CD24-Fc resolves inflammation and enhances anti-HIV CD8 T cells with polyfunctionality during HIV-1 infection under cART

The persistence of HIV-1 reservoirs during combination anti-retroviral therapy (cART) is associated with chronic inflammation and systemic immune activation in people infected with HIV-1 (PWH), leading to a suboptimal immune reconstitution as well as an increased risk of non-AIDS events. In this study, we assessed the effect of CD24-Fc, a fusion protein with anti-inflammatory properties that interacts with danger-associated molecular patterns (DAMPs) and siglec-10, in humanized mice with chronic HIV-1 infection under suppressive cART in vivo and in peripheral blood mononuclear cells (PBMCs) from PWH in vitro. We report that CD24-Fc treatment significantly reduced inflammation and immune hyperactivation in humanized mice with HIV-1 infection and cART. CD24-Fc treatment improved recovery of CD4 T cells, reduced immune hyper-activation, increased functional central memory T cells. Notably, CD24-Fc treatment increased CXCR5 + CD8 central memory T cells (TCM) with increased HIV-specific polyfunctionality in humanized mice and in PBMC from PWH. This enhanced anti-HIV T cell activity was associated with improved control of HIV-1 viral rebound and reduced HIV-1 pathogenesis upon cART cessation. Our findings indicate that CD24-Fc may provide a promising new therapeutic for treating chronic inflammation and associated diseases in PWH.