April 12, 2011
Dr. Paul Denton (left) at UNC-Chapel Hill, with Dr. Victor Garcia-Martinez, has created a "humanized" mouse model that could greatly assist research into HIV prevention for women.
Two widely reported clinical trials in 2009 and 2010 demonstrated that HIV vaccines as well as anti-HIV drugs used as microbicides have the potential to reduce the global spread of HIV among women. But the potency of both methods as currently used is quite modest. In addition, our ability to build upon these initial successes is hampered by the huge expense of such trials, which must be conducted with hundreds if not thousands of volunteers.
amfAR fellow Dr. Paul Denton and colleagues from the University of North Carolina at Chapel Hill have now designed a mouse model that could greatly assist in these efforts. Writing in the March issue of the Journal of Reproductive Immunology, Denton observes that developing vaccines and microbicides capable of more completely protecting women against sexual acquisition of HIV requires a better understanding of the critical events at the site of HIV exposure: the female reproductive tract. Testing biopsy tissues obtained from women in a test tube or using an ordinary animal model can only go so far because these systems fail to take into account key aspects of human biology that may influence HIV infection, such as female hormones, local immune responses, and viral spread into adjacent tissues. A small animal with the immune features of a human female reproductive tract would dramatically boost research efforts to find ways to prevent HIV transmission.
Recently Denton and colleagues developed a mouse reconstituted with human immune system-forming stem cells -- that is, the mouse was partially "humanized" following receipt of fetal human liver and thymus gland cells. An abundance of human immune system cells, particularly CD4+ T cells, macrophages, and dendritic cells, were then found throughout the vagina, cervix, and uterus of these animals, and they were rendered susceptible to vaginal infection with HIV.
Following vaginal infection, these humanized mice went on to exhibit the immune system signs characteristic of total body infection as seen in humans, including loss of CD4+ T cells in the intestines and blood. Even more promising, pre-treatment of other mice with the same two anti-HIV drugs being studied to prevent HIV infection in humans, emtricitabine and tenofovir, provided complete protection against vaginal challenge with a high dose of HIV.
Denton and associates conclude with a strong statement. These animals provide the field of HIV research "with a powerful new tool," they feel. "This model permits study of the earliest events of HIV-1 transmission and the pathogenic mechanisms of the virus during infection. [These] mice can be used to systematically analyze the efficacy of HIV-1 prevention, therapeutic and eradication interventions, key experiments aimed at stopping the spread of HIV-1."
Dr. Laurence is amfAR's senior scientific consultant.