Research sheds light on heterosexual transmission
Test for potential blocking agents may be possible
HIV investigators have long found it difficult to study the way the virus is transmitted in cervical tissue. Replicating the factors important to heterosexual transmission is not easy, particularly when conducting animal studies.
"People have done work with felines, but felines don’t have the typical cell structure that presents in women’s vagina or cervix," says Phalguni Gupta, PhD, professor in the department of infectious diseases and microbiology at the University of Pittsburgh’s graduate school of public health.
Gupta and co-investigators have found at least one solution to this problem. "What we did was develop an organ culture using squamous cervical tissue from premenopausal women, and we have shown in the culture that it maintains a lot of different properties of cellular structure," he says. "In using these organ cultures, we have shown that you can show transmission across the mucosal layer, and you can even show which of the cells get infected."
Investigators place a dime-size piece of squamous cervical tissue in a top chamber of a transwell device. HIV is added on top of the epithelium layer, and HIV transmission is measured in the bottom chamber. Their technique provides a natural in vivo tissue architecture that includes stratified squamous epithelium, submucosa, and immune cells.1
A model to test agents
The research paves the way for a system that will test the efficacy of antimicrobials and compounds typically applied in the vagina to see if they can block transmission, Gupta adds. "This is a model to test and screen potential agents that block transmission. This will be available for use before a clinical trial."
That possibility could be a significant improvement in the methods currently available for testing antimicrobials designed to prevent HIV transmission during sexual intercourse.
Women’s health activists and international health organizations have promoted microbicide research as a possible solution for women in developing nations who need an agent to block transmission of HIV that is cheap, easy-to-use, and entirely within their own control.
In addition to financing problems, that research has had a number of setbacks, including the recent study that showed the once-believed promising spermicide nonoxynol-9 does not reduce the rate of HIV, gonorrhea, or chlamydia infection in a group of sex workers who used the treatment. The African women involved in the research also were given condoms and had a 90% use rate.
A new model for studying such spermicides within the laboratory could prevent unfortunate results as produced by the nonoxynol-9 clinical trials, Gupta says. "If this organ culture model was available, we could have said, Don’t do these clinical trials, because we have seen these results.’"
The University of Pittsburgh researchers have received a grant from the National Institutes of Health in Bethesda, MD, to test a number of different creams, suppositories, and other products that might be able to block transmission of HIV, Gupta says.
Here are some more details about the research:
• The organ culture system method proved durable. Stratified squamous epithelial layers remained unchanged after one day in culture, although the thickness of the epithelial layer started to decrease after three days. The basal layer of the epithelium remained intact for five to six days in culture, and there was no evidence of necrosis or autolysis in the tissues.1
• The model demonstrated transmission of infectious HIV-1 across the mucosal barrier. When HIV-1 was inactivated by ultraviolet irradiation, it was not transmitted.1
• Between 20% and 30% of tissues did not support HIV-1 transmission in this organ culture system, supporting the theory that not all exposures result in infection.1
• An estimated risk of HIV infection for every vaginal exposure to infected semen is only about 0.01%, according to Rhesus macaque studies.1
• The model’s results in a localization of cells expressing HIV-1 immediately below the epithelial layer were similar to those of the Rhesus macaque studies.1
• The model may be very useful in determining the types of cells that become infected initially during heterosexual transmission of HIV-1.1
• The model can help determine whether transmission efficacy is higher with cell-free virus or cell-associated virus, and it can be used to determine whether viral transmission is dependent on the phenotypic and genotypic properties of HIV-1.1
Gupta says additional research using this model might be able to determine at which stages of a woman’s menstrual cycle she is more susceptible to HIV transmission.
Reference
1. Collins KB, Patterson BK, Naus GJ, et al. Development of an in vitro organ culture model to study transmission of HIV-1 in the female genital tract. Nat Med 2000; 6:475-479.
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