CHICAGO --- Women with sexually transmitted disease or elevated progesterone levels who have unprotected sex with an HIV-positive man significantly increase their risk for also contracting HIV, according to a study by Northwestern University Medical School scientists.
Northwestern AIDS researcher Bruce K. Patterson, M.D., and colleagues published results of the study in the August issue of the American Journal of Pathology.
The research group showed that sexually transmitted diseases, such as herpes, human papillomavirus, chlamydia and genital ulcer disease, and elevated progesterone levels increase certain chemokine receptors for HIV in the female genital tract.
Chemokine receptors are protein molecules on the surface of host cells that play an integral role in mounting the body?s immune response to infection. Two chemokine receptors, CCR5 and CXCR4, enable HIV to enter and infect cells involved in the immune response.
First, a cell surface protein on the HIV virus, gp120, attaches to a receptor known as CD4 on infection-fighting T cells. But for HIV to enter and infect T cells, a chemokine co-receptor is required. After binding to the CD4 receptor, HIV undergoes changes that allow it to bind to the chemokine receptor. The chemokine receptor then passes the gp120-CD4 complex through the T cell membrane, while part of the HIV envelope protein passes the HIV virus into the T cell.
Strains of HIV that use the chemokine receptor CCR5 are most often found early in the course of disease in an HIV-infected person. HIV strains that act later use CXCR4.
Male-to-female transmission of HIV, which is now the leading mode of transmission worldwide, involves exposure of virus in semen to cells in cervical and vaginal mucus membranes. Many studies have noted a gender imbalance for heterosexual HIV transmission that places women at greater risk for acquiring HIV from infected male partners. And related research has demonstrated an increased rate of HIV infection in women older than 45.
But aside from gender, other factors may increase susceptibility to HIV-1 infection, including co-infection with sexually transmitted diseases and genital ulcers, as well as hormonal influences, Patterson said.
Post-menopausal women have higher levels of progesterone relative to estrogen, compared with normal premenopausal women, in whom estrogen predominates in the first two weeks of the menstrual cycle. Hormone replacement therapy with progesterone alone also increases progesterone levels.
Additionally, laboratory studies have shown that progesterone enhances transmission of simian immunodeficiency virus, presumably by allowing more of the virus to move through the thinned vaginal tissues that occur in menopause.
Patterson and his research group wanted to determine the factors that influence the expression and regulation of HIV co-receptors in human tissue. Specifically, they looked at whether sexually transmitted disease and/or progesterone increase either the number of target cells present, the immune response or expression of cell type-specific chemokine receptors that are necessary for HIV-1 infection.
They used immunological and extremely sensitive molecular methods to determine expression levels of CCR5, CXCR4 and other chemokine receptors in circulating blood and cervical biopsy specimens of 12 women with and without sexually transmitted disease, genital ulcer disease and progesterone-predominant conditions.
Their results showed that CCR5 is the major HIV co-receptor expressed in cervical tissues and CXCR4 is the major co-receptor in the circulating blood in women with HIV and human papillomavirus or progesterone-dominant conditions.
Because CCR5 chemokine receptor expression is confined primarily to the cervicovaginal tract rather than the blood, therapy should be directed at decreasing sexual transmission by blocking chemokine receptors in genital tissues, Patterson said.
"Understanding the dynamics of male-to-female HIV sexual transmission is critical to designing effective prevention strategies," he said.
Patterson is an assistant professor of obstetrics and gynecology and of medicine and a specialist in viral pathology at Northwestern University Medical School. His co-researchers on this study were Alan Landay, associate professor of immunology/microbiology at Rush Medical Center, Chicago; Jan Andersson, M.D., professor of immunology, microbiology and pathology at the Karolinska Institute, Stockholm, Sweden; and Clark Brown, Homira Behbahani, Dan Jiyamapa, Zareefa Burki, Donna Stanislawski, Mary Ann Czerniewski and Patricia Garcia, M.D., assistant professor of medicine, at Northwestern University Medical School.
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Journal
American Journal Of Pathology