Gut Mucosal FOXP3 + Regulatory CD4 + T Cells and Nonregulatory CD4 + T Cells Are Differentially Affected by Simian Immunodeficiency Virus Infection in Rhesus Macaques

Abstract

The gastrointestinal tract represents a major site for human and simian immunodeficiency virus (HIV and SIV) replication and CD4 + T-cell depletion. Despite severe depletion of mucosal CD4 + T cells, FOXP3 + regulatory CD4 + T cells (T reg ) are highly increased in the gut mucosa of chronically HIV-infected individuals and may contribute to HIV pathogenesis, either by their immunosuppressive function or as a significant target cell population for virus production. Little is known about the susceptibility of mucosal T reg to viral infection and the longitudinal effect of HIV/SIV infection on T reg dynamics. In this study, we determined the level of SIV infection in T reg and nonregulatory CD4 + T cells (non-T reg ) isolated from the colon of SIV-infected rhesus macaques. The dynamics of mucosal T reg and alterations in the mucosal CD4 + T-cell pool were examined longitudinally. Our findings indicate that mucosal T reg were less susceptible to productive SIV infection than non-T reg and thus were selectively spared from SIV-mediated cell death. In addition to improved survival, local expansion of T reg by SIV-induced proliferation of the mucosal CD4 + T-cell pool facilitated the accumulation of mucosal T reg during the course of infection. High frequency of mucosal T reg in chronic SIV infection was strongly related to a reduction of perforin-expressing cells. In conclusion, this study suggests that mucosal T reg are less affected by productive SIV infection than non-T reg and therefore spared from depletion. Although SIV production is limited in mucosal T reg , T reg accumulation may indirectly contribute to viral persistence by suppressing antiviral immune responses.