Balinang Joyce M, Masvekar Ruturaj R, Hauser Kurt F, Knapp Pamela E
aDepartment of Anatomy and Neurobiology bDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.
AIDS. 2017 Mar 27;31(6):753-764. doi: 10.1097/QAD.0000000000001398.
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.
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.
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.
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.
1型人类免疫缺陷病毒（HIV-1）可引发一系列中枢神经系统（CNS）并发症；许多并发症会因同时接触阿片类药物而恶化。人类神经祖细胞（hNPCs）可分化为所有中枢神经系统神经元和大胶质细胞。我们检验了这样一个假设，即HIV和阿片类药物会改变hNPC的成熟和命运，从而导致与HIV-1相关的神经病理学改变。关于hNPC感染的报道仍存在争议。我们对这个问题进行了严格研究，测试hNPCs是否传播感染，以及HIV在未感染hNPCs的情况下是否会对其产生影响。
对原代hNPCs进行多代特征分析。在暴露于R5 HIV-1BaL后，通过p24、Nef和tat检测监测感染情况；采用连续稀释法测试感染是否会转移至未接触过病毒的hNPCs。通过溴脱氧尿苷摄取、群体倍增时间和免疫染色评估增殖和分化情况。同时接触吗啡以评估阿片类药物的相互作用。比较来自HIV-1BaL感染的外周血单核细胞（HIVsup）、HIV-1BaL以及紫外线灭活的HIVsup的上清液，以测试炎症环境与病毒或感染本身的影响。
hNPCs（CD4/CD8/Iba/CXC3CL1/CD11b）可被感染，并能将感染转移至未接触过病毒的hNPCs。马拉维若可部分阻断感染，提示与CCR5有关。HIVsup降低了hNPC的增殖，并导致其过早分化为神经元/星形胶质细胞。对增殖的影响是由可溶性因子/病毒蛋白引起的，而非感染本身。同时接触吗啡会加剧HIVsup的某些功能后果，并维持hNPCs的感染。
hNPCs在体外可被感染并传播病毒。hNPCs或其后代可能是一个未被充分认识的病毒储存库。来自感染细胞的因子会改变hNPC的增殖和神经细胞成熟，这可能会损害中枢神经系统的结构和功能。吗啡与HIV的相互作用可能会使功能障碍恶化并维持感染。
