Mouse Model Of HIV Can Yield Useful Information
A new kind of laboratory mouse can be used to test the efficacy of much-needed methods to prevent transmission of HIV, the virus that causes AIDS, according to research by J. Victor Garcia and colleagues at the University of Texas Southwestern Medical Center in Dallas.
The findings demonstrate the utility of such mice for animal testing of pre-exposure antiviral drugs to protect against HIV infection. Such mice also provide a new way of evaluating microbicides and other prevention approaches that have generally required testing in macaques, using viruses that are related, but not identical, to HIV.
Unmodified mice cannot be infected with HIV. Earlier laboratory-modified mice, such as the SCID-hu mouse, contain human thymic tissue that can only become infected after direct injection, but not through any of the natural routes of HIV transmission in humans including the genital route. However, of the 2.5 million newly acquired HIV infections estimated to have occurred in 2007, more than half were in women, mostly through unprotected vaginal sex with an infected male partner.
The new development involves “BLT” mice, which have been transplanted with human blood cells, liver, and thymus tissue. The researchers found that human cells necessary for HIV infection distributed themselves in the female reproductive tract of BLT mice, rendering them susceptible to vaginal infection with HIV. They also found that infection spread to other organs in a way that resembles the course of HIV infection in humans. Finally, they showed that vaginal infection could be blocked by treating the mice with antiretroviral drugs that are currently being evaluated as pre-exposure prophylaxis (PrEP) — a possible means of HIV prevention in humans at risk for sexual exposure to HIV.
These findings support the promising results of PrEP studies from established, but costly, macaque models. Whether the BLT mouse — or any animal model — provides a reliable predictor of HIV prevention in humans can only be determined by comparison of animal experiments to actual human trials.
The paper is discussed in a related perspective article by Barbara Shacklett (University of California Davis), entitled “Can the New Humanized Mouse Model Give HIV Research a Boost?” At this stage, says Dr Shacklett, “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.”
PLoS Med 5(1): e16 doi:10.1371/journal.pmed.0050016
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
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).
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.