Age-Dependent Cytokine Profiles and Co-Inhibitory Receptor Dynamics Drive HIV Reservoir Persistence in Children Living with HIV 4811

Description A latent HIV reservoir persists in children living with HIV (CLWH) despite treatment. We tested whether levels of expression of cytokines and co-inhibitory receptors in early life influenced size and persistence of the HIV reservoir. PBMC and plasma from CLWH (n = 64, aged 5–18 years) were analyzed for cell surface co-inhibitory receptor expression and levels of 33 cytokines, respectively. Frequencies of CD4+ and CD8+ T cells expressing PD-1 or TIGIT increased with age and positively correlated with frequency of cells with total HIV DNA and inducible HIV RNA. Specifically, CLWH <10 years exhibited elevated levels of 7 cytokines, including IL-7, IL-15, and TGF-β1/2, with high HIV DNA and inducible RNA linked to cytokine profiles driving CD4+ T cell effector differentiation (e.g., IFN-γ, IL-4). High levels of IL-17A, TNF-α, and M-CSF were linked to stable HIV DNA over two years, while their decrease corresponded with HIV DNA decay. Reduced TGF-b1/2, in CLWH >10 years, were significantly associated with high inducible HIV RNA. Our data demonstrate that increased levels of T helper differentiation cytokines despite high TGF-b in younger CLWH are associated with persistently high HIV DNA in PBMCs from ART-suppressed children. These cytokines and expression of immune checkpoint markers on T cells correlates with heightened HIV inducibility. Overall, the data suggest that effector differentiation of dysfunctional T cells during early childhood drives persistence of the HIV reservoir.