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Tenofovir/FTC Prevents Vaginal HIV Infection in Mice
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ART Pre-exposure Prophylaxis Prevents Vaginal Transmission of HIV-1 in Humanized BLT Mice
PLoS Medicine Jan 15, 2008
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 Garcia1*
1 Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America, 2 Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America, 3 Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America
"....As a female-controlled prevention measure, antiretroviral pre-exposure prophylaxis and/or topical microbicides could provide women with a powerful tool to protect themselves from infection. However, any candidate drug(s) must be safe, especially in individuals without disease, and efficacious and, in order to be successful, must be easy to use [4]. The combination of FTC/TDF appears to meet the criteria for drugs to be used for pre-exposure prophylaxis [31]. In addition, it is one of the few drug combinations that can be administered once daily without food restrictions.....
....What Did the Researchers Do and Find?
When the researchers examined the female reproductive tract of humanized BLT mice for human immune system cells, they found CD4+ T cells, dendritic cells and macrophages, all of which are involved in HIV infection. Furthermore, half of the blood cells of the BLT mice were human. Most of the BLT mice, the researchers report, were susceptible to intravaginal HIV infection as shown, for example, by a rapid loss of human CD4+ T cells from their blood. However, BLT mice pretreated with antiretroviral drugs (a mixture of emtricitabine and tenofovir disoproxil fumarate) were resistant to intravaginal HIV infection. As in human HIV infections, CD4+ T cells were also depleted in several other organs of the BLT mice after intravaginal HIV infection. Again, this depletion was prevented by antiretroviral pre-exposure prophylaxis. Finally, human CD4+ T cells also disappeared from the gut-associated lymphoid tissue (an important site for HIV replication and CD4+ T cell depletion during human HIV disease) of the BLT mice after infection with HIV.
As with all animal models, any approach that works in humanized BLT mice will still have to be tested in people. Nevertheless, these findings provide preclinical evidence that pre-exposure prophylaxis with antiretroviral drugs may be an effective way to prevent intravaginal transmission of HIV and, therefore, provide valuable support for clinical trials of this approach...."
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.
Funding: This work has been supported in part with federal funds from National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) grants AI028246 (ATH), AI071940, CA082055 and AI039416 (JVG), and the Department of Obstetrics and Gynecology's Tissue Procurement Facility of the University of Texas Southwestern Medical Center at Dallas (NIH grant HD011149). 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.
Academic Editor: Barbara L. Shacklett, University of California Davis, United States of America
Discussion
The present study demonstrates efficient intravaginal HIV-1 transmission in humanized BLT mice that results in a systemic reduction of engrafted human CD4+ T cells and a loss of GALT effector memory human CD4+ T cells, as has been observed in humans [24,38-41]. In addition, we provide evidence of the effectiveness of antiretrovirals for pre-exposure prophylaxis to prevent intravaginal HIV-1 transmission.
In the absence of an effective vaccine or topical microbicide, alternative preventative measures are desperately needed to help block the spread of AIDS. Antiretroviral drugs have considerable potential for preventing HIV-1 transmission [42]. The expectation for pre-exposure prophylaxis is that antiretroviral drugs taken appropriately can prevent HIV infection [4]. There is as yet no clinical evidence for the effectiveness of this approach [43-46]. However, precedent for the administration of antiretrovirals to large populations of individuals at high risk for infection is exemplified by the widespread use of nevirapine for the prevention of mother-to-child transmission of HIV [47,48]. Similarly, if proven safe and effective, pre-exposure prophylaxis together with other behavioral interventions could provide protection to men and women at risk of HIV infection by preventing sexual transmission. Therefore, it is critical to evaluate new prevention methods aimed at the populations at highest risk. Despite the urgency to develop and implement novel approaches capable of preventing HIV transmission, this process has been hindered by the lack of adequate animal models readily available for pre-clinical efficacy and safety testing [49].
We investigated the possibility that BLT mice might serve as an efficient, relatively fast, and cost-effective small animal model of intravaginal HIV-1 infection. We demonstrate that the female reproductive tract of BLT mice is populated with in situ-generated human cells critical for the transmission and dissemination of HIV-1. We observed that a single intravaginal exposure to HIV-1 results in infection in 88% of the exposed humanized BLT mice, demonstrating their susceptibility to vaginal transmission. These observations distinguish the BLT system (with its self-renewing, hematopoietic stem cell-based systemic human reconstitution, including throughout the female reproductive tract) from SCID mice injected with human peripheral blood lymphocyte (SCID-hu PBL) with respect to vaginal HIV-1 transmission [50,51]. The systemic nature of BLT human reconstitution facilitated examination of the pathogenic effects caused by infection in BLT mice. Our analyses revealed that HIV-1 disseminates from the vaginal mucosa to cause systemic CD4+ T cell loss, including GALT CD4+ effector memory T cell loss, as in humans [38]. Thus, humanized BLT mice represent a useful model for HIV-1 intravaginal transmission, systemic spread, and pathogenesis.
We utilized the fact that BLT mice are susceptible to intravaginal HIV-1 infection to demonstrate that this system is well suited for the preclinical evaluation of pre-exposure prophylactic regimens to prevent intravaginal HIV-1 transmission. Our results show that the BLT model can serve as a relatively fast and simple system to test whether pre-exposure prophylaxis can prevent vaginal HIV-1 transmission. Using this system, we found that FTC/TDF can afford complete protection from vaginal HIV-1 transmission. These results suggest that the BLT model could also be suitable for testing topical microbicides. Our results serve as preclinical evidence for the potential success of this approach aimed at preventing the further spread of AIDS.
As with all animal models of human disease, there are limitations to this study. Although our findings are consistent with findings from non-human primate research regarding the potential of pre-exposure prophylaxis to prevent HIV-1 transmission [2,42], neither model has been shown to predict efficacy or safety in humans. This is due to the lack of any kind of data from similar pre-exposure prophylaxis in humans. Therefore, an important limitation is that the BLT model currently has no known predictive value for clinical medicine. It is essential that this and future BLT studies be validated against data from human clinical trials, some of which are ongoing. Variables between humanized BLT mice and humans include possible differences in drug concentrations, in adherence, in renal and liver biology, virus dosage, and coinfections with viruses such as hepatitis B virus. Although many aspects of HIV-1 GALT pathogenesis are recapitulated in BLT mice, we have not determined whether there is a direct and/or indirect pathologic effect of HIV-1 on enterocytes, as seen in humans. Many of these limitations can be addressed in future studies. In the interim, our data support the potential for antiretrovirals in general and FTC/TDF in particular to function as a pre-exposure prophylaxis measure against the spread of HIV/AIDS in humans.
More women are being infected by HIV-1 now than at any other time during the AIDS epidemic. The number of infected women worldwide has increased to almost 15.4 [1]. As a female-controlled prevention measure, antiretroviral pre-exposure prophylaxis and/or topical microbicides could provide women with a powerful tool to protect themselves from infection. However, any candidate drug(s) must be safe, especially in individuals without disease, and efficacious and, in order to be successful, must be easy to use [4]. The combination of FTC/TDF appears to meet the criteria for drugs to be used for pre-exposure prophylaxis [31]. In addition, it is one of the few drug combinations that can be administered once daily without food restrictions. In this report, we provide preclinical evidence regarding the potential efficacy of antiretroviral pre-exposure prophylaxis in humans. Our results should provide further impetus for the continued implementation of clinical trials using oral antiretroviral pre-exposure prophylaxis, particularly in parts of the world with highest HIV prevalence, where pre-exposure prophylaxis would be most beneficial and cost effective.
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