Antiretroviral Pre-exposure Prophylaxis Prevents Vaginal Transmission of HIV-1 in Humanized BLT Mice

Abstract

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.

Abstract

J. Victor Garcia and colleagues show that mice with immune systems reconstituted from human bone marrow, liver, and thymus transplants provide a model for prevention of intravaginal HIV infection.

Editors' Summary

Background.

Since the first cases of acquired immunodeficiency syndrome (AIDS) in 1981, the AIDS epidemic has spread rapidly. About 33 million people are now infected with the human immunodeficiency virus (HIV), the cause of AIDS. More than half of newly acquired infections now occur in women, mostly through unprotected vaginal sex with an infected male partner. Women are biologically more susceptible than men to HIV infection during vaginal intercourse and often cannot persuade their partner to use a condom. Consequently, alternative strategies that prevent intravaginal transmission of HIV (infection through the vagina) are urgently needed, particularly strategies that women can use without their partner's agreement. A vaccine would be ideal but it could be many years before an effective HIV vaccine is available so researchers are investigating other preventative strategies such as the use of microbicides—compounds that protect against HIV when applied inside the vagina—and pre-exposure treatment (prophylaxis) with antiretroviral drugs.

Why Was This Study Done?

Before any new strategy to prevent intravaginal HIV transmission is tried by women, it has to be tested in animals. Currently, this can only be done in macaques, an expensive option. In this study, the researchers have investigated whether “humanized BLT” mice could be used instead. When HIV enters the human body during vaginal intercourse, it sticks to dendritic cells (a type of immune system cell) in the vaginal lining. These cells carry the virus to the body's lymphoid tissues (collections of immune cells), where it infects and kills CD4 ⁺ T cells (another type of immune cell). Dendritic cells and CD4 ⁺ T cells have molecules on their surface that HIV recognizes. Mice are not normally susceptible to infection with HIV because their immune system cells lack these molecules. Humanized BLT mice have a nearly human immune system—BLT stands for bone marrow, liver, thymus. They are produced by implanting pieces of human fetal liver and thymus (the organ where T cells learn to recognize foreign invaders) under the kidney capsule of immunodeficient mice (animals born without an immune system) and then transplanting human hematopoietic stem cells (the source of the major immune system cells) into the mice.

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.

What Do These Findings Mean?

These findings show that humanized BLT mice are susceptible to intravaginal infection with HIV and that many aspects of HIV infection in these mice closely mimic infection in people. In addition, by showing that pre-exposure prophylaxis with antiretroviral drugs prevents HIV infection, these results suggest that humanized BLT mice could be used to test new strategies designed to prevent intravaginal infection. 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.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050016.

• Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and on HIV infection in women

• HIVInSite has comprehensive information on all aspects of HIV/AIDS, including articles on women and HIV and on safer sex, which includes information on pre-exposure prophylaxis and microbicides

• Information is available from Avert, an international AIDS charity, on HIV prevention, on women, HIV, and AIDS, and on microbicides

• The US Centers for Disease Control and Prevention provides information on HIV/AIDS, including information on HIV/AIDS among women and on CDC trials of pre-exposure prophylaxis for HIV prevention (in English and some information in Spanish)

• PrEP Watch is a comprehensive information source on pre-exposure prophylaxis for HIV prevention