Nühn Marieke M, Gumbs Stephanie B H, Schipper Pauline J, Drosou Irene, Gharu Lavina, Buchholtz Ninée V E J, Snijders Gijsje J L J, Gigase Frederieke A J, Wensing Annemarie M J, Symons Jori, de Witte Lot D, Nijhuis Monique
Translational Virology, Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Viruses. 2025 Mar 25;17(4):467. doi: 10.3390/v17040467.
A proviral reservoir persists within the central nervous system (CNS) of people with HIV, but its characteristics remain poorly understood. Research has primarily focused on cerebrospinal fluid (CSF), as acquiring brain tissue is challenging. We examined size, cellular tropism, and infection-dynamics of the viral reservoir in post-mortem brain tissue from five individuals on and off antiretroviral therapy (ART) across three brain regions. Microglia-enriched fractions (CD11b) were isolated and levels of intact proviral DNA were quantified (IPDA). Full-length envelope reporter viruses were generated and characterized in CD4 T cells and monocyte-derived microglia. HIV DNA was observed in microglia-enriched fractions of all individuals, but intact proviruses were identified only in one ART-treated individual, representing 15% of the total proviruses. Phenotypic analyses of clones from this individual showed that 80% replicated efficiently in microglia and CD4 T cells, while the remaining viruses replicated only in CD4 T cells. No region-specific effects were observed. These results indicate a distinct HIV brain reservoir in microglia for all individuals, although intact proviruses were detected in only one. Given the unique immune environment of the CNS, the characteristics of microglia, and the challenges associated with targeting these cells, the CNS reservoir should be considered in cure strategies.
前病毒储存库存在于HIV感染者的中枢神经系统（CNS）中，但其特征仍知之甚少。由于获取脑组织具有挑战性，研究主要集中在脑脊液（CSF）上。我们研究了来自三名脑区接受和未接受抗逆转录病毒治疗（ART）的五名个体的死后脑组织中病毒储存库的大小、细胞嗜性和感染动力学。分离富含小胶质细胞的组分（CD11b）并对完整前病毒DNA水平（IPDA）进行定量。在CD4 T细胞和单核细胞衍生的小胶质细胞中产生并表征全长包膜报告病毒。在所有个体富含小胶质细胞的组分中均观察到HIV DNA，但仅在一名接受ART治疗的个体中鉴定出完整前病毒，占总前病毒的15%。对该个体克隆的表型分析表明，80%在小胶质细胞和CD4 T细胞中有效复制，而其余病毒仅在CD4 T细胞中复制。未观察到区域特异性效应。这些结果表明，尽管仅在一名个体中检测到完整前病毒，但所有个体的小胶质细胞中均存在独特的HIV脑储存库。鉴于CNS独特的免疫环境、小胶质细胞的特征以及靶向这些细胞相关的挑战，在治愈策略中应考虑CNS储存库。
