Abstract
OBJECTIVES: HIV-1 enters the central nervous system (CNS) early in infection, and a significant proportion of people with HIV experience CNS complications despite anti-retroviral therapy. Chronic immune dysfunction, inflammatory cytokines and chemokines, and viral proteins like Tat and gp120 released by HIV-1-infected immune cells are implicated in the pathogenesis of HIV-1-associated neurocognitive disorders (HAND). METHODS: To elucidate the contribution of non-viral factors to CNS complications in people with HIV-1, a comparative analysis of neurovirulent subtype B (HIV-1(ADA)) and non-neurovirulent subtype C (HIV-1(Indie-C1)) isolates was performed. Culture supernatants from HIV-1-infected PBMCs, either with or without immunodepletion of Tat and gp120, were used to treat SH-SY5Y neuroblastoma cells. RESULTS: HIV-1(ADA)-infected PBMC media showed significantly higher neurotoxicity than HIV-1(IndieC1)-infected PBMC media, notwithstanding the depletion of Tat and gp120, highlighting the role of non-viral factors (e.g., cytokines) contributing to neurotoxicity. A comparison of inflammatory profiles revealed that HIV-1(ADA) media contained elevated levels of cytokines (IL-1α, IL-1β, IL-6 and TNFα) and chemokines (CCL2, CCL3, CCL4 and IP-10). Given the involvement of Tat in upregulating immune mediators, we tested the role of purified Tat proteins from HIV-1 subtypes B and C in inducing an inflammatory phenotype in PBMCs. PBMCs from healthy subjects were treated with recombinant purified Tat from subtype B or C. Subtype B Tat induced a stronger inflammatory response than subtype C Tat. CONCLUSIONS: These results confirm that both viral and non-viral immune factors mediate neuronal damage in people with HIV.