Nef-mediated ARP2/3 inhibition drives CD4+ T cell dysfunction and dysregulated immunity in HIV progressors 2658

Abstract Description The life cycle of HIV is heavily influenced by actin cytoskeleton dynamics. We hypothesize that HIV Nef inhibits ARP2/3-mediated actin branching, leading to defects in CD4+ T cell function and immune dysregulation in HIV progressors. We used spatial transcriptomics to assess gene expression changes in lymph nodes at different stages of HIV disease. CD4+ T cells within viremic tissues showed significantly altered proinflammatory signatures and reduced ARP2/3 gene expression. Further analysis of HIV-infected primary human CD4+ T cells was performed using ultrastructural and time-lapse microscopy. HIV infection induced five distinct abnormal phenotypes, including a pointed needle-like structure and polarized blebbing at the lamellipodium. These pathological morphologies are identical to those seen in leukocytes from patients with ARP2/3-deficient primary immunodeficiencies. Reporter viruses were used to show that HIV Nef significantly contributed to the phenotypes. Our findings suggest that HIV Nef contributes to ARP2/3 inhibition, disrupting CD4+ T cell function and immunity in normal HIV progressors. Although every normal progressor or uninfected control exhibited these cytopathologies, two-thirds of HIV controllers we tested maintained cortical actin stability despite productive HIV infection, suggesting inherent resistance to Nef-mediated ARP2/3 inhibition. Restoring ARP2/3 functionality may improve therapeutic strategies that target the reservoir in HIV progressors. Funding Sources Funded in part by NIH grants UM1AI126617, UM1AI164559, U01DA058527, R01CA260691, and R01DA052027. Topic Categories Viral Immunology (VIR)