Research Article: CXCR6 + natural killer cell immunotherapy preserves CD4 + T helper cells in humanized mice
Abstract:
Human immunodeficiency virus (HIV) persists despite antiretroviral therapy because long-lived viral reservoirs are not eliminated, and ongoing or rebound infection contributes to progressive loss of CD4 + T helper cells. Natural killer (NK) cells can acquire adaptive, antigen-experienced functions, including recall responses to HIV envelope protein, suggesting that defined NK-cell subsets may be therapeutically useful against HIV. Because HIV-responsive adaptive NK-cell activity is enriched among CXC chemokine receptor 6-positive (CXCR6 + ) NK cells, we tested whether CXCR6 + NK cells provide enhanced antiviral activity and CD4 + T-cell protection compared with CXCR6 ? NK cells. In co-cultures with HIV-infected primary CD4 + T cells, PBMC-derived CXCR6 + and CXCR6 ? NK cells both reduced viral replication, but CXCR6 + NK cells mediated significantly greater suppression. In HIV-infected humanized mice, weekly infusion of expanded PBMC-derived NK cells lowered plasma viral burden, with CXCR6 + NK cells providing stronger preservation of circulating CD4 + T cells and significant preservation of splenic CD4 + T cells. HIV-Env vaccination further enriched NK cells with enhanced therapeutic activity. CXCR6 + NK cells derived from HIV-Env–vaccinated humanized mice produced the strongest suppression of HIV replication and restored CD4 + T-cell frequencies in blood and spleen to levels comparable to uninfected controls. Together, these findings identify CXCR6 + NK cells as an HIV-responsive adaptive NK-cell subset that combines antiviral activity with preservation of CD4 + T-cell immunity in vivo . These data support further development of CXCR6 + NK-cell therapy as a vaccine-informed cellular immunotherapy strategy for HIV.
Introduction:
Over 40.8 million people currently live with human immunodeficiency virus (HIV)-1, and 630,000 HIV-1-related deaths were reported in 2024 ( 1 ). HIV remains a global health burden because lifelong antiretroviral therapy is required to suppress viremia, and viral persistence is maintained by long-lived latent reservoirs that are not eliminated by current treatment ( 2 ). Viral persistence is coupled to progressive immunologic injury, including depletion and dysfunction of CD4 + Th cells ( 3 , 4 ), which is the…
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