期刊
VIROLOGY
卷 373, 期 2, 页码 342-351出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.virol.2007.11.020
关键词
HIV/AIDS pathogenesis; HIV vaginal and rectal transmission; microbicides; humanized mice; HIV-1 mucosal transmission/infection; animal disease models; hematopoietic stem cells; SCID-hu mice; Rag2(-/-)gamma c(-/-) mice; RAG-hu mice
类别
资金
- NIAID NIH HHS [R01 AI057066, P30 AI054907, R01 AI050492, R01 AI073255, R01 AI057066-04, R01 AI50492, R21 AI050492, R01 AI073255-01A2, R01 AI050492-05] Funding Source: Medline
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.
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