Latent/persistant HIV/SIV infection in brain

HIV感染者的高效逆转录病毒疗法(HAART)对艾滋病的进展产生了深远的影响，降低了血浆病毒载量，并能改善免疫功能。 然而，HAART对中枢神经系统的影响更具变异性，脑脊液中病毒载量的减少并不一定反映血浆中病毒载量的减少(ReFS)。此外，外周血中静息的CD4+淋巴细胞构成了潜伏感染细胞的稳定、持久的储存库。HAART上HW感染者血液中的单核细胞也表达病毒，因此存在额外的病毒库。中枢神经系统可能存在潜伏和持续感染的细胞，因为抗逆转录病毒药物要么不能穿透血脑屏障，要么在大脑中达不到同等水平。在这个项目中，使用联合抗逆转录病毒疗法(CART)治疗的SIV感染猕猴将被用来识别体内的CNS储存库，并确定建立和维持HIV/SIV潜伏期和/或持久性并促进CNS疾病发展的机制。 该项目的假设是，HIV/SW的潜在和持久储备库在CNS早期建立，病毒潜伏或持续存在于CNS中的巨噬细胞/小胶质细胞和星形胶质细胞中，感染者终生保持。此外，在特定的中枢神经系统细胞内存在调节病毒基因表达的机制，这些机制将在感染和接受CART治疗的SIV猕猴中进行检验。本项目的目的是研究大脑中何时建立稳定的SIV储存库；CART控制外周血中病毒复制的同时是否伴随着大脑中较低水平的病毒复制；确定CART对SIV在急性、无症状和晚期感染期间脑内SIV基因表达调控水平的影响；并研究在经脑内CART和SIV感染猕猴脑脊液治疗/未治疗的情况下，SIV感染猕猴中枢神经系统早期病毒复制的控制机制。

Highly active retroviral therapy (HAART) in HIV infected patients has had a profound effect on the progression of AIDS, decreases plasma viral load and can result in improvements in immune function. However, the effects of HAART on the CNS are more variable and the reduction in viral load in the cerebrospinal fluid does not necessarily mirror reductions in the plasma (refs). In addition, resting CD4+ lymphocytes in the peripheral blood constitute a stable, long-lived reservoir of latently infected cells. Monocytes in the blood of HW-infected individuals on HAART also express virus, thus additional viral reserviors exist. The CNS is likely to harbor latently and persistently infected cells, since antiretroviral drugs either do not penetrate the blood brain barrier or do not reach equivalent levels in the brain. In this project SIV-infected macaques treated with combination antiretroviral therapy (CART) will be used to identify CNS reservoirs in vivo and to identify the mechanisms that establish and maintain HIV/SIV latency and/or persistence and contribute to the development of CNS disease. The hypothesis for this project is that latent and persistent reserviors of HIV/SW are established early in the CNS and that viral latency or persistence is maintained in macrophages/microglia and astrocytes in the CNS in infected individuals lifelong. Further, within specific CNS cells mechanisms exist that regulate virus gene expression and these mechanisms will be examined in SIV macaques infected and treated with CART. The aims of this project are to examine when a stable reservoir of SIV is established in the brain; whether control of virus replication in the peripheral blood by CART is accompanied by lower levels of viral replication in the brain; to identify the effect of CART on the level of regulation of SIV gene expression in brain from acute through asymptomatic and late stage infection andto examine mechanisms that control early virus replication in the CNS in SW infected macaques treated/untreated with CART in the brain and CSF in SIV infected macaques.