Productive infection of human neural progenitor cells by R5 tropic HIV-1: opiate co-exposure heightens infectivity and functional vulnerability.

ABSTRACT

OBJECTIVE: HIV type-1 (HIV-1) causes a spectrum of central nervous system (CNS) complications; many are worsened by opiate co-exposure. Human neural progenitor cells (hNPCs) give rise to all CNS neurons and macroglia. We tested the hypothesis that hNPC maturation and fate are altered by HIV and opiates, contributing to HIV-1-related neuropathology. Reports of hNPC infection remain controversial. We rigorously examined this question, testing whether hNPCs propogated infection, and whether HIV affected hNPCs absent their infection. DESIGN AND METHODS: Primary hNPCs were characterized over multiple passages. Following R5 HIV-1BaL exposure, p24, Nef, and tat assays monitored infection; a serial dilution approach tested infection transfer to naive hNPCs. Bromodeoxyuridine uptake, population doubling time, and immunostaining assessed proliferation and differentiation. Morphine co-exposure assessed opiate interactions. Supernatant from HIV-1BaL-infected PBMCs (HIVsup), HIV-1BaL, and ultraviolet light-inactivated HIVsup were compared to test effects of inflammatory milieu versus virus or infection per se. RESULTS: The hNPCs (CD4/CD8/Iba/CXC3CL1/CD11b) were infectable and could transfer infection to naive hNPCs. Infection was partly blocked by maraviroc, implicating CCR5. HIVsup reduced hNPC proliferation and caused premature differentiation into neurons/astroglia. Effects on proliferation were due to soluble factors/viral proteins, not infection per se. Morphine co-exposure exacerbated certain functional consequences of HIVsup, and sustained the infection of hNPCs. CONCLUSION: hNPCs can be infected and propagate virus in vitro. hNPCs or their progeny may represent an underappreciated viral reservoir. Factors from infected cells alter hNPC proliferation and neural cell maturation, which likely compromises CNS structure and function. Morphine-HIV interactions may worsen dysfunction and sustain infection.