Astrocytes sustain long-term productive HIV-1 infection without establishment of reactivable viral latency
Astrocytes sustain long-term productive HIV-1 infection without establishment of reactivable viral latency
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DOI：
10.1002/glia.23310
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发表时间：
2018-07-01
期刊：
影响因子：
6.2
通讯作者：
Tremblay, Michel J.
中科院分区：
文献类型：
--
作者：
Barat, Corinne;Proust, Alize;Tremblay, Michel J.
“休克和杀死”HIV-1治疗策略提出通过潜伏期逆转剂（LRA）的临床治疗根除稳定的细胞储库。虽然潜伏感染HIV-1的静息CD 4（+）T细胞构成了这些方法的主要靶向宿主，但它们对其他宿主（如中枢神经系统）的影响仍然未知，应予以考虑。我们进行了旨在确定星形胶质细胞在HIV-1在大脑中持续存在的可能作用以及LRA治疗对该病毒避难所的影响的实验。我们首先证明，在增殖星形胶质细胞培养减少HIV-1的生产是由于病毒感染的细胞与未感染的星形胶质细胞相比，增殖能力降低。相比之下，非增殖星形胶质细胞的感染导致持续超过60天的强烈HIV-1感染。为了鉴定潜伏感染HIV-1的星形胶质细胞，我们设计了一种新的双色报告病毒，称为NL4.3 eGFP-IRES-Crimson，它具有完全的感染性，并编码所有的病毒蛋白。虽然我们检测到一小部分星形胶质细胞携带沉默的HIV-1前病毒，我们没有观察到任何重新激活使用各种LRA，甚至强诱导剂，如肿瘤坏死因子，从而表明，这些前病毒要么没有转录能力或处于深潜伏状态。我们的研究结果表明，星形胶质细胞本身可能并不构成一个潜在的水库，但无情的病毒生产由这个脑细胞群体可能有助于在HIV-1感染者接受联合抗逆转录病毒治疗的神经系统疾病。
The "shock and kill" HIV-1 cure strategy proposes eradication of stable cellular reservoirs by clinical treatment with latency-reversing agents (LRAs). Although resting CD4(+) T cells latently infected with HIV-1 constitute the main reservoir that is targeted by these approaches, their consequences on other reservoirs such as the central nervous system are still unknown and should be taken into consideration. We performed experiments aimed at defining the possible role of astrocytes in HIV-1 persistence in the brain and the effect of LRA treatments on this viral sanctuary. We first demonstrate that the diminished HIV-1 production in a proliferating astrocyte culture is due to a reduced proliferative capacity of virus-infected cells compared with uninfected astrocytes. In contrast, infection of non-proliferating astrocytes led to a robust HIV-1 infection that was sustained for over 60 days. To identify astrocytes latently infected with HIV-1, we designed a new dual-color reporter virus called NL4.3 eGFP-IRES-Crimson that is fully infectious and encodes for all viral proteins. Although we detected a small fraction of astrocytes carrying silent HIV-1 proviruses, we did not observe any reactivation using various LRAs and even strong inducers such as tumor necrosis factor, thus suggesting that these proviruses were either not transcriptionally competent or in a state of deep latency. Our findings imply that astrocytes might not constitute a latent reservoir per se but that relentless virus production by this brain cell population could contribute to the neurological disorders seen in HIV-1-infected persons subjected to combination antiretroviral therapy.