Identification of CD8⁺ T cell subsets that normalize in early-treated people living with HIV receiving antiretroviral therapy

Background: Although combined antiretroviral therapy (cART) has decreased the mortality associated with HIV infection, complete immune reconstitution is not achieved despite viral suppression. Alterations of CD8⁺ T cells and some of their subpopulations, such as interleukin (IL)-17-producing cells, are evidenced in treated individuals and are associated with systemic inflammation and adverse disease outcomes. We sought to evaluate if different CD8⁺ T cell subsets are differentially normalized during a clinical follow-up of people living with HIV (PLWH) receiving suppressive cART. Methods: We explored the changes in the frequencies, activation/exhaustion phenotypes (HLA-DR, CD38, PD-1, and TIM-3), and function (total and HIV-specific cells expressing CD107a, perforin, granzyme B, interferon [IFN]-γ and IL-17) of CD8⁺ T cells from early-treated PLWH receiving cART in a 1-year follow-up, using a multidimensional flow cytometry approach. Results: Despite continuous cART-induced viral suppression and recovery of CD4⁺ T cells, after a 1-year follow-up, the CD8⁺ T cell counts, CD4:CD8 ratio, PD-1 expression, and IL-17 production by CD8⁺ T cells exhibited incomplete normalization compared with seronegative controls. However, the proportion of CD8⁺ T cells with an exhausted phenotype (co-expressing PD-1 andTIM-3), and cells co-expressing cytotoxic molecules (Perforin and Granzyme B), reached normalization. Conclusions: Although suppressive cART achieves normalization of CD4⁺ T cell counts, only particular subsets of CD8⁺ T cells are more rapidly normalized in PLWH receiving cART, which could be routinely used as biomarkers for therapy efficiency in these patients.