Memory and naive-like regulatory CD4 ⁺ T cells expand during HIV-2 infection in direct association with CD4 ⁺ T-cell depletion irrespectively of viremia

Objective: The dynamics of CD4 ⁺ regulatory T cells (Treg) during HIV-1 infection remains unclear. To further investigate Treg in this context, we characterized, for the first time, this population in HIV-2-positive individuals. Although both HIV infections are associated with hyperimmune activation and CD4 ⁺ T-cell lymphopenia, most HIV-2-positive individuals display slower disease progression and low-to-undetectable viremia. DESIGN/Methods: Samples were obtained from cohorts of untreated HIV-2-positive and HIV-1-positive, treated HIV-1-positive and seronegative individuals. The proportion of CD4 ⁺ T cells bearing a Treg phenotype, defined in terms of high-level CD25 or Foxp3 expression, was assessed by flow cytometry and correlated with markers of disease progression. The proportions of naive and memory-like subsets as well as cycling cells were determined. Results: We observed an increased proportion of Treg, associated with disease progression, as well as increased proportions of cycling (Ki67) memory Treg, in untreated HIV-2-positive and HIV-1-positive individuals. We also noted an expansion of Treg that persisted over time in treated, immunologically discordant HIV-1-positive individuals, who, similarly to HIV-2-positive patients, present undetectable viremia and low CD4 ⁺ T-cell count. Conclusion: Overall, we demonstrated that Treg frequency was increased in all lymphopenic HIV-2-positive and HIV-1-positive individuals irrespective of the presence or absence of viremia or antiretroviral treatment. This, in turn, suggests that the observed alterations in Treg frequency in HIV/AIDS are more directly related to the degree of CD4 ⁺ depletion than to viremia.