TNF-α and TLR agonists increase susceptibility to HIV-1 transmission by human Langerhans cells ex vivo
TNF-α and TLR agonists increase susceptibility to HIV-1 transmission by human Langerhans cells ex vivo
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DOI：
10.1172/jci34721
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发表时间：
2008-10-01
影响因子：
15.9
通讯作者：
Geijtenbeek, Teunis B. H.
中科院分区：
文献类型：
--
作者：
de Jong, Marein A. W. P.;de Witte, Lot;Geijtenbeek, Teunis B. H.
生殖器合并感染会增加个体通过性接触感染 HIV-1 的风险。已经提出了几种机制来解释这一点，例如由共感染病原体引起的溃疡和出血。在这里，我们证明朗格汉斯细胞 (LC) 与生殖器合并感染时 HIV-1 易感性增加有关。尽管 LC 是生殖器组织中 HIV-1 感染的目标，但我们发现，在离体人类皮肤外植体模型中，未成熟的 LC 不能有效介导 HIV-1 传播。然而，炎症刺激 TNF-α 和 Pam3CysSerLys4 (Pam3CSK4)（TLR1/TLR2 异二聚体的配体）通过不同的机制强烈增加了 LC 的 HIV-1 传播。 TNF-α 通过增加 LC 中的 HIV-1 复制来增强传播，而 Pam3CSK4 通过增加 LC 对 HIV-1 的捕获以及随后 T 细胞的反式感染来发挥作用。白色念珠菌和淋病奈瑟菌等生殖器感染不仅会触发 TLR，还会诱导阴道和皮肤外植体中 TNF-α 的产生。因此，在合并感染过程中，LCs可能被致病结构直接激活，并被炎症因子间接激活，从而增加感染HIV-1的风险。我们的数据证明了 LC 在生殖器合并感染期间的 HIV-1 传播中起决定性作用，并建议炎症疗法作为预防 HIV-1 传播的潜在策略。
Genital coinfections increase an individual's risk of becoming infected with HIV-1 by sexual contact. Several mechanisms have been proposed to explain this, such as the presence of ulceration and bleeding caused by the coinfecting pathogen. Here we demonstrate that Langerhans cells (LCs) are involved in the increased susceptibility to HIV-1 in the presence of genital coinfections. Although LCs are a target for HIV-1 infection in genital tissues, we found that immature LCs did not efficiently mediate HIV-1 transmission in an ex vivo human skin explant model. However, the inflammatory stimuli TNF-alpha and Pam3CysSerLys4 (Pam3CSK4), the ligand for the TLR1/TLR2 heterodimer, strongly increased HIV-1 transmission by LCs through distinct mechanisms. TNF-alpha enhanced transmission by increasing HIV-1 replication in LCs, whereas Pam3CSK4 acted by increasing LC capture of HIV-1 and subsequent trans-infection of T cells. Genital infections such as Candida albicans and Neisseria gonorrhea not only triggered TLRs but also induced TNF-alpha production in vaginal and skin explants. Thus, during coinfection, LCs could be directly activated by pathogenic structures and indirectly activated by inflammatory factors, thereby increasing the risk of acquiring HIV-1. Our data demonstrate a decisive role for LCs in HIV-1 transmission during genital coinfections and suggest and inflammatory therapies as potential strategies to prevent HIV-1 transmission.