评估大脑和淋巴组织中的 HIV DNA 存档。

Evaluation of Archival HIV DNA in Brain and Lymphoid Tissues.

机构信息

Department of Medicine, University of California San Diego, La Jolla, California, USA.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

出版信息

J Virol. 2023 Jun 29;97(6):e0054323. doi: 10.1128/jvi.00543-23. Epub 2023 May 15.

Abstract

HIV reservoirs persist in anatomic compartments despite antiretroviral therapy (ART). Characterizing archival HIV DNA in the central nervous system (CNS) and other tissues is crucial to inform cure strategies. We evaluated paired autopsy brain-frontal cortex (FC), occipital cortex (OCC), and basal ganglia (BG)-and peripheral lymphoid tissues from 63 people with HIV. Participants passed away while virally suppressed on ART at the last visit and without evidence of CNS opportunistic disease. We quantified total HIV DNA in all participants and obtained full-length HIV-envelope (FL HIV-) sequences from a subset of 14 participants. We detected HIV DNA () in most brain (65.1%) and all lymphoid tissues. Lymphoid tissues had higher HIV DNA levels than the brain ( < 0.01). Levels of HIV between BG and FC were similar ( > 0.2), while OCC had the lowest levels ( = 0.01). Females had higher HIV DNA levels in tissues than males (,  = 0.03; 2-LTR,  = 0.05), suggesting possible sex-associated mechanisms for HIV reservoir persistence. Most FL HIV- sequences ( = 143) were intact, while 42 were defective. Clonal sequences were found in 8 out of 14 participants, and 1 participant had clonal defective sequences in the brain and spleen, suggestive of cell migration. From 10 donors with paired brain and lymphoid sequences, we observed evidence of compartmentalized sequences in 2 donors. Our data further the idea that the brain is a site for archival HIV DNA during ART where compartmentalized provirus may occur in a subset of people. Future studies assessing FL HIV-provirus and replication competence are needed to further evaluate the HIV reservoirs in tissues. HIV infection of the brain is associated with adverse neuropsychiatric outcomes, despite efficient antiretroviral treatment. HIV may persist in reservoirs in the brain and other tissues, which can seed virus replication if treatment is interrupted, representing a major challenge to cure HIV. We evaluated reservoirs and genetic features in postmortem brain and lymphoid tissues from people with HIV who passed away during suppressed HIV replication. We found a differential distribution of HIV reservoirs across brain regions which was lower than that in lymphoid tissues. We observed that most HIV reservoirs in tissues had intact envelope sequences, suggesting they could potentially generate replicative viruses. We found that women had higher HIV reservoir levels in brain and lymphoid tissues than men, suggesting possible sex-based mechanisms of maintenance of HIV reservoirs in tissues, warranting further investigation. Characterizing the archival HIV DNA in tissues is important to inform future HIV cure strategies.

摘要

尽管抗逆转录病毒疗法(ART)已经存在,但 HIV 储库仍存在于解剖学隔室中。描述中枢神经系统(CNS)和其他组织中存档的 HIV DNA 对于告知治愈策略至关重要。我们评估了来自 63 名 HIV 感染者的配对尸检脑 - 额叶皮质(FC)、枕叶皮质(OCC)和基底节(BG)-和外周淋巴组织。参与者在最后一次就诊时接受了抑制病毒的 ART 治疗,并且没有 CNS 机会性疾病的证据。我们对所有参与者的总 HIV DNA 进行了定量,并从 14 名参与者的亚组中获得了全长 HIV 包膜(FL HIV-)序列。我们在大多数脑(65.1%)和所有淋巴组织中检测到 HIV DNA()。淋巴组织的 HIV DNA 水平高于大脑(<0.01)。BG 和 FC 之间的 HIV 水平相似(>0.2),而 OCC 的水平最低(=0.01)。女性的组织 HIV DNA 水平高于男性(,=0.03;2-LTR,=0.05),这表明 HIV 储存库的维持可能存在与性别相关的机制。大多数 FL HIV-序列(=143)是完整的,而 42 个是有缺陷的。在 8 名参与者中发现了克隆序列,1 名参与者的大脑和脾脏中存在克隆缺陷序列,提示细胞迁移。从 10 名具有配对脑和淋巴组织序列的供体中,我们观察到 2 名供体中存在隔室化序列的证据。我们的数据进一步证明,大脑是 ART 期间存档 HIV DNA 的部位,在一部分人中,可能会发生隔室化的前病毒。需要进一步评估 FL HIV-前病毒和复制能力的研究,以进一步评估组织中的 HIV 储库。尽管抗逆转录病毒治疗(ART)有效,但 HIV 感染大脑仍与不良神经精神结局相关。HIV 可能在大脑和其他组织中的储库中持续存在,如果治疗中断,可能会引发病毒复制,这是治愈 HIV 的主要挑战。我们评估了 HIV 感染者死后尸检大脑和淋巴组织中的储库和遗传特征,这些感染者在抑制 HIV 复制期间死亡。我们发现,HIV 储库在大脑区域的分布存在差异,低于淋巴组织。我们观察到,大多数组织中的 HIV 储库都具有完整的包膜序列,这表明它们可能具有潜在的复制病毒生成能力。我们发现,女性的大脑和淋巴组织中的 HIV 储库水平高于男性,这表明维持组织中 HIV 储库的可能存在基于性别的机制,值得进一步研究。描述组织中存档的 HIV DNA 对于告知未来的 HIV 治愈策略很重要。

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