HIV-1 transcriptional regulation in the central nervous system and implications for HIV cure research.
HIV-1 transcriptional regulation in the central nervous system and implications for HIV cure research.
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DOI：
10.1007/s13365-014-0271-5
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发表时间：
2015-06
影响因子：
3.2
通讯作者：
Gray LR
中科院分区：
文献类型：
--
作者：
Churchill MJ;Cowley DJ;Wesselingh SL;Gorry PR;Gray LR
人类免疫缺陷病毒1型(HIV-1)在急性感染期间入侵中枢神经系统(CNS)，即使在联合抗逆转录病毒治疗(CART)的情况下，也可能导致高达50%的患者出现HIV相关的神经认知障碍(HAND)。在中枢神经系统内，高效的HIV-1感染发生在血管周围巨噬细胞和小胶质细胞中。星形胶质细胞也会受到感染，尽管它们的感染受到限制，不会产生新的病毒颗粒。消除HIV-1的主要障碍是在全身不同解剖部位建立病毒库，以及在CART长期治疗期间病毒的持久性。虽然主要的病毒储存库被认为是血液中静止的CD4+T细胞，但包括中枢神经系统、肠道相关淋巴组织、骨髓和生殖道在内的其他解剖部位也可能存在持续感染的HIV-1细胞储存库。病毒潜伏期是HIV-1持续存在的主要原因，很可能是在转录水平上控制的。目前的临床试验正在CART的背景下测试转录激活剂，试图清除这些病毒库并逆转病毒潜伏期。这些策略旨在激活构成病毒库的细胞中的病毒转录，因此它们可以被免疫系统识别和清除，同时通过联合使用CART来阻止新一轮感染。中枢神经系统有几个独特的特征，可能会导致病毒转录和潜伏期建立方式的不同。这些因素包括中枢神经系统特有的细胞类型、不同的转录因子、免疫监视的改变以及抗逆转录病毒药物生物利用度的降低。需要全面了解病毒在中枢神经系统中的转录和潜伏时间，以便在中枢神经系统内使用转录激活剂时确定治疗结果。
Human immunodeficiency virus type-1 (HIV-1) invades the central nervous system (CNS) during acute infection which can result in HIV-associated neurocognitive disorders (HAND) in up to 50% of patients, even in the presence of combination antiretroviral therapy (cART). Within the CNS, productive HIV-1 infection occurs in the perivascular macrophages and microglia. Astrocytes also become infected, although their infection is restricted and does not give rise to new viral particles. The major barrier to the elimination of HIV-1 is the establishment of viral reservoirs in different anatomical sites throughout the body and viral persistence during long-term treatment with cART. While the predominant viral reservoir is believed to be resting CD4+ T-cells in the blood, other anatomical compartments including the CNS, gut-associated lymphoid tissue, bone marrow, and genital tract can also harbor persistently infected cellular reservoirs of HIV-1. Viral latency is predominantly responsible for HIV-1 persistence, and is most likely governed at the transcriptional level. Current clinical trials are testing transcriptional activators, in the background of cART, in an attempt to purge these viral reservoirs and reverse viral latency. These strategies aim to activate viral transcription in cells constituting the viral reservoir, so they can be recognized and cleared by the immune system, while new rounds of infection are blocked by co-administration of cART. The CNS has several unique characteristics that may result in differences in viral transcription and in the way latency is established. These include CNS-specific cell types, different transcription factors, altered immune surveillance, and reduced antiretroviral drug bioavailability. A comprehensive understanding of viral transcription and latency in the CNS is required in order to determine treatment outcomes when using transcriptional activators within the CNS.