Systemic Administration of Antiretrovirals Prior to Exposure Prevents Rectal and Intravenous HIV-1 Transmission in Humanized BLT Mice

Systemic Administration of Antiretrovirals Prior to Exposure Prevents Rectal and Intravenous HIV-1 Transmission in Humanized BLT Mice

References
Paul W. Denton1¤a, John F. Krisko1¤a, Daniel A. Powell1, Melissa Mathias1, Youn Tae Kwak1, Francisco Martinez-Torres1¤a, Wei Zou1¤a, Deborah A. Payne2¤b, Jacob D. Estes3, J. Victor Garcia1¤a*

1 Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America, 2 Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America, 3 The AIDS and Cancer Virus Program, SAIC-Frederick, Inc, National Cancer Institute, Frederick, Maryland, United States of America

Abstract
Successful antiretroviral pre-exposure prophylaxis (PrEP) for mucosal and intravenous HIV-1 transmission could reduce new infections among targeted high-risk populations including discordant couples, injection drug users, high-risk women and men who have sex with men. Targeted antiretroviral PrEP could be particularly effective at slowing the spread of HIV-1 if a single antiretroviral combination were found to be broadly protective across multiple routes of transmission. Therefore, we designed our in vivo preclinical study to systematically investigate whether rectal and intravenous HIV-1 transmission can be blocked by antiretrovirals administered systemically prior to HIV-1 exposure. We performed these studies using a highly relevant in vivo model of mucosal HIV-1 transmission, humanized Bone marrow/Liver/Thymus mice (BLT). BLT mice are susceptible to HIV-1 infection via three major physiological routes of viral transmission: vaginal, rectal and intravenous. Our results show that BLT mice given systemic antiretroviral PrEP are efficiently protected from HIV-1 infection regardless of the route of exposure. Specifically, systemic antiretroviral PrEP with emtricitabine and tenofovir disoproxil fumarate prevented both rectal (Chi square = 8.6, df = 1, p = 0.003) and intravenous (Chi square = 13, df = 1, p = 0.0003) HIV-1 transmission. Our results indicate that antiretroviral PrEP has the potential to be broadly effective at preventing new rectal or intravenous HIV transmissions in targeted high risk individuals. These in vivo preclinical findings provide strong experimental evidence supporting the potential clinical implementation of antiretroviral based pre-exposure prophylactic measures to prevent the spread of HIV/AIDS.

Citation: Denton PW, Krisko JF, Powell DA, Mathias M, Kwak YT, et al. (2010) Systemic Administration of Antiretrovirals Prior to Exposure Prevents Rectal and Intravenous HIV-1 Transmission in Humanized BLT Mice. PLoS ONE 5(1): e8829. doi:10.1371/journal.pone.0008829

Editor: Mark Wainberg, McGill University AIDS Centre, Canada


Received: October 16, 2009; Accepted: December 23, 2009; Published: January 21, 2010

This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

Funding: This work was supported in part with federal funds from National Institute of Allergy and Infectious Diseases, National Institutes of Health grants AI073146 and AI071940 (J.V.G.), 5T32AI005284 (J.F.K.), and the National Cancer Institute, National Institutes of Health, under contract HHSN266200400088C (J.E.D.). This work was supported in part by fellowship number 107183-44-RFRL from The Foundation for AIDS Research (amfAR) (P.W.D.). M. M. was supported by the UT Southwestern Summer Medical Student Research Program. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: victor_garcia@med.unc.edu

¤a Current address: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina, Chapel Hill, North Carolina, United States of America

¤b Current address: Unipath LLC, Denver, Colorado, United States of America

abrir aquí:
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008829