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

Abstract

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.

Keywords: CXCR3; HIV; HPV; cancer; mucosal immunity; skin; tissue-resident memory T cells.