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首页> 外文期刊>AIDS Research and Human Retroviruses >Reduced basal transcriptional activity of central nervous system-derived HIV type 1 long terminal repeats
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Reduced basal transcriptional activity of central nervous system-derived HIV type 1 long terminal repeats

机译：降低中枢神经系统来源的HIV 1型长末端重复序列的基础转录活性

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New evidence indicates that astrocytes of the central nervous system (CNS) are extensively infected with human immunodeficiency virus type 1 (HIV-1) in vivo. Although no new virus is produced, this nonproductive or restricted infection contributes to the pathogenesis of HIV-associated dementia (HAD) and compromises virus eradication strategies. The HIV-1 long terminal repeat (LTR) plays a critical role in regulating virus production from infected cells. Here, we determined whether LTRs derived from CNS and non-CNS compartments are genetically and functionally distinct and contribute to the restricted nature of astrocyte infection. CNS- and/or non-CNS-derived LTRs (n=82) were cloned from primary HIV-1 viruses isolated from autopsy tissues of seven patients who died with HAD. Phylogenetic analysis showed interpatient and intrapatient clustering of LTR nucleotide sequences. Functional analysis showed reduced basal transcriptional activity of CNS-derived LTRs in both astrocytes and T cells compared to that of non-CNS-derived LTRs. However, LTRs were heterogeneous in their responsiveness to activation by Tat. Therefore, using a relatively large, independent panel of primary HIV-1 LTRs derived from clinically well-characterized subjects, we show that LTRs segregate CNS- from non-CNS-derived tissues both genetically and functionally. The reduced basal transcriptional activity of LTRs derived from the CNS may contribute to the restricted HIV-1 infection of astrocytes and latent infection within the CNS. These findings have significance for understanding the molecular basis of HIV-1 persistence within cellular reservoirs of the CNS that need to be considered for strategies aimed at eradicating HIV-1.
机译：新证据表明，中枢神经系统（CNS）的星形胶质细胞在体内广泛感染了1型人类免疫缺陷病毒（HIV-1）。尽管未产生新病毒，但这种非生产性或限制性感染导致了HIV相关痴呆（HAD）的发病机理，并破坏了病毒根除策略。 HIV-1长末端重复序列（LTR）在调节感染细胞产生的病毒中起关键作用。在这里，我们确定了源自中枢神经系统和非中枢神经系统隔室的LTRs是否在遗传和功能上是不同的，并且有助于限制星形胶质细胞感染。从7例死于HAD的患者的尸检组织中分离出的原代HIV-1病毒中克隆了CNS和/或非CNS衍生的LTR（n = 82）。系统发育分析表明，LTR核苷酸序列的患者之间和患者内部聚集。功能分析显示，与非CNS衍生的LTR相比，星形胶质细胞和T细胞中CNS衍生的LTR的基础转录活性降低。但是，LTR对Tat激活的反应性是异质的。因此，使用相对较大，独立小组的，来源于临床特征明确的受试者的原代HIV-1 LTR，我们显示LTR从遗传和功能上将CNS-与非CNS衍生的组织隔离开来。源自CNS的LTR的基础转录活性降低可能会导致星形胶质细胞的HIV-1受限感染和CNS内的潜伏感染。这些发现对于理解中枢神经系统细胞储库中HIV-1持续存在的分子基础具有重要意义，而对于消除HIV-1的策略则需要考虑这些基础。

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