HLA-F expression on CD4 T cells in HIV-1 is linked to the presence of viremia and modulated by KIR3DS1

KIR3DS1 is an activating natural killer (NK) cell receptor gene– present in 10-40% of humans– and is associated with extended AIDS-free survival. Although its ligand HLA-F has been identified, the underlying protective mechanism in HIV-1 is not yet understood. We sought to uncover the role of the KIR3DS1/HLA-F axis through investigating HLA-F surface and transcriptional changes during acute and chronic HIV-1 infection. HLA-F ⁺ CD4 T cells were detected in people living with HIV (PLHIV) without antiretroviral treatment (N=102) and frequencies correlated with viremia but not with CD4 T cell count. Single-cell transcriptome analyses of PLHIV following acute HIV-1 acquisition revealed increased HLA-F mRNA levels in CD4 T cells associated with innate signaling signatures. In vitro, HLA-F mRNA was upregulated in both HIV-1–infected and bystander CD4 T cells. Functional studies demonstrated that bystander-activated CD4 T cells were reduced in the presence of NK cells during HIV-1 infection, and depleting NK cells increased the frequency of HLA-F ⁺ CD4 T cells. Genotyping of our cohort revealed that KIR3DS1 ⁺ PLHIV exhibited significantly lower frequencies of HLA-F ⁺ CD4 T cells. Taken together, these results establish HLA-F as a novel marker of innate T cell activation that is linked to HIV-1 viremia and suggest an immunoregulatory role of NK cells in controlling HIV-1-mediated inflammation by killing activated bystander CD4 T cells.