Animal Models, Viral Infection and Pathogenesis, HIV (human immunodeficiency virus), HTLV (human T-cell leukemia virus), Sexually transmitted diseases, Microbicide, Polybiguanides

In vitro studies have provided valuable insight into the molecular mechanisms of retroviral infection and pathogenesis. The focus of our research is to build upon this knowledge by developing new and modifying existing animal models to study the complex interactions that influence viral transmission, infection, and pathogenesis in vivo; and to utilize animal models to evaluate strategies for the prevention, diagnosis, and treatment of human disease.  Specifically, our laboratory focuses on the development of small animal models for the study of HIV-1 (human immunodeficiency virus type 1) and HTLV-1 (human T cell leukemia virus type 1).  Our group has collaborated with several researchers in the field to develop animal models that recapitulate the immunologic dysfunction, malignancies, and progressive neurological disorders that result from these viral infections. The development of mouse and rat models for HIV-1 and HTLV-1 utilize viral recombination, xenografting, and transgenic techniques to allow for the study of viral immunity and pathogenesis.

Small animal models play a critical role in evaluating drug safety and efficacy prior to human clinical trials.  Our laboratory has developed a Swiss Webster murine model for the evaluation of topical vaginal microbicides, which are products that will be used to prevent the transmission of HIV-1 and other sexually transmitted disease (STD) pathogens.  This model was specifically designed to measure cervicovaginal tissue integrity and inflammation following exposure to candidate vaginal microbicides. Our published observations in this murine model parallel clinical trial findings.  First, studies within this model yielded two critical findings with respect to N-9, the first candidate microbicide evaluated in Phase III clinical trials. Studies with N-9 vaginal formulations demonstrated that the cervical columnar epithelia were more sensitive to physical tissue disruption (figure panel C) and inflammation (figure panel D) than the stratified squamous epithelium of the vagina.Subsequently, this model illustrated the urgent need to refocus current toxicity assessment protocols to include both the cervical and vaginal mucosa. Second, application of formulated N-9resulted in acute cervical epithelial damage accompanied by an intense inflammatory infiltrate within the lamina propria 2 hours post-application.  However, the damaged tissue was restored by 8-24 hours post-application to the extent that these tissues resembled the saline-exposed controls.  The observed damage correlates with the time when potential exposure to an STD pathogen is most likely to occur and has provided evidence supporting the conclusion of clinical trials, which indicated that vaginal application of N-9 may increase the transmission of HIV-1.  Because many clinical trials have assessed toxicity at 24 hours post-application, N-9 induced tissue damage was not observed during early safety profiles, resulting in the advancement of N-9 into large-scale efficacy trials.   Second, this model was also able to demonstrate differential toxicity between 1% and 1.7% preparations of candidate microbicide C31G, which correlated with clinical trial observations using formulations with the same C31G concentrations. 

We have, therefore, demonstrated that this model system can be used as a valuable prescreening tool to identify compounds with undesirable safety profiles, which would otherwise be evaluated in costly and time-consuming clinical trials. At present, we are using this model to evaluate candidate vaginal microbicides, including compounds belonging to the polybiguanide family. In addition, this model is being expanded to study toxicity and inflammation associated with anal and penile exposure to candidate microbicides.

1. Kish, T. M., Budgeon, L. R., Welsh, P. A., and M. K. Howett. Immunological characterization of human vaginal xenografts in immunocompromised mice: development of a small animal model for the study of human immunodeficiency virus-1 infection. Am J Pathol, 159(6): 2331-45, 2001.

2. Kish, T. M., Ward, M. G., Welsh, P. A., Budgeon, L. R., Wigdahl, B., and M. K. Howett. Human immunodeficiency virus-1 infection in human vaginal xenografts in a small animal model. XIV International AIDS Conference, 2002.

3. Kish, T. M., Ward, M. G., Welsh, P. A., Budgeon, L. R., Wigdahl, B., and M. K. Howett. HIV-1 infection in a small animal human vaginal xenograft model. J Acquired Immune Defic Syndr, 34(5):454-60, 2003.

4. Catalone, B. J., Kish-Catalone, T. M., Budgeon, L. R., Neely, E. B., Ferguson, M., Krebs, F. C., Howett, M. K., Labib, M., Rando, R., and B. Wigdahl. Mouse model of cervicovaginal toxicity and inflammation for the preclinical evaluation of topical vaginal microbicides. Antimicrobial Agents Chemother, 48: 1837-1847, 2004.

5. Catalone, B. J., Kish-Catalone, T. M., Neely, E. B., Budgeon, L. R., Ferguson, M., Stiller, C., Malamud, D., Krebs, F. C., Howett, M. K., and B. Wigdahl. Comparative safety evaluation of the candidate vaginal microbicide C31G. Antimicrobial Agents Chemother, 49: 1509-1520, 2005.

6. Catalone, B. J., Ferguson, M. L., Miller, S. R., Malamud, D., Kish-Catalone, T., Thakkar, T. Krebs, F. C., and B. Wigdahl. Prolonged exposure to the candidate microbicide C31G differentially reduces cellular sensitivity to agent re-exposure. Biomed Pharmacother, 59, 460-468, 2005.

7. Catalone, B. J., Miller, S. R., Ferguson, M. L., Malamud, D., Kish-Catalone, T., Thakkar, T. Krebs, F. C., and B. Wigdahl. Toxicity, inflammation, and anti-human immunodeficiency virus type-2 activity following exposure to chemical moieties of C31G. Biomed Pharmacother, 59, 430-437, 2005.

8. Sun, L., Finnegan, C., Kish-Catalone, T. M., Blumenthal, R., Garzino-Demo, P., La Terra Maggiore, G. M., Berrone, S., Kleinman, C., Wu, Z., Abdel-Wahab, S., Lu, W., and A. Demo-Garzino. Human beta-defensins suppress HIV infection: potential role in mucosal protection. J Virology, 79(22), 14318-29, 2005.

9. Kish-Catalone, T. M., Lu, W., Gallo, R. C., and A. L. Devico. Preclinical evaluation of synthetic -2 RANTES as a candidate vaginal microbicide to target CCR5. Antimicrobial Agents Chemother, submitted, 2005.

10. Kish-Catalone, T. M., Pal, R., Parrish, J., Rose, J. N., Reitz, M., Gallo, R., and A. Devico. Evaluation of -2 RANTES vaginal microbicide in a nonhuman primate simian/human immunodeficiency virus (SHIV) challenge model. Antimicrobial Agents Chemother, submitted, 2005.

11. Krebs, F.C., Miller, S.R., Ferguson, M.L., Catalone, B.J., Kish-Catalone, T.M., Rando, R., Labib, M., Howett, M.K., and B. Wigdahl. Structure-activity relationships of microbicidal polybiguanides with activity against human immunodeficiency virus type-1. Antiviral Research, submitted, 2005.