Resting Regulatory CD4 T Cells: A Site of HIV Persistence in Patients on Long-Term Effective Antiretroviral Therapy

Background: In HIV-infected patients on long-term HAART, virus persistence in resting long-lived CD4 T cells is a major barrier to curing the infection. Cell quiescence, by favouring HIV latency, reduces the risk of recognition and cell destruction by cytotoxic lymphocytes. Several cell-activation-based approaches have been proposed to disrupt cell quiescence and then virus latency, but these approaches have not eradicated the virus. CD4(+)CD25(+) regulatory T cells (Tregs) are a CD4(+) T-cell subset with particular activation properties. We investigated the role of these cells in virus persistence in patients on long-term HAART. Methodology/Principal Findings: We found evidence of infection of resting Tregs (HLADR(-)CD69(-)CD25(hi)FoxP3(+)CD4(+) T cells) purified from patients on prolonged HAART. HIV DNA harbouring cells appear more abundant in the Treg subset than in non-Tregs. The half-life of the Treg reservoir was estimated at 20 months. Since Tregs from patients on prolonged HAART showed hyporesponsiveness to cell activation and inhibition of HIV-specific cytotoxic T lymphocyte-related functions upon activation, therapeutics targeting cell quiescence to induce virus expression may not be appropriate for purging the Treg reservoir. Conclusions: Our results identify Tregs as a particular compartment within the latent reservoir that may require a specific approach for its purging.