Mucosal transmission of R5 and X4 tropic HIV-1 via vaginal and rectal routes in humanized Rag-/- γc-/- (RAG-hu) mice
Mucosal transmission of R5 and X4 tropic HIV-1 via vaginal and rectal routes in humanized Rag-/- γc-/- (RAG-hu) mice
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DOI：
10.1016/j.virol.2007.11.020
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发表时间：
2008-04-10
期刊：
影响因子：
3.7
通讯作者：
Akkina, Ramesh
中科院分区：
文献类型：
--
作者：
Berges, Bradford K.;Akkina, Sarah R.;Akkina, Ramesh
迄今为止，由于缺乏合适的易受阴道和/或直肠途径HIV-1感染的动物模型，对HIV-1粘膜传播进行研究以评估发病机制的早期事件和开发有效的预防/预防方法受到阻碍。在这方面，虽然灵长类-SIV/SHfV和猫-FIV模型提供了有用的替代平台来获得比较数据，但这些病毒与HIV-1不同。因此，一个最佳的模型，允许直接研究HIV-1通过粘膜途径传播是非常可取的。新一代人源化NOD/SCID BLT、NOD/SCID gamma c（-/-）和Rag 2（-/-）gamma c（-/-）小鼠模型显示出实现这一目标的巨大希望。在这里，我们发现，人源化的Rag 2（-/-）γ c（-/-）小鼠（RAG-hu）移植CD 34造血祖细胞窝藏HIV-1易感的人类细胞在直肠和阴道粘膜，当暴露于无细胞的HIV-1通过阴道或直肠感染时，易受HIV-1感染。感染可在没有任何激素调节或粘膜磨损的情况下建立。R5和X4嗜性病毒都能够粘膜感染，导致病毒血症和相关的辅助性T细胞耗竭。病毒全身扩散，在包括肠粘膜在内的不同器官中检测到感染细胞。R5病毒在两种途径的粘膜传播中效率很高，而X4病毒在引起感染方面效率相对较低。如本文所示，通过阴道和直肠途径感染RAG-hu小鼠的HIV-1代表了HIV-1通过完整粘膜屏障传播的第一个体内模型，因此可能证明对于研究体内HIV-1发病机制的早期事件以及测试杀微生物剂、抗HIV疫苗/治疗剂和其他预防HIV-1传播的新策略非常有用。(C)2007爱思唯尔公司All rights reserved.
Studies on HIV-1 mucosal transmission to evaluate early events in pathogenesis and the development of effective preventive/prophylactic methods have thus far been hampered by the lack of a suitable animal model susceptible to HIV-1 infection by either vaginal and/or rectal routes. In this regard, while primate-SIV/SHfV and cat-FIV models provided useful surrogate platforms to derive comparative data, these viruses are distinct and different from that of HIV-1. Therefore an optimal model that permits direct study of HIV-1 transmission via mucosal routes is highly desirable. The new generation of humanized NOD/SCID BLT, NOD/SCID gamma c(-/-), and Rag2(-/-)gamma c(-/-) mouse models show great promise to achieve this goal. Here, we show that humanized Rag2(-/-)gamma c(-/-) mice (RAG-hu) engrafted with CD34 hematopoietic progenitor cells harbor HIV-1susceptible human cells in the rectal and vaginal mucosa and are susceptible to HIV-1 infection when exposed to cell-free HIV-1 either via vagina or rectum. Infection could be established without any prior hormonal conditioning or mucosal abrasion. Both R5 and X4 tropic viruses were capable of mucosal infection resulting in viremia and associated helper T cell depletion. There was systemic spread of the virus with infected cells detected in different organs including the intestinal mucosa. R5 virus was highly efficient in mucosal transmission by both routes whereas X4 virus was relatively less efficient in causing infection. HIV-1 infection of RAG-hu mice by vaginal and rectal routes as shown here represents the first in vivo model of HIV-1 transmission across intact mucosal barriers and as such may prove very useful for studying early events in HIV-1 pathogenesis in vivo, as well as the testing of microbicides, anti-HIV vaccines/therapeutics, and other novel strategies to prevent HIV-1 transmission. (C) 2007 Elsevier Inc. All rights reserved.