Research Summaries

James E. K. Hildreth
Professor
Director CAHDR

HIV/AIDS is foremost a disease of biology strongly enabled by behavior. The Meharry Center for AIDS Health Disparities Research is based on a 6-year NIH grant to establish a comprehensive HIV research center. The guiding structure of the Center is to pursue biological avenues to this problem, while recognizing that the solution will depend on understanding the behaviors that have contributed to HIV infection and providing the awareness and education to the community to break the cycle. Dr. Hildreth took directorship of the Center in 2005, and brought a strong background of biological and translational insights to the Center both personally and through the outstanding faculty he has recruited to Meharry.

Locally applied biomedical barriers and microbicides have proven ineffectual in preventing sexual transmission of HIV. HIV requires intact lipid rafts, cholesterol-rich subregions in cell membranes, for entry into cells and for budding of infectious particles. Beta-cyclodextrin (β-CD), a cyclic heptasaccharide that removes cholesterol from cell membranes and disperses lipid rafts, has been shown to block HIV infection and abolish infectivity of budding HIV particles. Cholesterol is also required by other pathogens including many viruses, some of which are associated with STDs such as HSV-2. β-CD is non-toxic and in wide human use in food products and as a carrier for drugs. A number of studies in humans and animals have shown that β-CD can be safely applied to mucosal surfaces. Thus properly formulated, this molecule may be a safe microbicide effective against HIV and other pathogens. The central hypothesis of Dr. Hildreth’s work is that because it efficiently depletes cholesterol from lipid membranes thereby blocking virus infection and has an extensive and well-established safety profile in humans, β-CD is an outstanding candidate for use as a topical vaginal HIV microbicide.

During this project we have shown that β-CD blocks HIV infection at the level of cells and virus and we have defined mechanisms by which the compound inactivates virions. We also have shown that β-CD effectively blocked vaginal HIV transmission in a Hu-SCID mouse model. Our studies have identified three criteria essential for the most effective HIV microbicide: inactivate every virus particle; do not disrupt the natural barriers to infection; and do not induce an inflammatory response. In continuing this project we remain focused on mechanisms while optimizing parameters for use of β-CD as an HIV microbicide. The specific aims are: 1. To determine the effects of formulation of β-CD on its anti-HIV-1 activity; 2. To determine the effect of β-CD on vaginal epithelium in vitro and in vivo in mouse and rhesus macaque models; 3. To determine if deleterious effects of β-CD on cell membranes can be attenuated by exogenous lipid; 4. To determine if β-CD is synergistic with other agents in blocking HIV infection. These studies should provide important insights regarding the development of HIV microbicides generally and β-CD in particular. The results should provide the basis for further animal studies and pilot human studies of this novel microbicide candidate.