Latent/persistant HIV/SIV infection in brain

大脑中潜伏/持续的 HIV/SIV 感染

• 批准号: 7321668
• 负责人: JANICE E CLEMENTS
• 金额: $ 25.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7321668
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Acute; Affect; Animals; Anti-Retroviral Agents; Astrocytes; Autopsy; Binding; Blood; Blood - brain barrier anatomy; Brain; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Central Nervous System Diseases; Central Nervous System Viral Diseases; Cerebrospinal Fluid; Combined Modality Therapy; Confounding Factors (Epidemiology); Controlled Study; DNA; DNA Maintenance; Development; Down-Regulation; Drug usage; EMSA; Effectiveness; Event; Gene Expression; Goals; HIV; HIV-1; HIV-2; Highly Active Antiretroviral Therapy; Ifni; Immune response; In Vitro; Incidence; Individual; Infection; Inflammatory; Length; Lesion; Life; Macaca; Maintenance; Measures; Microglia; Modeling; NF-kappa B; Nelfinavir; Nucleosides; Patients; Penetration; Peripheral; Pharmaceutical Preparations; Plasma; Protease Inhibitor; RNA; RNA Splicing; Reader; Regulation; Reporting; Rest; Reverse Transcriptase Inhibitors; SIV; SIV encephalitis; SIV protease; Source; Staging; Time; Viral; Viral Load result; Viral load measurement; Virus; Virus Diseases; Virus Latency; Virus Replication; antiretroviral therapy; cell type; cognitive function; day; immune function; improved; in vivo; macrophage; monocyte; peripheral blood; pinacolyl methylphosphonic acid; programs; reconstitution; viral DNA; viral RNA

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.

高效逆转录病毒治疗（HAART）对艾滋病的进展有深远的影响，降低血浆病毒载量，并可导致免疫功能的改善。 然而，HAART对CNS的影响更加多变，脑脊液中病毒载量的减少不一定反映血浆中病毒载量的减少（参考文献）。此外，外周血中的静息CD 4+淋巴细胞构成潜伏感染细胞的稳定、长寿命的储存库。接受HAART治疗的HW感染个体血液中的单核细胞也表达病毒，因此存在额外的病毒储备库。中枢神经系统很可能隐藏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，要么不能在脑中达到同等水平。在这个项目中，SIV感染的猕猴联合抗逆转录病毒治疗（CART）将被用来确定中枢神经系统水库在体内，并确定建立和维持HIV/SIV潜伏期和/或持久性的机制，并有助于中枢神经系统疾病的发展。 该项目的假设是，HIV/SW的潜伏性和持久性储存库在CNS中早期建立，并且病毒潜伏或持久性在感染个体的CNS中的巨噬细胞/小胶质细胞和星形胶质细胞中维持终身。此外，在特定的CNS细胞内存在调节病毒基因表达的机制，这些机制将在感染SIV并用CART治疗的猕猴中进行检查。该项目的目的是检查何时在大脑中建立稳定的SIV储存库;通过CART控制外周血中的病毒复制是否伴随着大脑中较低水平的病毒复制;为了确定CART对急性无症状和晚期感染脑中SIV基因表达调节水平的影响，SW感染的猕猴中的CNS在脑中用CART处理/未用CART处理，SIV感染的猕猴中的CSF。