIV-1 infection correlates negatively with set point viral load and positively with anti-p24 IgG titers. 41 Interestingly, a higher frequency of CXCR3 + CXCR5 + CD4 + T cells able to produce IL-21 and IFN-γ has been observed in healthy HIV-1-negative PW during the third trimester of gestation, as compared with nPW ones. 32 Here, there is a possibility that ARV raised the frequency In the context of HIV, neutralization of antibodies for different HIV-1 strains has been observed among patients who spontaneously control the virus.…”

The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

“…Protection correlated with high levels of anti‐viral IgG, dependent on CD4 T‐cell responses, while vaccine‐driven IgA was associated with an increased risk of infection 90, 91, 92. Immune protection to this highly diverse virus is thought to require broadly neutralizing antibodies (bnAbs) that recognize more conserved regions of the virus 93. The development of bnAbs likely requires repeated exposure to the antigen and continued input from Tfh cells 93.…”

“…[90][91][92] Immune protection to this highly diverse virus is thought to require broadly neutralizing antibodies (bnAbs) that recognize more conserved regions of the virus. 93 The development of bnAbs likely requires repeated exposure to the antigen and continued input from Tfh cells. 93 Successful HIV vaccines will probably, therefore, require the induction of effective Tfh memory cells that can coordinate the development of protective bnAbs.…”

Germinal center enhancement by extended antigen availability

“…Longitudinal analyses of BCR and viral lineages throughout HIV infection has provided clear evidence that bnAbs undergo high amounts of affinity maturation before obtaining their broadly neutralizing activity [6,7]. The development of bnAbs via immunization is a major challenge and it is likely that certain conditions that resemble natural infection, including persistent antigen presence, are required for HIV bnAb development [8]. …”