Immunogenic and tolerogenic signatures in human immunodeficiency virus (HIV)-infected controllers compared with progressors and a conversion strategy of virus control

Epidemiological studies have identified a small cohort of controllers of human immunodeficiency virus (HIV)-1 infection, who without treatment have no detectable virus, and others who progress at a variable rate. The objective of this study was to distinguish immune signatures in HIV controllers and progressors, by evaluating tolerogenic and immunogenic factors in untreated HIV-1 infected individuals. The recruited population was divided into putative elite controllers (PEC), long-term non-progressors (LTNP), normal progressors (NP) and fast progressors (FP). The proportion of regulatory T cells [T-regs, CD4(+)CD25(+)forkhead box P3 (FoxP3(+))], programmed death (PD)-1 and cytotoxic T lymphocyte antigen (CTLA)-inhibitory molecules and CD40L, CD69 and Ki67 activation markers were evaluated in peripheral blood mononuclear cells (PBMC) by flow cytometry. Significant differences were found between HIV controllers and HIV progressors, with up-regulation of T-regs, PD-1 and CTLA-4 and decrease of CD40L expression in progressors compared with controllers. Expression of CD40L and concentrations of interleukin (IL)-6, CCL-3, and CCL-4 were significantly higher in PEC and LTNP than in NP and FP. In an attempt to convert immune signatures of progressors to those of controllers, seven agents were used to stimulate PBMC from the four cohorts. Treatment with CD40L and IL-4 or PD-1 antibodies in vitro were most effective in converting the immune signatures of progressors to those observed in controllers by down-regulating T-regs and up-regulating CD40L expression in CD4(+) T cells. The conversion concept merits translation to in vivo immune control of HIV infection.