January 15, 2002
Scientists Succeed in Blocking Transmission of Cell-Associated AIDS Virus
Scientists at the Johns Hopkins Bloomberg School of Public Health and their colleagues have made a significant advance in understanding how to block the transmission of the AIDS virus from one sexual partner to another. They have developed a mouse model that allows them to identify and test agents that can stop the migration of white blood cells in semen or cervical mucus that are carrying the human immunodeficiency virus (HIV) nested within them. Using this animal model, the authors have already identified one compound that blocks this type of HIV transmission. The study appears in the January 15, 2002, issue of the Journal of Clinical Investigation.
HIV is transmitted between sexual partners in two principal ways. First, it is transmitted by the "naked" virus itself when it enters the body of an uninfected sexual partner during intercourse. Until now, most efforts to prevent HIV transmission have focused on ways of killing naked, cell-free HIV, which, for example, can be eliminated by the antibodies generated by vaccines. A second, less well known mode of transmission is by cell-associated viruses, viruses that hide inside normal white blood cells and are carried Trojan horse-style into the body. These cell-associated viruses may not be blocked by a vaccine that targets the naked virus.
First author Kristen Khanna, PhD, a research associate in the Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health, notes, "While considerable effort has been directed toward the identification of intervention strategies such as vaccines directed against cell-free viruses, there has been little effort to identify strategies for interrupting the migration of cells that are infected with HIV. We know that such infected cells are present in semen and vaginal secretions of infected individuals and many studies suggest that cell-associated transmission of HIV may, in fact, be more efficient that transmission of cell-free virus. We believe that any successful intervention therapy against the AIDS virus should include a component that can block infected-cell migration into the sexual partner."
Efforts to block cell-associated HIV transmission have been stymied by the lack of an animal model that could mimic this type of transmission. In the present study, the researchers tell how they developed a mouse that is susceptible to the vaginal transmission of cell-associated HIV, but that is not susceptible to infection by cell-free virus. "These animals," said Richard Markham, MD, a professor of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health and senior investigator on the studies, "allowed us to examine the process of cell-associated HIV-1 transmission in the absence of the possibility that cell-free viruses were also contributing to the infection."
Armed with their new animal model, the scientists were quickly able to identify a candidate agent that was highly effective in interrupting vaginal transmission of cell-associated HIV. The researchers focused on a cholesterol-depleting agent, beta-cyclodextrin (beta-CD), shown previously in the laboratory of co-author Dr. James Hildreth, an associate professor in the Department of Pharmacology, Johns Hopkins School of Medicine, to interfere with the ability of cell-free virus to establish infection. The authors found that application of beta-CD within the vagina of the mouse prior to inoculation with HIV-infected cells dramatically reduced transmission.
Moreover, beta-CD, a water-soluble carbohydrate sometimes used as a food additive, was substantially less toxic to the vaginal wall than the widely used spermicide nonoxynol-9. "Beta-cyclodextrin could therefore be a safe solution to the problem of infection by cell-associated HIV. It is particularly appealing because it offers a method of disease prevention that could be controlled by women," said Markham.
In summary, the authors state, "The current studies indicate that the mouse model of vaginal transmission of cell-associated virus provides a simple and inexpensive model to identify agents that may be necessary components of vaginal products for preventing the sexual transmission of HIV. These studies demonstrate that beta-CD significantly blocks vaginal transmission of cell-associated HIV-1 and warrants further study in the preclinical and clinical settings."
Support for this study was provided by the National Institute for Allergy and Infectious Diseases and the National Institute on Drug Abuse.