Memory stem T cells (T_SCM) constitute a long-lived, self-renewing lymphocyte population essential for the maintenance of functional immunity. The hallmarks of HIV-1 pathogenesis are CD4⁺ T cell depletion and abnormal cellular activation. We investigated the impact of HIV-1 infection on the T_SCM compartment, as well as any protective role these cells may have in disease progression, by characterizing this subset in a cohort of 113 subjects with various degrees of viral control on and off highly active antiretroviral therapy (HAART). We observed that the frequency of CD8⁺ T_SCM was decreased in all individuals with chronic, untreated HIV-1 infection and that HAART had a restorative effect on this subset. In contrast, natural controllers of HIV-1 had the highest absolute number of CD4⁺ T_SCM cells among all of the infected groups. The frequency of CD4⁺ T_SCM predicted higher CD8⁺ T_SCM frequencies, consistent with a role for the CD4⁺ subset in helping to maintain CD8⁺ memory T cells. In addition, T_SCM appeared to be progenitors for effector T cells (T_EM), as these two compartments were inversely correlated. Increased frequencies of CD8⁺ T_SCM predicted lower viral loads, higher CD4⁺ counts, and less CD8⁺ T cell activation. Finally, we found that T_SCM express the mucosal homing integrin α4β7 and can be identified in gut-associated lymphoid tissue (GALT). The frequency of mucosal CD4⁺ T_SCM was inversely correlated with that in the blood, potentially reflecting the ability of these self-renewing cells to migrate to a crucial site of ongoing viral replication and CD4⁺ T cell depletion.

IMPORTANCE HIV-1 infection leads to profound impairment of the immune system. T_SCM constitute a recently identified lymphocyte subset with stem cell-like qualities, including the ability to generate other memory T cell subtypes, and are therefore likely to play an important role in controlling viral infection. We investigated the relationship between the size of the CD8⁺ T_SCM compartment and HIV-1 disease progression in a cohort of chronically infected individuals. Our results suggest that HAART restores a normal frequency of CD8⁺ T_SCM and that the natural preservation of this subset in the setting of untreated HIV-1 infection is associated with improved viral control and immunity. Therefore, the CD8⁺ T_SCM population may represent a correlate of protection in chronic HIV-1 infection that is directly relevant to the design of T cell-based vaccines, adoptive immunotherapy approaches, or the pharmacologic induction of T_SCM.