Antiretroviral Pre-exposure Prophylaxis Prevents Vaginal Transmission of HIV-1 in Humanized BLT Mice

PLoS Med. 2008 Jan 15;5(1):e16 doi:10.1371/journal.pmed.0050016

Paul W. Denton¹, Jacob D. Estes², Zhifeng Sun¹, Florence A. Othieno¹, Bangdong L. Wei¹, Anja K. Wege¹, Daniel A. Powell¹, Deborah Payne³, Ashley T. Haase², J. Victor Garcia ^1
1Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America, ²Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America, ³Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America

BACKGROUND: Worldwide, vaginal transmission now accounts for more than half of newly acquired HIV-1 infections. Despite the urgency to develop and implement novel approaches capable of preventing HIV transmission, this process has been hindered by the lack of adequate small animal models for preclinical efficacy and safety testing. Given the importance of this route of transmission, we investigated the susceptibility of humanized mice to intravaginal HIV-1 infection.

METHODS AND FINDINGS: We show that the female reproductive tract of humanized bone marrow–liver–thymus (BLT) mice is reconstituted with human CD4+ T and other relevant human cells, rendering these humanized mice susceptible to intravaginal infection by HIV-1. Effects of HIV-1 infection include CD4+ T cell depletion in gut-associated lymphoid tissue (GALT) that closely mimics what is observed in HIV-1–infected humans. We also show that pre-exposure prophylaxis with antiretroviral drugs is a highly effective method for preventing vaginal HIV-1 transmission. Whereas 88% (7/8) of BLT mice inoculated vaginally with HIV-1 became infected, none of the animals (0/5) given pre-exposure prophylaxis of emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) showed evidence of infection (Chi square = 7.5, df=1, p=0.006).

CONCLUSIONS: The fact that humanized BLT mice are susceptible to intravaginal infection makes this system an excellent candidate for preclinical evaluation of both microbicides and pre-exposure prophylactic regimens. The utility of humanized mice to study intravaginal HIV-1 transmission is particularly highlighted by the demonstration that pre-exposure prophylaxis can prevent intravaginal HIV-1 transmission in the BLT mouse model.

Abbreviations: BLT, bone marrow–liver–thymus; FRT, female reproductive tract; FTC, emtricitabine; GALT, gut-associated lymphoid tissue; HSC, hematopoietic stem cell; IEL, intraepithelial lymphocytes; LI, large intestine; LPL, lamina propria lymphocytes; SHIV, chimeric simian–human immunodeficiency virus; SI, small intestine; TDF, tenofovir disoproxil fumarate

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2008-01-15
10.1371_journal.pmed.0050016

Copyright: © 2008 Denton et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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