美國波士頓大學醫(yī)學院研究人員發(fā)現(xiàn)兩種分子,，當它們被藥物激活后可以抑制HIV傳播中的多個方面。這項發(fā)表在《公共科學圖書館 病原體》（PLoS Pathogens）上的研究有可能導致針對粘膜HIV傳播的治療方法,。
在世界范圍內(nèi),，對于新HIV感染，異性傳播占大多數(shù),，而且主要是在發(fā)達國家,。陰道、子宮頸或直腸粘膜上的免疫細胞是HIV性傳播感染的主要目標,。研究認為,，粘膜組織中的樹突細胞在HIV傳播上起了關(guān)鍵作用,。它們可以有效地捕捉到病毒并移送給淋巴結(jié)，并在淋巴結(jié)中通過“反式感染”將病毒傳遞給T細胞,。T細胞是支持病毒復制的主要細胞,。除此以外，樹突細胞還可以促進粘膜的炎癥,，為病毒復制創(chuàng)造了有利的環(huán)境,。生 物 谷啟用新域名 www.bioon.net
在基因調(diào)節(jié)的核受體家族中的某些成員，包括PPARγ和LXR,，被證明是炎癥的抑制劑,。研究人員因此想證明，一些能夠激活PPARγ和LXR的藥物能否抑制HIV的傳播,。為了證明這一點,，他們從血液中分離出了樹突細胞和T細胞，并對PPARγ和LXR在HIV傳播中的活性作用進行了驗證,。研究報告說,，一些能激活PPARγ和LXR的藥物可以抑制樹突細胞捕捉HIV以及將病毒傳遞給T細胞的能力。此外證明,，同樣是這些藥物,，可以抑制被認為能夠增加HIV性傳播發(fā)病率、由某些細菌感染（如淋病奈瑟菌）所誘導的炎癥,。
“重要的是,，我們發(fā)現(xiàn)，這些藥物抑制樹突細胞介導的反式感染達5倍以上,，著重說明了這些藥物在抑制HIV傳播中的潛力,。”微生物學副教授格雷戈里 維利安蒂博士說。
“在沒有有效的疫苗情況下,，開發(fā)有效的抑制HIV傳播的藥物成為了日益增加的需求,。我們的研究證明，PPARγ和LXR可成為同時抑制HIV粘膜傳播中,，包括炎癥,、樹突細胞遷移和樹突細胞介導的HIV傳播等方面藥物的作用靶點。因此,，我們的研究提供了一個理論基礎(chǔ),，就是把針對PPARγ和LXR的藥物與傳統(tǒng)的針對HIV傳播其它方面的抗病毒藥物結(jié)合在一起進行治療。”他說,。(生物谷Bioon.net)
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生物谷推薦原文出處：
PLoS Pathogens 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
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.
