Acute HIV-1 infection is characterized by high viremia and massive depletion of CD4⁺ T cells throughout all tissue compartments. During this time the latent viral reservoir is established but the dynamics of memory CD4⁺ T cell subset development, their infectability and influence on disease progression during acute HIV-1 infection has not been carefully described. We therefore investigated the dynamics of CD4⁺ T cell memory populations in the RV217 (ECHO) cohort during the acute phase of infection. Interestingly, while we found only small changes in central or effector memory compartments, we observed a profound expansion of stem cell-like memory CD4⁺ T cells (SCM) (2.7-fold; P < 0.0001). Furthermore, we demonstrated that the HIV-1 integration and replication preferentially take place in highly differentiated CD4⁺ T cells such as transitional memory (TM) and effector memory (EM) CD4⁺ T cells, while naive and less mature memory cells prove to be more resistant. Despite the relatively low frequency of productively infected SCM, we suggest that their quiescent phenotype, increased susceptibility to HIV-1 integration compared to naive cells and extensive expansion make them one of the key players in establishment and persistence of the HIV-1 reservoir. Moreover, the expansion of SCM in acute HIV-1 infection was a result of Fas upregulation on the surface of naive CD4⁺ T cells. Interestingly, the upregulation of Fas receptor and expansion of SCM in acute HIV-1 infection was associated with the early viral set point and disease progression (rho = 0.47, P = 0.02, and rho = 0.42, P = 0.041, respectively). Taken together, our data demonstrate an expansion of SCM during early acute HIV-1 infection which is associated with disease outcome.

IMPORTANCE Understanding the immunopathology of acute HIV-1 infection will help to develop eradication strategies. We demonstrate here that a CD4⁺ T cell memory subset expands during acute HIV-1 infection, which is associated with disease progression.