Date Published: January 15, 2008
Publisher: Public Library of Science
Author(s): Paul W Denton, Jacob D Estes, Zhifeng Sun, Florence A Othieno, Bangdong L Wei, Anja K Wege, Daniel A Powell, Deborah Payne, Ashley T Haase, J. Victor Garcia, Barbara L Shacklett
Abstract: BackgroundWorldwide, 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 FindingsWe 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).ConclusionsThe 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.
Partial Text: HIV, the causative agent of AIDS, is predominantly transmitted by unprotected sexual contact . Currently, women worldwide account for more than half of the estimated 6,800 newly acquired infections every day, with a majority of those transmissions occurring via the vaginal route . Therefore, it is critical that strategies to prevent vaginal transmission of HIV be developed and implemented.
The FRT represents a highly specialized and complex anatomical site where initial infection occurs following intravaginal exposure [25–27]. Therefore, we used immunohistochemistry to determine whether human lymphocytes and other cells important for HIV-1 infection were present in the vagina, ectocervix, endocervix, and uterus after reconstitution of BLT mice with human HSC. All populations of human cells necessary for HIV-1 infection (CD4+ T cells, macrophages, and dendritic cells) were found to be abundant throughout the FRT of BLT mice (Figure 1). Specifically, human CD4+ cells were distributed throughout the FRT. Also, human CD68+ monocyte/macrophage cells and clusters of human CD11c+ dendritic cells were identified throughout the FRT. Together, these data establish that in situ differentiation of human HSC leads to reconstitution of the FRT of BLT mice with the human hematopoietic cells relevant to mucosal HIV-1 transmission [28–30].
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.