Instituto de Investigaciones Médicas en Retrovirus y SIDA (INBIRS), Facultad de Medicina, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
PLoS One. 2013 Aug 23;8(8):e72814. doi: 10.1371/journal.pone.0072814. eCollection 2013.
Macrophages are one of the most important HIV-1 target cells. Unlike CD4(+) T cells, macrophages are resistant to the cytophatic effect of HIV-1. They are able to produce and harbor the virus for long periods acting as a viral reservoir. Candida albicans (CA) is a commensal fungus that colonizes the portals of HIV-1 entry, such as the vagina and the rectum, and becomes an aggressive pathogen in AIDS patients. In this study, we analyzed the ability of CA to modulate the course of HIV-1 infection in human monocyte-derived macrophages. We found that CA abrogated HIV-1 replication in macrophages when it was evaluated 7 days after virus inoculation. A similar inhibitory effect was observed in monocyte-derived dendritic cells. The analysis of the mechanisms responsible for the inhibition of HIV-1 production in macrophages revealed that CA efficiently sequesters HIV-1 particles avoiding its infectivity. Moreover, by acting on macrophages themselves, CA diminishes their permissibility to HIV-1 infection by reducing the expression of CD4, enhancing the production of the CCR5-interacting chemokines CCL3/MIP-1α, CCL4/MIP-1β, and CCL5/RANTES, and stimulating the production of interferon-α and the restriction factors APOBEC3G, APOBEC3F, and tetherin. Interestingly, abrogation of HIV-1 replication was overcome when the infection of macrophages was evaluated 2-3 weeks after virus inoculation. However, this reactivation of HIV-1 infection could be silenced by CA when added periodically to HIV-1-challenged macrophages. The induction of a silent HIV-1 infection in macrophages at the periphery, where cells are continuously confronted with CA, might help HIV-1 to evade the immune response and to promote resistance to antiretroviral therapy.
巨噬细胞是 HIV-1 的最重要的靶细胞之一。与 CD4(+) T 细胞不同，巨噬细胞对 HIV-1 的细胞病变效应具有抗性。它们能够长时间产生和携带病毒，充当病毒储存库。白色念珠菌（CA）是一种共生真菌，定植于 HIV-1 进入的门户，如阴道和直肠，并在 AIDS 患者中成为侵袭性病原体。在这项研究中，我们分析了 CA 调节人单核细胞衍生巨噬细胞中 HIV-1 感染过程的能力。我们发现，当在病毒接种后 7 天评估时，CA 可阻断巨噬细胞中的 HIV-1 复制。在单核细胞衍生的树突状细胞中观察到类似的抑制作用。对负责抑制巨噬细胞中 HIV-1 产生的机制的分析表明，CA 有效地隔离 HIV-1 颗粒，避免其感染性。此外，CA 通过作用于巨噬细胞本身，通过降低 CD4 的表达、增强 CCR5 相互作用的趋化因子 CCL3/MIP-1α、CCL4/MIP-1β 和 CCL5/RANTES 的产生，以及刺激干扰素-α和限制因子 APOBEC3G、APOBEC3F 和 tetherin 的产生，减少了巨噬细胞对 HIV-1 感染的许可性，从而降低了其对 HIV-1 感染的许可性。有趣的是，当在病毒接种后 2-3 周评估巨噬细胞的感染时，HIV-1 复制的阻断被克服。然而，当周期性添加到受到 HIV-1 挑战的巨噬细胞时，CA 可以沉默这种 HIV-1 感染的重新激活。在周围环境中诱导巨噬细胞中沉默的 HIV-1 感染，其中细胞不断受到 CA 的挑战，可能有助于 HIV-1 逃避免疫反应并促进对抗逆转录病毒治疗的抗性。
