Cheung Allen Ka Loon, Huang Yiru, Kwok Hau Yee, Chen Min, Chen Zhiwei
AIDS Institute, Department of Microbiology, Research Center for Infection and Immunity, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Yunnan Center for Disease Control and Prevention, Kunming, China; and.
Blood Adv. 2017 Jan 16;1(5):306-318. doi: 10.1182/bloodadvances.2016000638. eCollection 2017 Jan 24.
Individuals who have been preinfected by human cytomegalovirus (HCMV) are more prone to AIDS disease progression after subsequent HIV-1 infection but the underlying mechanism remains elusive. HCMV is a ubiquitous DNA virus that commonly establishes lifelong latent infection in CD34 progenitor cells, where latency-specific HCMV genes may modulate host restriction to HIV-1 infection. To test this hypothesis, we studied progenitor cells that are known to resist replicative HIV-1 infection because of the intrinsic expression of host restriction factors. Interestingly, in primary CD34 cells undergoing latent HCMV infection, an enhanced level of HIV-1 proviral DNA and replication was observed as measured by digital polymerase chain reaction, quantitative polymerase chain reaction, and Gag expression, and confirmed using dual-reporter pseudovirus encoding X4- or R5-tropic envelope and T-cell transfer. This phenomenon may be partially explained by the upregulation of HIV-1 entry coreceptors, including chemokine receptors CXCR4 and CCR5, but not of the primary receptor CD4. Furthermore, latent HCMV infection downregulated the expression of HIV-1 restriction factors SAMHD1, APOBEC3G, tetherin, and Mx2 in CD34 progenitor cells, which may confer to enhanced HIV-1 infection. However, this enhancement was abrogated when ultraviolet-inactivated HCMV was used for comparison, suggesting that expression of latent HCMV genes is essential for this effect. Importantly, HCMV gB and HIV-1 p24 can be detected in the same cell by immunofluorescence and flow cytometry; therefore, the establishment of HCMV latency in CD34 cells likely leads to host cell gene modulation that favors HIV-1 infection.
曾感染过人巨细胞病毒（HCMV）的个体在随后感染HIV-1后更容易出现艾滋病病情进展，但其潜在机制仍不清楚。HCMV是一种普遍存在的DNA病毒，通常在CD34祖细胞中建立终身潜伏感染，在这些细胞中，潜伏特异性HCMV基因可能会调节宿主对HIV-1感染的限制。为了验证这一假设，我们研究了已知因宿主限制因子的内在表达而抵抗HIV-1复制性感染的祖细胞。有趣的是，在经历潜伏性HCMV感染的原代CD34细胞中，通过数字聚合酶链反应、定量聚合酶链反应和Gag表达检测到HIV-1前病毒DNA水平和复制增强，并使用编码X4或R5嗜性包膜和T细胞转移的双报告假病毒进行了验证。这种现象可能部分由HIV-1进入共受体（包括趋化因子受体CXCR4和CCR5，但不包括主要受体CD4）的上调来解释。此外，潜伏性HCMV感染下调了CD34祖细胞中HIV-1限制因子SAMHD1、APOBEC3G、束缚素和Mx2的表达，这可能导致HIV-1感染增强。然而，当使用紫外线灭活的HCMV进行比较时，这种增强作用被消除，这表明潜伏性HCMV基因的表达对于这种效应至关重要。重要的是，通过免疫荧光和流式细胞术可以在同一细胞中检测到HCMV gB和HIV-1 p24；因此，CD34细胞中HCMV潜伏状态的建立可能导致宿主细胞基因调节，有利于HIV-1感染。
