抑制HIV传播的关键分子被发现（PPARγ and LXR Signaling Inhibit）

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美国波士顿大学医学院研究人员发现两种分子，当它们被药物激活后可以抑制HIV传播中的多个方面。这项发表在《公共科学图书馆·病原体》上的研究有可能导致针对粘膜HIV传播的治疗方法。   
　　在世界范围内，对于新HIV感染，异性传播占大多数，而且主要是在发达国家。阴道、子宫颈或直肠粘膜上的免疫细胞是HIV性传播感染的主要目标。研究认为，粘膜组织中的树突细胞在HIV传播上起了关键作用。它们可以有效地捕捉到病毒并移送给淋巴结，并在淋巴结中通过“反式感染”将病毒传递给T细胞。T细胞是支持病毒复制的主要细胞。除此以外，树突细胞还可以促进粘膜的炎症，为病毒复制创造了有利的环境。   
　　在基因调节的核受体家族中的某些成员，包括PPARγ和LXR，被证明是炎症的抑制剂。研究人员因此想证明，一些能够激活PPARγ和LXR的药物能否抑制HIV的传播。为了证明这一点，他们从血液中分离出了树突细胞和T细胞，并对PPARγ和LXR在HIV传播中的活性作用进行了验证。研究报告说，一些能激活PPARγ和LXR的药物可以抑制树突细胞捕捉HIV以及将病毒传递给T细胞的能力。此外证明，同样是这些药物，可以抑制被认为能够增加HIV性传播发病率、由某些细菌感染（如淋病奈瑟菌）所诱导的炎症。   
　　“重要的是，我们发现，这些药物抑制树突细胞介导的反式感染达5倍以上，着重说明了这些药物在抑制HIV传播中的潜力。”微生物学副教授格雷戈里·维利安蒂博士说。   
　　“在没有有效的疫苗情况下，开发有效的抑制HIV传播的药物成为了日益增加的需求。我们的研究证明，PPARγ和LXR可成为同时抑制HIV粘膜传播中，包括炎症、树突细胞迁移和树突细胞介导的HIV传播等方面药物的作用靶点。因此，我们的研究提供了一个理论基础，就是把针对PPARγ和LXR的药物与传统的针对HIV传播其它方面的抗病毒药物结合在一起进行治疗。”他说。


PLoS Pathog 6(7): e1000981. doi:10.1371/journal.ppat.1000981
PPARγ and LXR Signaling Inhibit Dendritic Cell-Mediated HIV-1 Capture and trans-Infection

Timothy M. Hanley, Wendy Blay Puryear, Suryaram Gummuluru, Gregory A. Viglianti*
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America
Abstract  
   Dendritic cells (DCs) contribute to human immunodeficiency virus type 1 (HIV-1) transmission and dissemination by capturing and transporting infectious virus from the mucosa to draining lymph nodes, and transferring these virus particles to CD4+ T cells with high efficiency. Toll-like receptor (TLR)-induced maturation of DCs enhances their ability to mediate trans-infection of T cells and their ability to migrate from the site of infection. Because TLR-induced maturation can be inhibited by nuclear receptor (NR) signaling, we hypothesized that ligand-activated NRs could repress DC-mediated HIV-1 transmission and dissemination. Here, we show that ligands for peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor (LXR) prevented proinflammatory cytokine production by DCs and inhibited DC migration in response to the chemokine CCL21 by preventing the TLR-induced upregulation of CCR7. Importantly, PPARγ and LXR signaling inhibited both immature and mature DC-mediated trans-infection by preventing the capture of HIV-1 by DCs independent of the viral envelope glycoprotein. PPARγ and LXR signaling induced cholesterol efflux from DCs and led to a decrease in DC-associated cholesterol, which has previously been shown to be required for DC capture of HIV-1. Finally, both cholesterol repletion and the targeted knockdown of the cholesterol transport protein ATP-binding cassette A1 (ABCA1) restored the ability of NR ligand treated cells to capture HIV-1 and transfer it to T cells. Our results suggest that PPARγ and LXR signaling up-regulate ABCA1-mediated cholesterol efflux from DCs and that this accounts for the decreased ability of DCs to capture HIV-1. The ability of NR ligands to repress DC mediated trans-infection, inflammation, and DC migration underscores their potential therapeutic value in inhibiting HIV-1 mucosal transmission.

Author Summary  
     Heterosexual transmission is the primary mode of HIV transmission worldwide. In the absence of an effective vaccine, there is an increasing demand for the development of effective microbicides that block HIV sexual transmission. Dendritic cells (DCs) play a critical role in HIV transmission by efficiently binding virus particles, migrating to lymph nodes, and transmitting them to CD4+ T cells, a process called trans-infection. In addition, DCs secrete proinflammatory cytokines that create a favorable environment for virus replication. DC maturation by pathogen-encoded TLR ligands or proinflammatory cytokines dramatically increases their capacity to capture HIV, migrate to lymphoid tissue, and trans-infect T cells. Here, we report that signaling through the nuclear receptors PPARγ and LXR prevents DC maturation and proinflammatory cytokine production, as well as migration. In addition, PPARγ and LXR signaling prevents efficient DC capture and transfer of infectious HIV by increasing ABCA1-mediated cholesterol efflux. Our studies suggest that PPARγ and LXR may be targets for drugs that can inhibit specific aspects of HIV mucosal transmission, namely inflammation, migration, and virus capture and transfer. These findings provide a rationale for considering PPARγ and LXR agonists as potential combination therapies with conventional anti-viral microbicides that target other aspects of mucosal HIV transmission.


发表于 2010-7-10 01:22 版主503817