Microbicides, vaccines may need to repel HIV contact at mucosa

Keith Alcorn
Published: 09 April 2010

HIV can damage the walls of cells in the mucous membranes in the genital tract and the intestines, permitting the virus to pass across these barriers and infect vulnerable cells below, even when the tissue is undamaged, Canadian researchers report this week in the journal PLoS Pathogens.

The findings suggest that microbicides and vaccines may have the greatest chance of success if they can limit or prevent completely contacts between HIV's gp120 surface protein and cells in the mucous membranes of the genital tract and the intestines.

The events taking place when HIV comes into contact with mucous membranes and the immune reactions that occur within the mucosa are a critical area of research for scientists hoping to develop new methods of preventing HIV infection. All sexual transmission of HIV occurs through mucous membranes.

In their research the group from McMaster University, Ontario, with colleagues from the University of Toronto and Laval University found that in the test tube HIV’s envelope protein gp120 stimulated production of inflammatory cytokines in mucous membrane cells which made the membrane more permeable.

The authors say that this mechanism could allow HIV to enter cells below the mucous membrane surface even when it is undamaged, and may also explain why bacteria `translocate` across the intestinal wall in people with HIV more frequently than in uninfected people.

This translocation of bacteria is responsible for immune activation in people with HIV, in the view of some researchers, and may drive not only HIV disease progression but also the development of serious conditions such as atherosclerosis which are promoted by the inflammatory state that exists in people with highly activated immune systems.

Previously researchers into HIV transmission had thought that transmission was most likely to occur either when the mucous membrane was damaged (for example through trauma or ulceration) or when many activated immune cells were present (such as during a sexually transmitted infection like gonorrhoea).

But the McMaster University group found that HIV can weaken the integrity of surface cells, even when they are undamaged.

"What it does is that it makes the electrical barrier resistance of epithelial cells decrease. By doing that, the virus can cross the barrier," said lead researcher Charu Kaushic, associate professor in the Centre for Gene Therapeutics at McMaster University.

Scientists have been faced with the question of how HIV actually gets underneath epithelial cells to infect other cells that are susceptible to HIV. "It's not the cells on top," Kaushic said. "It is the immune cells underneath that have all the receptors that HIV likes to latch on to and that allow the virus to replicate and establish infection. But it has to cross the epithelial barrier first!"

The McMaster researchers grew purified primary epithelial cells in the laboratory from small pieces of tissues that were removed from women's uterus during hysterectomies, with their consent. Then, they began to study how HIV actually interacts with these cells. The electrical resistance in these cultures is used to monitor how well the epithelial cell cultures are growing and functioning.

Aisha Nazli, a researcher in Kaushic's laboratory, noticed every time she put HIV on epithelial cells their resistance went down significantly. Repeated tests confirmed this.

Kaushic said the surface protein of the virus causes the epithelial barrier to break. "The surface protein signals to the inside of the epithelial cells by binding to it", she said. "The epithelial cells start making inflammatory proteins which cause these cells to go on their self-destructive pathway."

The researchers say that providing viral load and exposure time are sufficient, HIV can probably disrupt any mucosal barrier in the body, although infection may not necessarily occur every time.

"This is a significant step forward in defining where prevention strategies, such as microbicides and vaccine, need to focus. Instead of trying to stop HIV from infecting the target cells underneath the epithelium, we need to think about ways to stop the virus from attaching to epithelial cells themselves," said Charu Kaushic.

Reference

Nazli A et al. Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PLoS Pathogens 6 (4): e1000852, 2010.

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