Project 2: Latent/persistant infection in brain

项目2：脑部潜伏/持续感染

• 批准号: 6983310
• 负责人: JANICE E CLEMENTS
• 金额: $ 23.32万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6983310
• 关键词: AIDS /HIV neuropathy; AIDS therapy; HIV infections; Macaca nemestrina; antiviral agents; brain; cerebrospinal fluid; combination chemotherapy; latent virus infection; nervous system infection; neurotropic virus; pathologic process; simian immunodeficiency virus; virus load

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.

艾滋病毒感染患者的高活性逆转录病毒疗法（HAART）对艾滋病的进展产生了深远的影响，减少了血浆病毒载量，并可能改善免疫功能。 但是，HAART对中枢神经系统的影响较大，并且脑脊液中病毒载量的减少不一定反映出血浆中的减少（参考）。此外，外周血中静止的CD4+淋巴细胞构成了潜在感染细胞的稳定，长期寿命的储层。 HAART上HW感染个体的血液中的单核细胞也表达病毒，因此存在其他病毒储量。中枢神经系统可能会携带潜在地且持续感染的细胞，因为抗逆转录病毒药物要么不穿透血脑屏障，要么无法达到大脑中的等效水平。在该项目中，用抗逆转录病毒疗法（CART）处理的SIV感染猕猴将用于体内识别中枢神经系统储层，并确定建立和维持HIV/SIV潜伏期和/或持久性的机制，并有助于CNS疾病的发展。 该项目的假设是，HIV/SW的潜在和持续的储量是在中枢神经系统的早期建立的，并且在感染个体的巨噬细胞/小胶质细胞和星形胶质细胞中，病毒潜伏期或持久性在受感染个体的CNS中保持。此外，在特定的CNS细胞机制中存在调节病毒基因表达的机制，这些机制将在感染和用CART的SIV猕猴中检查。该项目的目的是检查何时在大脑中建立SIV的稳定水库；通过CART控制病毒复制是否伴随着大脑的病毒复制水平较低；确定CART对大脑中SIV基因表达水平的影响，从急性到无症状和晚期感染，并检查在SW感染的猕猴中，通过在大脑和CSF中用CART处理的SW感染猕猴中CNS中的早期病毒复制的机制在SIV中感染了猕猴。