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.
Highlights
human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), is predominantly transmitted by unprotected sexual contact [1]
We show that the female reproductive tract of humanized bone marrow–liver–thymus (BLT) mice is reconstituted with human CD4þ T and other relevant human cells, rendering these humanized mice susceptible to intravaginal infection by HIV-1
The utility of humanized mice to study intravaginal HIV-1 transmission is highlighted by the demonstration that pre-exposure prophylaxis can prevent intravaginal HIV-1 transmission in the BLT mouse model
Summary
HIV, the causative agent of AIDS, is predominantly transmitted by unprotected sexual contact [1]. 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 [1]. The only surrogate animal model used to study intravaginal HIV transmission are macaques infected with simian immunodeficiency virus (SIV) or SIV/HIV (SHIV) chimeric viruses [6,7]. This model recapitulates several aspects of human infection, but does not support HIV-1 replication. More than half of newly acquired infections occur in women, mostly through unprotected vaginal sex with an infected male partner. 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
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