Of the 38 million people worldwide living with HIV, roughly 700,000 are newly infected men, primarily via sexual transmission. Sexually transmitted HIV infections in exclusively heterosexual men are acquired through the penis. As well as, semen which is produced within the male genital tract (MGT) has been recognized as the first vector for vaginal and rectal HIV transmission. Notably, the danger of sexual HIV transmission increases with the presence of a concurrent sexually transmitted infection.

For the vast majority of patients, antiretroviral therapy (ART) rapidly decreases the viral load in blood and semen, and this leads to a dramatic reduction in HIV transmission. Nonetheless, in some individuals with an undetectable plasma viral load, HIV and HIV-infected cells may persist in tissues despite ART. Subsequently, the origin of virus present in semen is extremely relevant to the implementation of recent therapies aimed toward effectively reducing HIV transmission. Yet the direct evaluation of HIV infection throughout your complete MGT has not been possible, until now.

Led by Martina Kovarova, PhD, member of the laboratory of J. Victor Garcia, PhD, a team of researchers on the International Center for the Advancement of Translational Science and Institute for Global Health and Infectious Diseases at UNC addressed three critical problems with HIV transmission: how is HIV acquired via the penis; where is HIV produced within the MGT; and might penile HIV acquisition be prevented? For this they implemented a novel in vivo model that allows, for the primary time, an in depth evaluation of HIV infection throughout your complete male genital tract. Using this mouse model, the team showed that productive HIV infection occurs in all of the organs that comprise the male genital tract, leading to a dramatic reduction in human CD4 T cells, key components of the immune system present in these organs.

Previous work addressing HIV infection in men was deal with rectal transmission and its prevention. The importance of this study is that it addresses a unique mode of HIV transmission that’s of fundamental importance to HIV prevention in heterosexual men. We have now established the sites of HIV production throughout your complete male genital tract, demonstrated how it could actually be suppressed, and that pre-exposure prophylaxis with an antiviral drug can prevent penile HIV infection.”

J. Victor Garcia, PhD, Director of the International Center for the Advancement of Translational Science at UNC and senior creator of the study

The study approach began with an in depth evaluation of your complete MGT (foreskin, urethra, glans, epididymis, seminal vesicles, prostrate, and testes) for the presence of human immune cells. Results showed that your complete MGT of those mice was repopulated with human T and myeloid cells, essential targets of HIV infection. The investigators demonstrated that whatever the route of infection HIV is produced in all tissues of the MGT and that HIV production might be efficiently suppressed by treatment with the antiviral drug EFdA (4′-Ethynyl-2′-fluoro-2-deoxyadenosine). Drug treatment had the additional advantage of restoring the degrees of CD4+ T cells throughout the MGT and other tissues.

Having established the susceptibility of the cells within the MGT to HIV infection the investigators determined if HIV infection on this model could occur after direct exposure to HIV via the penis. Direct penile exposure to HIV led to HIV replication throughout the MGT, systemic infection and depletion of CD4+ T cells in all tissues analyzed. The investigators then determined whether treatment with EFdA prior to direct penile exposure could prevent HIV infection. Their results demonstrated that pre-exposure prophylaxis with EFdA administered orally can efficiently prevent HIV acquisition via the penis.

“EFdA is a brand new highly effective anti-HIV drug that we used as a tool to directly exhibit the nice potential of pre-exposure prophylaxis to stop penile HIV infection. Consistent with the essential concept of treatment as prevention pioneer by Myron Cohen, MD Director of the Institute for Global Health at UNC and co-author of this paper, our work also shows the efficient suppression of HIV replication throughout your complete MGT by antiretroviral treatment” said Martina Kovarova, PhD, first creator on the study. “We’ll have the opportunity to make use of this animal model to review the mechanism of HIV acquisition and HIV transmission via the MGT. This can even allow us to guage latest strategies for HIV treatment normally and for HIV prevention after penile exposure.”

The research team also included Sarah E. Wessel, Claire E. Johnson, Shelby V. Anderson, Mackenzie L. Cottrell, and Craig Sykes.