Innate immune mechanisms in HIV elite controllers

To synthesize current evidence on how innate immune mechanisms, including natural killer (NK) cells, dendritic cells (DCs), monocytes, and the cytokine milieu, contribute to durable HIV control in elite controllers (ECs), to highlight key gaps in our understanding of these pathways, and to discuss how EC-informed innate signatures can be harnessed to guide the design of cure-directed interventions.

Recent high-dimensional and functional studies have refined the innate immune signatures associated with spontaneous HIV control. NK cells in ECs exhibit distinctive phenotypes, including enrichment of CD69 + subsets, adaptive-like NKG2C + CD57 + populations, and unusual NKG2A/NKG2C co-expression, together with epigenetic remodeling suggestive of specialized antiviral programming. Parallel work has revealed substantial but heterogeneous alterations in monocyte homeostasis, with cohort-dependent shifts in classical and intermediate subsets and evidence of perturbed inflammatory potential. Dendritic-cell studies have identified enhanced intrinsic antiviral programs in ECs, including cooperative activation of cGAS-STING and RIG-I pathways and metabolically reinforced cDC maturation, pointing to improved sensing and antigen-presenting capacity. At the soluble level, newly generated data demonstrate that ECs maintain low circulating interferon alpha (IFN-α) and minimal cellular perturbation, supporting the model of a tightly regulated and spatially constrained IFN-I response.

Elite controllers provide a human model in which innate immunity, through specialized innate cell programs, contributes to durable HIV suppression alongside adaptive responses. However, our view of these pathways is fragmentary, particularly in tissues and over time. Defining which innate mechanisms are necessary, sufficient and safely targetable will be crucial for translating EC biology into rational, combination strategies aimed at achieving ART-free HIV remission.