A difference in the anatomy of the rectum and vagina may explain, in part, why anal intercourse is up to 10 times more likely than vaginal intercourse to result in HIV infection. This finding by investigators at the School of Public Health could help in the development of new microbicides against HIV.

The higher risk of HIV transmission among men who have sex with men has long perplexed physicians and researchers. They have been looking for answers since the AIDS epidemic began more than 20 years ago. “We decided to look at the cells that could be mediating this transmission on the mucosal surface,” said Akiko Iwasaki, Ph.D., assistant professor of epidemiology.

The key to viral entry, she found, lies in the location of the dendritic cells that express a protein called DC-SIGN in the vaginal and rectal mucosa. “The barrier between the outside world and the inside of the rectum is one single cell deep, whereas in the vaginal tract the barrier is 20 to 25 cells thick, depending on the stage of the menstrual cycle,” Iwasaki said. “We think that this difference, together with the abundance of DC-SIGN-expressing cells in the rectum, might explain the differences in risk.”

That 25-cell barrier is a daunting challenge to HIV, which must cross it to reach dendritic cells and begin its infectious process. Dendritic cells typically act as sentinels, alerting the immune system to the presence of microbial invaders. In the normal course of events, dendritic cells take microbial prisoners and present them to T lymphocytes, which then learn to recognize and repel them. HIV exploits that process by binding to DC-SIGN, then turning the dendritic cells into Trojan horses that carry the virus to the lymph nodes, where it replicates. “The clever thing about this is that when the virus binds to the DC-SIGN molecule, it is protected from degradation,” Iwasaki said.

DC-SIGN is highly expressed on dendritic cells near the surface of the rectum. In the vagina, however, the only dendritic cells that express DC-SIGN are underneath the skin covering the vaginal tract—25 cells away from the outside world.

Women with sexually transmitted infections such as herpes simplex or syphilis are also at higher risk of HIV infection, Iwasaki said, because the resulting inflammation brings T cells to the surface, where they can be targeted by the virus.

Iwasaki, who came to Yale two years ago from the National Institute of Allergies and Infectious Diseases, has long been interested in the mechanisms of viral transmission and their relevance to sexually transmitted disease. Her findings raise the possibility of a mechanism for a microbicide that would thwart the binding of HIV to DC-SIGN. The DC-SIGN molecule recognizes and binds to a sugar molecule on the viral envelope protein. A microbicide could act by binding another sugar to DC-SIGN, thereby blocking HIV, Iwasaki said.

The study was published in the February issue of the Journal of Virology. The research was conducted in collaboration with Robert Doms, M.D., Ph.D., at the University of Pennsylvania.