Interleukin-7 facilitates HIV-1 transmission to cervico-vaginal tissue ex vivo.
Interleukin-7 facilitates HIV-1 transmission to cervico-vaginal tissue ex vivo.
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DOI：
10.1371/journal.ppat.1003148
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发表时间：
2013-02
期刊：
影响因子：
6.7
通讯作者：
Margolis L
中科院分区：
文献类型：
--
作者：
Introini A;Vanpouille C;Lisco A;Grivel JC;Margolis L
大多数妇女感染艾滋病毒-1是通过阴道性交发生的，其中含有病毒的精液沉积在宫颈阴道粘膜上。精液不仅仅是HIV-1的载体，因为它含有许多可能影响HIV-1传播的生物因素，特别是细胞因子。白细胞介素(IL)-7是健康个体精液中最重要的细胞因子之一，在hiv -1感染男性精液中浓度进一步升高。在这里，我们研究了IL-7在人类宫颈阴道组织离体系统中HIV-1阴道传播中的潜在作用。我们模拟了一种体内情况，将HIV-1与IL-7一起沉积在宫颈阴道组织上，其浓度与HIV-1感染者精液中的浓度相当。我们发现IL-7在体外感染的宫颈阴道组织中显著增强病毒复制。同样，我们观察到HIV-1在淋巴组织外植体中的复制增强。从感染组织中分离的T细胞分析显示，IL-7减少CD4+ T细胞耗损，防止细胞凋亡，表现为表达凋亡标志物APO2.7的细胞数量减少，抗凋亡蛋白b细胞淋巴瘤(Bcl)-2表达增加。此外，核因子Ki-67染色表明，IL-7增加了循环CD4+ T细胞的比例。体内高水平的精液IL-7可能与感染初期宫颈阴道粘膜中HIV-1感染细胞的创始池的存活有关，促进了HIV感染的局部扩张和传播。男性对女性的HIV-1传播主要通过阴道性交发生，病毒通过精液传播。确定HIV-1传播到女性下生殖道的决定因素对于理解HIV-1感染的基本机制至关重要。这种认识对于制定预防或控制这种感染的新战略是必要的。HIV-1感染者的精液富含IL-7， IL-7是CD4+ T细胞生命周期的关键细胞因子，CD4+ T细胞是HIV-1的主要靶点。本研究利用体外人宫颈阴道和淋巴组织系统研究IL-7对HIV-1传播和传播的影响。我们的研究结果表明，IL-7的浓度与HIV-1感染者精液中发现的浓度相当，通过防止死亡和刺激CD4+ T细胞的增殖来增强HIV-1的复制。这允许受感染细胞持续产生病毒，并为感染传播提供新的细胞靶点。HIV-1感染男性精液中IL-7的浓度可能是HIV-1通过阴道性交传播给未感染女性伴侣的效率的关键决定因素。
The majority of HIV-1 infections in women occur through vaginal intercourse, in which virus-containing semen is deposited on the cervico-vaginal mucosa. Semen is more than a mere carrier of HIV-1, since it contains many biological factors, in particular cytokines, that may affect HIV-1 transmission. The concentration of interleukin (IL)-7, one of the most prominent cytokines in semen of healthy individuals, is further increased in semen of HIV-1-infected men. Here, we investigated the potential role of IL-7 in HIV-1 vaginal transmission in an ex vivo system of human cervico-vaginal tissue. We simulated an in vivo situation by depositing HIV-1 on cervico-vaginal tissue in combination with IL-7 at concentrations comparable with those measured in semen of HIV-1-infected individuals. We found that IL-7 significantly enhanced virus replication in ex vivo infected cervico-vaginal tissue. Similarly, we observed an enhancement of HIV-1 replication in lymphoid tissue explants. Analysis of T cells isolated from infected tissues showed that IL-7 reduced CD4+ T cell depletion preventing apoptosis, as shown by the decrease in the number of cells expressing the apoptotic marker APO2.7 and the increase in the expression of the anti-apoptotic protein B-cell lymphoma (Bcl)-2. Also, IL-7 increased the fraction of cycling CD4+ T cells, as evidenced by staining for the nuclear factor Ki-67. High levels of seminal IL-7 in vivo may be relevant to the survival of the founder pool of HIV-1-infected cells in the cervico-vaginal mucosa at the initial stage of infection, promoting local expansion and dissemination of HIV infection. Male-to-female HIV-1 transmission occurs predominantly through vaginal intercourse when the virus is transmitted with seminal fluid. The identification of the determinants of HIV-1 transmission to the female lower genital tract is of pivotal importance for understanding the basic mechanisms of HIV-1 infection. This understanding is necessary for the development of new strategies to prevent or contain this infection. Semen of HIV-1-infected individuals is highly enriched with IL-7, a crucial cytokine for the life cycle of CD4+ T cells, the primary target of HIV-1. Here, we utilized a system of human cervico-vaginal and lymphoid tissues ex vivo to study the effect of IL-7 on HIV-1 transmission and dissemination. Our results show that IL-7 at concentrations comparable to those found in semen of HIV-1-infected individuals enhanced HIV-1 replication by preventing the death and by stimulating the proliferation of CD4+ T cells. This allows sustained viral production by infected cells and provides new cellular targets for propagation of infection. The concentration of IL-7 in semen of HIV-1-infected men may be a key determinant of the efficiency of HIV-1 transmission to an uninfected female partner through vaginal intercourse.
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