Abreu Celina, Shirk Erin N, Queen Suzanne E, Mankowski Joseph L, Gama Lucio, Clements Janice E
Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, 21205, USA.
Department of Neurology, Johns Hopkins University, Baltimore, MD, 21205, USA.
J Neuroimmune Pharmacol. 2019 Mar;14(1):23-32. doi: 10.1007/s11481-018-9803-8. Epub 2018 Aug 30.
Lentiviruses are retroviruses that primarily infect myeloid cells, leading to acute inflammatory infections in many tissues particularly, lung, joints and the central nervous system (CNS). Acute infection by lentiviruses is followed by persistent/latent infections that are not cleared by the host immune system. HIV and SIV are lentiviruses that also infect CD4+ lymphocytes as well as myeloid cells in blood and multiple tissues. HIV infection of myeloid cells in brain, lung and heart cause tissue specific diseases as well as infect cells in gut, lymph nodes and spleen. AIDS dementia and other tissue specific disease are observed when infected individuals are immunosuppressed and the number of circulating CD4+ T cells declines to low levels. Antiretroviral therapy (ART) controls viral spread and dramatically changes the course of immunodeficiency and AIDS dementia. However, ART does not eliminate virus-infected cells. Brain macrophages contain HIV DNA and may represent a latent reservoir that persists. HIV latency in CD4+ lymphocytes is the main focus of current research and concern in efforts to eradicate HIV. However, a number of studies have demonstrated that myeloid cells in blood and tissues of ART suppressed individuals harbor HIV DNA. The resident macrophages in tissues such as brain (microglia), spleen (red pulp macrophages) and alveolar macrophages in lung are derived from the yolk sac and can self renew. The question of the latent myeloid reservoir in HIV has not been rigorously examined and its potential as a barrier to eradication been considered. Using a well characterized SIV ART suppressed, non-human primate (NHP) model, our laboratory developed the first quantitative viral outgrowth assay (QVOA) designed to evaluate latently infected CD4+ lymphocytes and more recently developed a similar protocol for the assessment of latently infected myeloid cells in blood and brain. Using an SIV ART model, it was demonstrated that myeloid cells in blood and brain harbor latent SIV that can be reactivated and produce infectious virus in vitro. These studies demonstrate for the first time that myeloid cells have the potential to be a latent reservoir of HIV that produces infectious virus that can be reactivated in the absence of ART and during HIV eradication strategies. Graphical Abstract.
慢病毒是逆转录病毒，主要感染髓细胞，导致许多组织尤其是肺、关节和中枢神经系统（CNS）发生急性炎症感染。慢病毒急性感染后会出现持续性/潜伏性感染，宿主免疫系统无法清除这些感染。HIV和SIV是慢病毒，它们还感染血液和多个组织中的CD4+淋巴细胞以及髓细胞。HIV感染脑、肺和心脏中的髓细胞会导致组织特异性疾病，还会感染肠道、淋巴结和脾脏中的细胞。当受感染个体免疫抑制且循环CD4+T细胞数量降至低水平时，会观察到艾滋病痴呆和其他组织特异性疾病。抗逆转录病毒疗法（ART）可控制病毒传播，并显著改变免疫缺陷和艾滋病痴呆的病程。然而，ART并不能消除病毒感染的细胞。脑巨噬细胞含有HIV DNA，可能代表一个持续存在的潜伏储存库。CD4+淋巴细胞中的HIV潜伏是当前根除HIV研究和关注的主要焦点。然而，多项研究表明，接受ART抑制治疗的个体血液和组织中的髓细胞携带HIV DNA。组织中的驻留巨噬细胞，如脑（小胶质细胞）、脾（红髓巨噬细胞）和肺中的肺泡巨噬细胞，来源于卵黄囊，能够自我更新。HIV潜伏性髓细胞储存库的问题尚未得到严格研究，其作为根除障碍的潜力也未得到考虑。利用一个特征明确的接受ART抑制治疗的非人灵长类动物（NHP）模型，我们实验室开发了首个旨在评估潜伏感染CD4+淋巴细胞的定量病毒生长测定法（QVOA），最近又开发了一个类似方案用于评估血液和脑中潜伏感染的髓细胞。使用SIV ART模型，已证明血液和脑中的髓细胞含有潜伏性SIV，这些潜伏性SIV可被重新激活并在体外产生传染性病毒。这些研究首次证明，髓细胞有可能成为HIV的潜伏储存库，在没有ART的情况下以及在HIV根除策略期间，这些潜伏储存库可产生可被重新激活的传染性病毒。图形摘要。
