HSV-2 Cellular Programming Enables Productive HIV Infection in Dendritic Cells
HSV-2 Cellular Programming Enables Productive HIV Infection in Dendritic Cells
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DOI：
10.3389/fimmu.2019.02889
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发表时间：
2019-12-06
影响因子：
7.3
通讯作者：
Larsson, Marie
中科院分区：
文献类型：
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作者：
Crisci, Elisa;Svanberg, Cecilia;Larsson, Marie
生殖器疱疹是由单纯疱疹病毒2型（HSV-2）引起的一种常见的性传播感染。生殖器疱疹通过在宿主中创造支持HIV感染的微环境，显著增强HIV-1的获得和传播。树突状细胞（DCs）是在生殖器粘膜中遇到HIV-1和HSV-2的第一种先天性细胞类型之一。已经显示HSV-2感染调节DC，使它们更容易接受HIV感染。在这里，我们研究了潜在的机制HSV-2介导的增强HIV-1感染。我们证明了HSV-2的存在增强了DC的HIV-1感染，并增强了炎症和抗病毒反应。HSV-2增强的HIV-1感染需要完整的HSV-2 DNA，但不需要活跃的HSV-2 DNA复制。此外，DC的增强的HIV感染涉及cGAS-STING途径。有趣的是，我们没有看到TLR 2或TLR 3的参与，也没有看到IFN-β产生对感染的抑制。在双重暴露的DC中通过HSV-2的调节降低了IFI 16、cGAS、STING和TBK 1的蛋白表达，这与通过STING途径的信号传导相关。双重暴露于HSV-2和HIV-1导致几种HIV-1限制因子的水平降低，尤其是SAMHD 1、TREX 1和APOBEC 3G。通过暴露于HSV-2和HIV-1两者激活DC中的STING途径最有可能导致HIV-1限制因子SAMHD 1、TREX 1和APOBEC 3G的蛋白水解降解，这应该释放它们在DC中对HIV感染的正常限制。这释放了DC中HIV感染的正常限制。我们发现，HSV-2在DC中的细胞信号传导途径和蛋白表达水平的重编程提供了一种环境，其中HIV-1可以在DC中建立更高的生产性感染。总之，HSV-2重编程为HIV-1感染打开了DC，并创造了有利于HIV-1传播的微环境。
Genital herpes is a common sexually transmitted infection caused by herpes simplex virus type 2 (HSV-2). Genital herpes significantly enhances the acquisition and transmission of HIV-1 by creating a microenvironment that supports HIV infection in the host. Dendritic cells (DCs) represent one of the first innate cell types that encounter HIV-1 and HSV-2 in the genital mucosa. HSV-2 infection has been shown to modulate DCs, rendering them more receptive to HIV infection. Here, we investigated the potential mechanisms underlying HSV-2-mediated augmentation of HIV-1 infection. We demonstrated that the presence of HSV-2 enhanced productive HIV-1 infection of DCs and boosted inflammatory and antiviral responses. The HSV-2 augmented HIV-1 infection required intact HSV-2 DNA, but not active HSV-2 DNA replication. Furthermore, the augmented HIV infection of DCs involved the cGAS-STING pathway. Interestingly, we could not see any involvement of TLR2 or TLR3 nor suppression of infection by IFN-beta production. The conditioning by HSV-2 in dual exposed DCs decreased protein expression of IFI16, cGAS, STING, and TBK1, which is associated with signaling through the STING pathway. Dual exposure to HSV-2 and HIV-1 gave decreased levels of several HIV-1 restriction factors, especially SAMHD1, TREX1, and APOBEC3G. Activation of the STING pathway in DCs by exposure to both HSV-2 and HIV-1 most likely led to the proteolytic degradation of the HIV-1 restriction factors SAMHD1, TREX1, and APOBEC3G, which should release their normal restriction of HIV infection in DCs. This released their normal restriction of HIV infection in DCs. We showed that HSV-2 reprogramming of cellular signaling pathways and protein expression levels in the DCs provided a setting where HIV-1 can establish a higher productive infection in the DCs. In conclusion, HSV-2 reprogramming opens up DCs for HIV-1 infection and creates a microenvironment favoring HIV-1 transmission.