Men, women and the risk of AIDS

The adhesion molecule that protects HIV from degradation is expressed differently in the rectum and vagina.

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.

Link between cocaine and self-control emerges from primate study

Cocaine users have trouble with self-control and decision making, even after they’ve given up the drug, according to a study by researchers at the School of Medicine. “It’s thought that this impairment in inhibitory control may contribute to certain aspects of drug abuse, such as craving, bingeing and risky behaviors,” said Jane R. Taylor, Ph.D., associate professor in the division of molecular psychiatry and senior author of the study, published in the February issue of Neuropsychopharmacology.

In a study of primates funded by the National Institute on Drug Abuse, Taylor and colleagues investigated whether an impairment in the orbitofrontal cortex leads to drug abuse, or whether it develops as a consequence of drug abuse.

The primates were trained to recognize that food was available under only one of three objects. Then the food was placed under a different object. The primates had to inhibit their learned response and choose the other object. Unlike the control animals, primates injected with cocaine were not able to inhibit their initial response and continued to reach for the original object. “While these deficits could be interpreted as indicating that addicts have an underlying orbitofrontal dysfunction that predisposes them to drug abuse, our results indicate that prior cocaine exposure is sufficient to produce cognitive defects reminiscent of orbitofrontal cortical dysfunction,” the researchers wrote. “The frontal-lobe impairments in drug abusers may be a consequence of, as well as a predisposing factor to, addiction.”

Et cetera

Case of the vanishing virus

Viruses that leave no molecular fingerprints as they destroy brain cells may be behind certain psychiatric and neurological disorders, according to Yale investigators. In a test of their hypothesis they introduced a recombinant virus, vesicular stomatitis virus, into an adult mouse through its nose. The virus, which is not dangerous to humans, traveled down the olfactory nerve, into the periglomerular neurons, past the mitral cell layer, through granule cells and toward the brain’s subventrical zone. Then it vanished.

“In young mice, the virus may get past the olfactory system and then may selectively infect and damage other brain regions such as the locus coeruleus and dorsal raphe that are the targets for many psychiatric medicines,” said Anthony N. van den Pol, Ph.D., professor of neurosurgery and lead author of the study, published in February in the Journal of Virology. “The virus can be eliminated by the immune system and leave no trace in the brain, but nerve cells in very specific areas of the brain are lost. This is a potential model for viruses that may infect the brain at one stage of life, and then disappear, but potentially cause long-lasting psychiatric and neurological dysfunction.”

How Legionella subverts the cell

Of the 35 species of Legionella bacteria, one is implicated in most outbreaks of Legionnaires’ disease, a severe pneumonia. Now researchers at Yale have revealed how that bacterium, L. pneumophila, subverts the normal functions of cells in order to replicate.

During infection the bacterium travels to the lungs and invades alveolar macrophages, white blood cells which normally hunt down and destroy bacteria. L. pneumophila injects a protein into the macrophage that thwarts its transport to lysosomes, where the bacterium would be destroyed. Instead, the bacterium moves to the nutrient-rich endoplasmic reticulum, where it replicates. “These results show that the Legionella bacteria have the ability to inject a bacterial protein directly into macrophages during infection,” said Craig R. Roy, Ph.D., associate professor of microbial pathogenesis. The results were published in the January 25 issue of Science.


			Originally published in Yale Medicine, Summer 2002. Copyright © 2002 Yale University School of Medicine. All rights reserved.