Excessive conversion and impaired thymic output contribute to disturbed regulatory T-cell homeostasis in AIDS patients with low CD4 cell counts

Abstract

T regulatory (Treg) cells are a heterogeneous population that consists of CD4(+)CD25(low)CD45RA(+) [naive Treg (nTreg) cells] and CD4(+)CD25(high)CD45RA(-) [activated Treg (aTreg) cells] subsets. We investigated the effects of HIV infection and HAART on distinct Treg subsets. HIV-infected adult patients naive to HAART (n=57), patients with acute HIV infection (n=13), and healthy controls (n=92) were recruited for a cross-sectional study. Patients receiving HAART were followed up in a longitudinal study. Compared with healthy controls, we observed a reduced proportion of nTreg cells and an elevated frequency of aTreg cells in peripheral blood from HAART-naïve patients. Moreover, nTreg cells showed a decreased CD31(+) frequency, whereas aTreg cells showed an increased CD31(+) frequency, indicating impaired thymic output and excessive conversion from nTreg to aTreg cells. nTreg and aTreg cells both displayed higher levels of Ki67(+), reflecting hyperproliferation. The longitudinal study showed that HAART successfully recovered nTreg but not aTreg cell frequency. Higher baseline naïve CD4 T-cell percentages were associated with faster reconstitution of nTreg cell frequency as well as CD4(+) T-cell count. Our data suggest that the disturbed homeostasis of Treg cells in HIV-infected patients is probably caused by excessive conversion from nTreg to aTreg cells, and impaired thymic output of nTreg cells. nTreg cells can be recovered by HAART, which was associated with baseline naive CD4(+) T-cell percentages, indicating that reconstitution of nTreg cells may benefit from earlier antiretroviral treatment.