HIV-1 replication in the central nervous system occurs in two distinct cell types.
HIV-1 replication in the central nervous system occurs in two distinct cell types.
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DOI：
10.1371/journal.ppat.1002286
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发表时间：
2011-10
期刊：
影响因子：
6.7
通讯作者：
Swanstrom R
中科院分区：
文献类型：
--
作者：
Schnell G;Joseph S;Spudich S;Price RW;Swanstrom R
人类免疫缺陷病毒1型（HIV-1）感染中枢神经系统（CNS）可导致HIV-1相关性痴呆（HAD）的发展。我们研究了HAD患者脑脊液（CSF）中HIV-1的病毒学特征，以探讨CNS中独立病毒复制与明显痴呆发展之间的关系。我们发现，在被诊断为HIV-1相关痴呆的受试者的CSF中，独立地检测到遗传上划分的CCR 5-嗜性（R5）T细胞嗜性和巨噬细胞嗜性HIV-1群体。嗜巨噬细胞的HIV-1人群的遗传多样性，代表建立中枢神经系统感染，而R5 T细胞嗜HIV-1人群克隆扩增，并与细胞增多症。R5 T细胞嗜性病毒需要高水平的表面CD 4才能进入细胞，并且它们的存在与CSF中病毒在治疗开始时的快速衰减相关（类似于在活化T细胞中复制的血液中的病毒）。嗜巨噬细胞病毒可以进入具有低水平CD 4的细胞，并且它们的存在与CSF中病毒的缓慢衰变相关，证明单独的长寿细胞是病毒的来源。这些研究证明了从诊断为HAD的受试者的CSF病毒推断的两种不同的病毒学状态。最后，嗜巨噬细胞病毒在很大程度上局限于CNS/CSF区室，而不是血液，在一个案例中，我们能够确定嗜巨噬细胞谱系作为一个较小的变异近两年前，其在CNS中的扩展。这些结果表明，CSF中的HIV-1变异体可以提供有关CNS中病毒复制和演变的信息，这些信息可能在HIV相关的神经认知障碍中发挥重要作用。人类免疫缺陷病毒1型（HIV-1）感染中枢神经系统（CNS）可导致一种严重的神经系统疾病，称为HIV-1相关性痴呆（HAD）。被诊断患有HAD的个体通常在其脑脊液（CSF）中具有遗传上不同的HIV-1变体，而在血液病毒群体中未检测到，这表明独立的病毒复制发生在患有严重神经系统疾病的HIV-1感染受试者的CNS中。我们检测了HAD患者血浆和CSF中的HIV-1变异体，以确定HIV-1感染期间与痴呆发展相关的病毒特征。我们发现，遗传上不同的HIV-1变异体在HAD受试者的CSF中的R5 T细胞嗜性或巨噬细胞嗜性。R5 T细胞嗜性病毒需要高水平的细胞表面受体CD 4才能进入细胞，而巨噬细胞嗜性病毒可以进入低水平CD 4的细胞，这表明HIV-1可以在痴呆过程中在CNS内的至少两种细胞类型中复制。最后，在CSF中检测到嗜巨噬细胞病毒，但在血液病毒群体中的代表性很差。我们的研究结果表明，在CSF中的HIV-1变异体可以提供有关HIV-1感染过程中CNS中独立病毒复制的信息。
Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) can lead to the development of HIV-1-associated dementia (HAD). We examined the virological characteristics of HIV-1 in the cerebrospinal fluid (CSF) of HAD subjects to explore the association between independent viral replication in the CNS and the development of overt dementia. We found that genetically compartmentalized CCR5-tropic (R5) T cell-tropic and macrophage-tropic HIV-1 populations were independently detected in the CSF of subjects diagnosed with HIV-1-associated dementia. Macrophage-tropic HIV-1 populations were genetically diverse, representing established CNS infections, while R5 T cell-tropic HIV-1 populations were clonally amplified and associated with pleocytosis. R5 T cell-tropic viruses required high levels of surface CD4 to enter cells, and their presence was correlated with rapid decay of virus in the CSF with therapy initiation (similar to virus in the blood that is replicating in activated T cells). Macrophage-tropic viruses could enter cells with low levels of CD4, and their presence was correlated with slow decay of virus in the CSF, demonstrating a separate long-lived cell as the source of the virus. These studies demonstrate two distinct virological states inferred from the CSF virus in subjects diagnosed with HAD. Finally, macrophage-tropic viruses were largely restricted to the CNS/CSF compartment and not the blood, and in one case we were able to identify the macrophage-tropic lineage as a minor variant nearly two years before its expansion in the CNS. These results suggest that HIV-1 variants in CSF can provide information about viral replication and evolution in the CNS, events that are likely to play an important role in HIV-associated neurocognitive disorders. Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) can lead to the development of a severe neurological disease termed HIV-1-associated dementia (HAD). Individuals diagnosed with HAD commonly have genetically distinct HIV-1 variants in their cerebrospinal fluid (CSF) that are not detected in the blood virus population, suggesting that independent viral replication is occurring in the CNS of HIV-1-infected subjects with severe neurological disease. We examined HIV-1 variants in the blood plasma and CSF of HAD subjects to determine the viral characteristics associated with the development of dementia during HIV-1 infection. We found that genetically distinct HIV-1 variants in the CSF of HAD subjects were either R5 T cell-tropic or macrophage-tropic. The R5 T cell-tropic viruses required high levels of the cellular surface receptor CD4 to enter cells, while macrophage-tropic viruses could enter cells with low levels of CD4, suggesting that HIV-1 can replicate in at least two cell types within the CNS during the course of dementia. Finally, macrophage-tropic viruses were detected in the CSF but poorly represented in the blood virus population. Our results suggest that HIV-1 variants in the CSF can provide information about independent viral replication in the CNS during the course of HIV-1 infection.
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