Date Published: January 15, 2008
Publisher: Public Library of Science
Author(s): Barbara L Shacklett
Abstract: The “BLT mouse” holds promise for the preclinical evaluation of microbicides and antiretroviral prophylaxis regimens.
Partial Text: Over the last few months, the medical community has received both good and bad news concerning the AIDS epidemic. The “good” news: the number of individuals infected with HIV worldwide was revised downward and was estimated at 33 million rather than 40 million ; although lower than expected, this still represents a staggeringly high figure. The bad news: two highly publicized vaccine trials were prematurely terminated due to a high frequency of seroconversions among vaccine recipients . The obvious message from both of these reports is that more research is needed to uncover better strategies for preventing HIV transmission and more effective treatments for those already infected.
Infection of rhesus macaques with simian immunodeficiency virus (SIV) has provided an excellent nonhuman primate model for studying HIV pathogenesis (reviewed in ). SIV is closely related to HIV on a molecular level, its replication may be inhibited by many of the same antiretroviral compounds, and it induces an acquired immunodeficiency syndrome (AIDS) that mimics human AIDS in many important respects. SIV can also be transmitted experimentally to rhesus macaques across the cervicovaginal or rectal mucosa, providing a means of testing microbicides as well as studying the earliest events involved in mucosal transmission. However, the SIV model also has two major disadvantages. First, rhesus macaques are costly and in high demand, and must be housed in accredited primate facilities; there are a limited number of such facilities nationwide. Second, despite its similarity to HIV, SIV and HIV differ in numerous subtle ways, including genetic organization (for example, the Vpx gene is unique to SIV; Vpu is unique to HIV) and disease course (simian AIDS generally develops within six to 12 months of infection with SIV, while it can take many years for human AIDS to develop after infection with HIV).
Rodent models for HIV infection are appealing for a number of reasons. Rodents are inexpensive, reproduce quickly, and may be housed in large numbers in a fairly small facility. Experiments may be set up with a large number of replicates. However, several barriers have historically prevented the establishment of a satisfactory rodent model for HIV infection. First, and most importantly, although mice and rats are hosts for a number of retroviruses that are distantly related to HIV, rodent cells are nonpermissive for HIV infection. Attempts to engineer rodents that are permissive for HIV replication and dissemination have been only partially successful . Rats stably expressing human CD4 and CCR5, the major receptor and coreceptor for HIV-1, respectively, are partially permissive ; addition of the human cyclin T1 gene further enhances HIV gene expression, but additional barriers remain .
In a new study published in PLoS Medicine, Paul Denton and colleagues have extended these findings to show that the female reproductive tissues of BLT mice are adequately reconstituted with HIV-susceptible human CD4+ T cells, as well as other relevant populations . Atraumatic intravaginal exposure of these mice to HIV-1 led to systemic HIV-1 infection coupled with a rapid loss of human CD4+ T cells from the gastrointestinal mucosa, now known to be a hallmark of acute HIV infection in humans and of SIV infection in macaques. In their study, vaginal HIV infection could be prevented by pre-exposure prophylaxis using a combination of emtricitabine and tenofovir disoproxil fumarate. Thus, this proof-of-concept study shows that the BLT mouse holds promise for the preclinical evaluation of microbicides and antiretroviral prophylaxis regimens.
From the perspective of a basic scientist searching for improved animal models in which to study human disease, the present study represents a clear advance in the field. However, given the uncertainties that remain, the BLT mouse is unlikely to replace the SIV model for studying pathogenesis and transmission. At this stage, the most prudent approach is to consider the new humanized rodents and the more established, nonhuman primate models as complementary systems, both of which can yield useful information but neither of which is infallible.