Reconstitution of Peripheral T Cells by Tissue-Derived CCR4(+) Central Memory Cells Following HIV-1 Antiretroviral Therapy

BACKGROUND: Highly active antiretroviral therapy induces clinical benefits to HIV-1 infected individuals, which can be striking in those with progressive disease. Improved survival and decreased incidence of opportunistic infections go hand in hand with a suppression of the plasma viral load, an increase in peripheral CD4(+) T-cell counts, as well as a reduction in the activation status of both CD4(+) and CD8(+) T cells. METHODS: We investigated T-cell dynamics during ART by polychromatic flow cytometry in total as well as in HIV-1-specific CD4(+) and CD8(+) T cells in patients with advanced disease. We also measured gene expression by single cell transcriptomics to assess functional state. RESULTS: The cytokine pattern of HIV-specific CD8(+) T cells was not altered after ART, though their magnitude decreased significantly as the plasma viral load was suppressed to undetectable levels. Importantly, while CD4(+) T cell numbers increased substantially during the first year, the population did not normalize: the increases were largely due to expansion of mucosal-derived CCR4(+) CD4(+) T(CM); transcriptomic analysis revealed that these are not classical Th(2)-type cells. CONCLUSION: The apparent long-term normalization of CD4(+) T-cell numbers following ART does not comprise a normal balance of functionally distinct cells, but results in a dramatic Th(2) shift of the reconstituting immune system.