Depletion of plasmacytoid dendritic cells rescues HIV-reactive stem-like CD8⁺ T cells during chronic HIV-1 infection.

Abstract

Plasmacytoid dendritic cells (pDCs) rapidly produce type I interferon (IFN-I) in response to acute virus infections. During chronic HIV-1 infection, persistent activation of pDCs contributes to inflammatory diseases. Combination antiretroviral therapy (cART) effectively suppresses HIV-1 replication and prolongs the life span of people living with HIV-1 (PLWH). The persistence of viral reservoir cells under cART, however, is associated with suboptimal immune reconstitution, impaired anti-HIV immunity, and non-AIDS-defining inflammatory diseases through unclear mechanisms. We report here that pDC depletion in HIV-infected humanized mice with suppressive cART alleviated HIV-associated inflammation, reversed T cell immune exhaustion, enhanced HIV-specific CD8⁺ T cell responses, and reduced HIV-1 reservoirs in lymphoid and nonlymphoid tissues through CD8⁺ T cell-dependent mechanisms. Specifically, pDC depletion in the mice led to an increase in TCF-1⁺PD-1⁺Tim-3^- stem-like memory CD8⁺ T cells in HIV-infected lymphoid tissues, which correlated with a reduction in the HIV-1 reservoir. We further showed that pDCs suppressed the polyfunctional activity of anti-HIV stem-like memory CD8⁺ T cells isolated from PLWH in vitro. As in the HIV-infected humanized mice, pDC depletion or IFN-I blockade functionally rescued the stem-like memory CD8⁺ T cells, enhancing their anti-HIV responses. Combination therapy with PD-1 blockade further improved stem-like memory T cell function both in vitro and in HIV-infected humanized mice. Our findings indicate that HIV-induced inflammatory pDCs impair anti-HIV stem-like memory CD8⁺ T cell responses and suggest that the combination of pDC depletion with PD-1 immune checkpoint blockade represents a candidate therapeutic approach to treating HIV-1 infection and its associated inflammatory diseases.