Latent human cytomegalovirus enhances HIV-1 infection in CD34+ progenitor cells
Latent human cytomegalovirus enhances HIV-1 infection in CD34+ progenitor cells
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DOI：
10.1182/bloodadvances.2016000638
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发表时间：
2017-01-24
期刊：
影响因子：
7.5
通讯作者：
Chen, Zhiwei
中科院分区：
文献类型：
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作者：
Cheung, Allen Ka Loon;Huang, Yiru;Chen, Zhiwei
人巨细胞病毒（HCMV）感染的个体在随后的HIV-1感染后更容易发生艾滋病疾病进展，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CD 34（+）祖细胞中建立终身潜伏感染，其中潜伏特异性HCMV基因可调节宿主对HIV-1感染的限制。为了验证这一假设，我们研究了祖细胞，已知的抵抗复制型HIV-1感染，因为宿主限制因子的内在表达。有趣的是，在经历潜伏性HCMV感染的原代CD 34（+）细胞中，通过数字聚合酶链反应、定量聚合酶链反应和Gag表达测量，观察到HIV-1前病毒DNA和复制水平增强，并使用编码X4的双报告基因假病毒证实-或R5-嗜性包膜和T细胞转移。这种现象可能部分解释了HIV-1进入辅助受体，包括趋化因子受体CXCR 4和CCR 5，但不是主要受体CD 4的上调。此外，潜伏性HCMV感染下调了CD 34（+）祖细胞中HIV-1限制性因子SAMHD 1、APOBEC 3G、tetherin和Mx 2的表达，这可能与增强的HIV-1感染有关。然而，当紫外线灭活的HCMV用于比较时，这种增强被废除，这表明潜伏HCMV基因的表达对于这种效果是必不可少的。重要的是，HCMV gB和HIV-1 p24可以通过免疫荧光和流式细胞术在同一细胞中检测到;因此，在CD 34（+）细胞中建立HCMV潜伏期可能导致有利于HIV-1感染的宿主细胞基因调节。
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.