Their studies, the first to demonstrate that the AIDS virus infects normal tissues throughout the female reproductive tract, could help unlock new approaches for AIDS treatment and prevention.
The implications are far-ranging. Vaccine development and disease prevention should aim to confer protection throughout the female reproductive tract and the right protocols could exclude the AIDS virus from the body by containing and destroying it within the tract.
The researchers have discovered that HIV, the AIDS-causing virus, can invade cells within any female reproductive tract organ--vagina, cervix, uterus, fallopian tubes--meaning that the entire tract is at risk. Until now, infection was presumed to occur when cells infected with HIV or HIV itself entered the body through the vagina or cervix.
A team headed by immunologist Alexandra Howell, a medical school research associate professor at the White River Junction VA, reported their results in the May issue of the Journal of Virology. Colleagues include Charles Wira, Michael Fanger, Grant Yeaman, Robert Edkins, Sherry Rier and Judy Stern.
"Our findings suggest that efforts to control heterosexual transmission of HIV-1 should include protection at all sites, not just the lower reproductive tract," Howell said.
Howell and her colleagues are part of a broad Dartmouth Medical School collaboration that is exploring immunity in the female reproductive tract to learn how hormones regulate protection.
The program, headed by co-author Wira, focuses on the lining of the female reproductive tract organs. This mucosa constitute a remarkably diverse protective system that fluctuates with the reproductive cycle and functions differently in each organ, offering some intriguing clues to disease susceptibility and protection.
As Wira explained, "Until this time, we thought that HIV infection was through a tear in the vaginal mucosa that allows virus to contact the blood, or after cells in the vagina pick up virus and transfer it to the body. These studies indicate that not only do cervical and vaginal cells have the potential to become infected, but so do uterine and fallopian tube cells." Virus may travel up the reproductive tract either free or in association with sperm and non-motile cells that are known to reach the fallopian tube, the site of fertilization.
The Dartmouth team obtained reproductive tract tissues from normal women undergoing hysterectomy for medical reasons. In the laboratory, they infected tissue sections as well as single cells from each organ with several strains of the human immunodeficiency virus-type 1 (HIV-1). They found that HIV-l infected cells at all sites, including the upper tract (fallopian tube) and that it infected other types of cells besides T cells and macrophages.
The researchers are currently examining whether female sex hormones, whose levels fluctuate during the normal menstrual cycle, alter susceptibility to HIV-1. The investigation builds on related Dartmouth findings that immune protection in the uterus is turned off during the latter part of the menstrual cycle, when implantation occurs. "This may mean that women are more susceptible to HIV infection during certain stages of the menstrual cycle," Howell said.
Linking results of several projects, Wira sets a possible scenario. "Hormonal changes during the menstrual cycle may create a window of opportunity for HIV infection via the uterus. Studies by (microbiologist) Hillary White, a program member, suggest that immune cells that would normally kill virally infected cells are shut down during the second half of the menstrual cycle when implantation is most likely to occur. HIV, which may be in the ejaculate, can enter into the uterus. Uterine surface cells not only become infected, but transmit virus systemically."
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