University of California, San Diego, La Jolla, California, USA.
University of California, San Diego, La Jolla, California, USA
J Virol. 2020 Sep 15;94(19). doi: 10.1128/JVI.00927-20.
Cytomegalovirus (CMV) almost universally infects persons with HIV (PWH), and it is a driver of persistent inflammation and HIV persistence. The mechanisms underlying the association between CMV (and possibly other herpesviruses) and HIV persistence are unclear. Serially collected blood samples were obtained from men who have sex with men (MSM) who started antiretroviral therapy (ART) within 1 year of their estimated date of HIV infection (EDI). Total CMV and Epstein-Barr virus (EBV) DNA were quantified in peripheral blood mononuclear cells by droplet digital PCR (ddPCR). Deep sequencing of the HIV DNA partial gene was performed, and the dynamics of viral diversity over time were analyzed in relation to CMV and EBV shedding status. In total, 37 MSM PWH were included and followed for a median of 23 months (IQR, 22 to 28). Participants started ART within a median of 3.1 months (IQR, 1.5 to 6.5) after EDI and remained virally suppressed thereafter. A total of 18 participants (48.6%) were classified as high EBV shedders, while 19 (51.4%) were classified as CMV shedders. In longitudinal analyses, normalized molecular diversity levels tended to increase over time among participants with detectable CMV and high EBV DNA (0.03 ± 0.02, = 0.08), while they significantly declined among participants with no/low viral shedding (-0.04 ± 0.02, = 0.047, interaction < 0.01). Subclinical CMV and EBV shedding could contribute to the dynamics of the HIV DNA reservoir during suppressive ART. Whether persistent CMV/EBV replication could be targeted as a strategy to reduce the size of the latent HIV reservoir is an avenue that should be explored. As part of this study, we evaluated the molecular characteristics of the HIV DNA reservoir over time during antiretroviral treatment (ART) in relation to those of other chronic viral infections (i.e., cytomegalovirus [CMV] and Epstein-Barr virus [EBV]). We demonstrated that the presence of CMV and high-level EBV DNA in peripheral blood cells was associated with changes in HIV DNA molecular diversity. Specifically, HIV DNA molecular diversity increased over time among participants with detectable CMV and high-level EBV DNA, while it significantly declined among participants with no/low viral shedding. Although the current study design does not allow causality to be inferred, it does support the theory that persistent CMV and EBV shedding could contribute to the dynamics of the HIV DNA reservoir during suppressive ART, even when ART is initiated during the earliest phases of HIV infection.
巨细胞病毒 (CMV) 几乎普遍感染人类免疫缺陷病毒 (HIV) 感染者 (PWH)，并且是持续性炎症和 HIV 持续存在的驱动因素。CMV（和可能其他疱疹病毒）与 HIV 持续存在之间的关联的机制尚不清楚。本研究从在 HIV 感染估计日期 (EDI) 后 1 年内开始接受抗逆转录病毒治疗 (ART) 的男男性行为者 (MSM) 中连续采集血液样本。通过液滴数字 PCR (ddPCR) 定量检测外周血单核细胞中的 CMV 和 Epstein-Barr 病毒 (EBV) DNA。对 HIV DNA 部分基因进行深度测序，并分析随着时间的推移病毒多样性的动态变化与 CMV 和 EBV 脱落状态的关系。共纳入 37 名 MSM HIV 感染者，并进行了中位数为 23 个月（IQR，22 至 28）的随访。参与者在 EDI 后中位数 3.1 个月（IQR，1.5 至 6.5）内开始接受 ART，此后病毒持续抑制。共有 18 名参与者（48.6%）被归类为 EBV 高脱落者，而 19 名参与者（51.4%）被归类为 CMV 脱落者。在纵向分析中，在可检测到 CMV 和高 EBV DNA 的参与者中，标准化分子多样性水平随时间呈上升趋势（0.03 ± 0.02， = 0.08），而在无/低病毒脱落的参与者中则显著下降（-0.04 ± 0.02， = 0.047，交互作用 < 0.01）。亚临床 CMV 和 EBV 脱落可能导致抑制性 ART 期间 HIV DNA 储存库的动态变化。持续性 CMV/EBV 复制是否可作为减少潜伏性 HIV 储存库大小的策略，这是一个值得探索的途径。作为本研究的一部分，我们评估了在抗逆转录病毒治疗 (ART) 期间 HIV DNA 储存库的分子特征随时间的变化与其他慢性病毒感染（即巨细胞病毒 [CMV] 和 Epstein-Barr 病毒 [EBV]）的关系。我们证明，外周血细胞中 CMV 和高水平 EBV DNA 的存在与 HIV DNA 分子多样性的变化有关。具体来说，在可检测到 CMV 和高水平 EBV DNA 的参与者中，HIV DNA 分子多样性随时间增加，而在无/低病毒脱落的参与者中则显著下降。尽管目前的研究设计不允许推断因果关系，但它确实支持这样一种理论，即持续性 CMV 和 EBV 脱落可能导致抑制性 ART 期间 HIV DNA 储存库的动态变化，即使在 HIV 感染的最早阶段开始 ART 也是如此。
