Nonhuman primate cohort.

HIV-associated neurocognitive disorders (HAND) affect ~40% of virally suppressed people with HIV (PWH), however, the precise viral dependent and independent changes to the brain are unclear. Here we characterized the CNS reservoir and immune environment of SIV-infected (SIV+) rhesus macaques during acute (n = 4), chronic (n = 12) or ART-suppressed SIV infection (n = 11). Multiplex immunofluorescence for markers of SIV infection (vRNA/vDNA) and immune activation was performed on frontal cortex and matched colon tissue. SIV+ animals contained detectable viral DNA+ cells that were not reduced in the frontal cortex or the gut by ART, supporting the presence of a stable viral reservoir in these compartments. SIV+ animals had impaired blood brain barrier (BBB) integrity and heightened levels of astrocytes or myeloid cells expressing antiviral, anti-inflammatory or oxidative stress markers which were not abrogated by ART. Neuroinflammation and BBB dysfunction correlated with measures of viremia and immune activation in the gut. Furthermore, SIV-uninfected animals with experimentally induced gut damage and colitis showed a similar immune activation profile in the frontal cortex to those of SIV-infected animals, supporting the role of chronic gut damage as an independent source of neuroinflammation. Together, these findings implicate gut-associated immune activation/damage as a significant contributor to neuroinflammation in ART-suppressed HIV/SIV infection which may drive HAND pathogenesis.HIV相关神经认知障碍（HIV-associated neurocognitive disorders, HAND）会影响约40%的病毒抑制型HIV感染者（people with HIV, PWH），但目前学界对病毒依赖性及非依赖性的脑部精准病理改变仍不明晰。本研究对急性感染（n=4）、慢性感染（n=12）及抗反转录病毒治疗（Antiretroviral Therapy, ART）后病毒抑制的猴免疫缺陷病毒（Simian Immunodeficiency Virus, SIV）感染恒河猴的中枢神经系统（Central Nervous System, CNS）病毒库与免疫微环境进行了表征。研究针对额皮层及配对结肠组织，开展了针对SIV感染标志物（病毒核糖核酸/病毒脱氧核糖核酸，vRNA/vDNA）与免疫激活状态的多重免疫荧光检测。SIV阳性动物体内可检测到病毒DNA阳性细胞，且ART并未使额皮层与肠道中的此类细胞数量减少，这表明上述组织区域存在稳定的病毒库。SIV阳性动物存在血脑屏障（blood brain barrier, BBB）完整性受损的情况，且表达抗病毒、抗炎或氧化应激标志物的星形胶质细胞与髓系细胞水平显著升高，此类改变并未被ART逆转。神经炎症与BBB功能障碍与肠道内的病毒血症水平及免疫激活状态呈显著相关。此外，实验诱导肠道损伤与结肠炎的SIV阴性动物，其额皮层的免疫激活特征与SIV感染动物高度相似，这证实慢性肠道损伤可作为神经炎症的独立诱因。综上，本研究结果表明，在ART抑制的HIV/SIV感染状态下，肠道相关免疫激活与损伤是神经炎症的重要诱因，或可推动HAND的发病进程。