Delayed antiretroviral therapy in HIV-infected individuals leads to irreversible depletion of skin- and mucosa-resident memory T cells.

People living with HIV (PLWH) are at increased risk for developing skin and mucosal malignancies despite systemic reconstitution of CD4 ⁺ T cells upon antiretroviral therapy (ART). The underlying mechanism of chronic tissue-related immunodeficiency in HIV is unclear. We found that skin CD4 ⁺ tissue-resident memory T (Trm) cells were depleted after HIV infection and replenished only upon early ART initiation. TCR clonal analysis following early ART suggested a systemic origin for reconstituting CD4 ⁺ Trm cells. Single-cell RNA sequencing in PLWH that received late ART treatment revealed a loss of CXCR3 ⁺ Trm cells and a tolerogenic skin immune environment. Human papilloma virus-induced precancerous lesion biopsies showed reduced CXCR3 ⁺ Trm cell frequencies in the mucosa in PLWH versus HIV ^- individuals. These results reveal an irreversible loss of CXCR3 ⁺ Trm cells confined to skin and mucosa in PLWH who received late ART treatment, which may be a precipitating factor in the development of HPV-related cancer.
Competing Interests: Declaration of interests The authors declare no competing interests
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