Pharmacological HIV-1 reactivation to reverse latent infection has been extensively studied. However, HIV-1 reactivation also occurs naturally, as evidenced by occasional low-level viremia ("viral blips") during antiretroviral treatment (ART). Clarifying where blips originate from and how they happen could provide clues to stimulate latency reversal more effectively and safely or to prevent viral rebound following ART cessation. We studied HIV-1 reactivation in the female genital tract, a dynamic anatomical target for HIV-1 infection throughout all disease stages. We found that primary endocervical epithelial cells from several women reactivated HIV-1 from latently infected T cells. The endocervical cells' HIV-1 reactivation capacity further increased upon Toll-like receptor 3 stimulation with poly(I·C) double-stranded RNA or infection with herpes simplex virus 2 (HSV-2). Notably, acyclovir did not eliminate HSV-2-induced HIV-1 reactivation. While endocervical epithelial cells secreted large amounts of several cytokines and chemokines, especially tumor necrosis factor alpha (TNF-α), CCL3, CCL4, and CCL20, their HIV-1 reactivation capacity was almost completely blocked by TNF-α neutralization alone. Thus, immunosurveillance activities by columnar epithelial cells in the endocervix can cause endogenous HIV-1 reactivation, which may contribute to viral blips during ART or rebound following ART interruption.IMPORTANCE A reason that there is no universal cure for HIV-1 is that the virus can hide in the genome of infected cells in the form of latent proviral DNA. This hidden provirus is protected from antiviral drugs until it eventually reactivates to produce new virions. It is not well understood where in the body or how this reactivation occurs. We studied HIV-1 reactivation in the female genital tract, which is often the portal of HIV-1 entry and which remains a site of infection throughout the disease. We found that the columnar epithelial cells lining the endocervix, the lower part of the uterus, are particularly effective in reactivating HIV-1 from infected T cells. This activity was enhanced by certain microbial stimuli, including herpes simplex virus 2, and blocked by antibodies against the inflammatory cytokine TNF-α. Avoiding HIV-1 reactivation could be important for maintaining a functional HIV-1 cure when antiviral therapy is stopped.

中文翻译：

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宫颈上皮细胞内源性HIV-1激活的机制。

逆转潜伏感染的药理学HIV-1活化已得到广泛研究。但是，HIV-1的再活化也自然发生，如在抗逆转录病毒治疗（ART）期间偶尔出现的低水平病毒血症（“病毒斑点”）所证明的。弄清斑点的起源和发生方式可以提供一些线索，以更有效，更安全地刺激潜伏期逆转，或防止ART停止后病毒反弹。我们研究了女性生殖道中的HIV-1活化，这是整个疾病阶段HIV-1感染的动态解剖目标。我们发现，几名妇女的原始宫颈上皮细胞从潜伏感染的T细胞中重新激活了HIV-1。子宫颈细胞 通过聚（I·C）双链RNA刺激Toll样受体3或感染单纯疱疹病毒2（HSV-2），HIV-1的激活能力进一步提高。值得注意的是，阿昔洛韦没有消除HSV-2诱导的HIV-1激活。虽然宫颈上皮细胞分泌大量的几种细胞因子和趋化因子，尤其是肿瘤坏死因子α（TNF-α），CCL3，CCL4和CCL20，但它们的HIV-1活化能力几乎完全被TNF-α中和所完全阻断。因此，子宫颈内柱状上皮细胞的免疫监视活性可引起内源性HIV-1激活，这可能在ART期间引起病毒性斑点或在ART中断后反弹。重要性无法普遍治愈HIV-1的一个原因是该病毒可以潜伏的前病毒DNA形式隐藏在感染细胞的基因组中。这种隐蔽的原病毒不受抗病毒药物的保护，直到最终重新激活以产生新的病毒体为止。人体中何处或这种再活化如何发生还不太清楚。我们研究了女性生殖道中的HIV-1活化，这通常是HIV-1进入的门户，并且仍然是整个疾病的感染部位。我们发现衬在子宫颈内膜（子宫下部）的柱状上皮细胞在激活被感染的T细胞中的HIV-1方面特别有效。某些微生物刺激（包括单纯疱疹病毒2）增强了这种活性，并被抗炎性细胞因子TNF-α的抗体所阻断。