HSV-2 infection of dendritic cells amplifies a highly susceptible HIV-1 cell target.
HSV-2 infection of dendritic cells amplifies a highly susceptible HIV-1 cell target.
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DOI：
10.1371/journal.ppat.1002109
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发表时间：
2011-06
期刊：
影响因子：
6.7
通讯作者：
Robbiani M
中科院分区：
文献类型：
--
作者：
Martinelli E;Tharinger H;Frank I;Arthos J;Piatak M Jr;Lifson JD;Blanchard J;Gettie A;Robbiani M
单纯疱疹病毒2型（HSV-2）增加了感染HIV-1的风险，尽管有几篇报道描述了这两种病毒之间的相互作用，但这种易感性增加的确切机制仍不清楚。在HSV-2和HIV-1进入部位的树突状细胞（dc）有助于病毒在粘膜中的传播。存在于肠道相关淋巴组织中的特化dc产生维甲酸（RA），这是一种重要的免疫调节剂，能够影响HIV-1的复制，也是淋巴细胞上整合素α4β7的关键介质。α4β7可以在细胞表面被HIV-1参与，表达高水平α4β7整合素的CD4+ T细胞对HIV-1感染特别敏感。本研究提供的猕猴体内数据显示，在直肠活体暴露（n = 11）后6天内，直肠粘膜、髂淋巴结和血液中α4β7高CD4+ T细胞的百分比增加，但紫外线处理（n = 8）的HSV-2没有增加。我们发现CD11c+ dc是体外暴露pbmc中HSV-2感染的主要靶点。我们发现，未成熟的单核细胞来源的dc （moDCs）表达醛脱氢酶ALDH1A1，这是一种产生RA所必需的酶，在HSV-2感染时增加。此外，hsv -2感染的moDCs显著增加CD4+ T淋巴细胞上α4β7的表达，并以ra依赖的方式增加DC-T细胞混合物中HIV-1的感染。因此，我们认为HSV-2调节其微环境，影响DC功能，增加RA生产能力，扩增a α4β7高cd4 + T细胞。这些因素可能在增加HIV-1易感性方面发挥作用。绝大多数HIV-1感染发生在生殖器和直肠粘膜。更好地了解有助于HIV-1复制的粘膜微环境的特征对于制定预防HIV-1传播的策略至关重要。2型单纯疱疹病毒感染生殖器和直肠粘膜，感染者感染1型单纯疱疹病毒的风险增加。阐明HSV-2阳性个体对HIV-1感染易感性增加的机制可能有助于理解促进HIV-1传播的粘膜微环境特征。我们之前描述了HIV-1和整合素α4β7之间的特异性相互作用，整合素α4β7是一种特征分子，允许淋巴细胞进入肠道组织，这是HIV-1复制的主要部位。维生素A及其代谢物维甲酸在平衡肠道免疫反应和整合素α4β7的表达中发挥重要作用。在这里，我们描述了HSV-2直肠感染猴子的血液和直肠组织中α4β7 + CD4+ T细胞的频率增加，这至少可以部分解释为HSV-2感染dc分泌视黄酸和上调CD4+ T细胞上α4β7的能力。这些现象可能是在DC-T细胞共培养中增加HIV-1复制的原因。
Herpes simplex virus type 2 (HSV-2) increases the risk of HIV-1 infection and, although several reports describe the interaction between these two viruses, the exact mechanism for this increased susceptibility remains unclear. Dendritic cells (DCs) at the site of entry of HSV-2 and HIV-1 contribute to viral spread in the mucosa. Specialized DCs present in the gut-associated lymphoid tissues produce retinoic acid (RA), an important immunomodulator, able to influence HIV-1 replication and a key mediator of integrin α4β7 on lymphocytes. α4β7 can be engaged by HIV-1 on the cell-surface and CD4+ T cells expressing high levels of this integrin (α4β7 high) are particularly susceptible to HIV-1 infection. Herein we provide in-vivo data in macaques showing an increased percentage of α4β7 high CD4+ T cells in rectal mucosa, iliac lymph nodes and blood within 6 days of rectal exposure to live (n = 11), but not UV-treated (n = 8), HSV-2. We found that CD11c+ DCs are a major target of HSV-2 infection in in-vitro exposed PBMCs. We determined that immature monocyte-derived DCs (moDCs) express aldehyde dehydrogenase ALDH1A1, an enzyme essential for RA production, which increases upon HSV-2 infection. Moreover, HSV-2-infected moDCs significantly increase α4β7 expression on CD4+ T lymphocytes and HIV-1 infection in DC-T cell mixtures in a RA-dependent manner. Thus, we propose that HSV-2 modulates its microenviroment, influencing DC function, increasing RA production capability and amplifying a α4β7 highCD4+ T cells. These factors may play a role in increasing the susceptibility to HIV-1. The vast majority of HIV-1 infections occur through genital and rectal mucosa. A better understanding of the characteristics of the mucosal microenvironment that help HIV-1 replication is critical to developing strategies for prevention of HIV-1 transmission. HSV-2 infects genital and rectal mucosa and infected individuals carry an increased risk for HIV-1 infection. Clarifying the mechanisms involved in the increased susceptibility of HSV-2 positive individuals to HIV-1 infection may help understating the characteristics of mucosal microenvironment that facilitate HIV-1 transmission. We previously described a specific interaction between HIV-1 and integrin α4β7, a signature molecule that allows lymphocytes to gain access to the gut tissue, a major site of HIV-1 replication. Vitamin A and its metabolite, retinoic acid, have an important role in balancing the immune response in the gut and in the expression of integrin α4β7. Here we describe that HSV-2 rectal infection in monkeys increases the frequency of α4β7 + CD4+ T cells in blood and rectal tissue and that this could be at least partially explained by the ability of HSV-2 infected DCs to secrete retinoic acid and up-regulate α4β7 on CD4+ T cells. These phenomena could be responsible for increasing HIV-1 replication in DC-T cell co-cultures.
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DOI：
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