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

• Published in: AIDS (London) Vol. 31; no. 6; pp. 753 - 764
• Main Authors: Balinang, Joyce M, Masvekar, Ruturaj R, Hauser, Kurt F, Knapp, Pamela E
• Format: Journal Article
• Language: English
• Published: England Copyright Wolters Kluwer Health, Inc 27-03-2017
• Subjects: Cells, Cultured; HIV-1 - growth & development; HIV-1 - physiology; Humans; Narcotics - metabolism; Neural Stem Cells - drug effects; Neural Stem Cells - virology; Opiate Alkaloids - metabolism; Viral Tropism
• ISSN: 0269-9370; 1473-5571
• DOI: 10.1097/QAD.0000000000001398

OBJECTIVE:Human immunodeficiency virus type-1 (HIV-1) causes a spectrum of 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. Since reports that hNPCs are infectable remain controversial, we rigorously examined hNPC infection and ability to propagate infection, and determined whether HIV effects on hNPC function required 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 naïve hNPCs. BrdU 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 UV-inactivated HIVsup were compared to test effects of milieu vs. virus/infection.
RESULTS:hNPCs (CD4/CD8/Iba/CXC3CL1/CD11b) were infectable; infection could transfer to naïve 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 functional consequences induced by HIVsup, and sustained the infection of hNPCs without altering initial infectivity.
CONCLUSIONS:hNPCs are infectable and can propagate virus in vitro. hNPCs or their progeny may represent an underappreciated viral reservoir. hNPC proliferation and CNS cell maturation are altered by factors released from infected cells, likely compromising CNS structure and function. Morphine-HIV interactions may worsen dysfunction and sustain infection.