Journal of Antivirals & Antiretrovirals
Open Access

Humanized mice as a preclinical model for testing a novel HIV-1 fusion inhibitor

International Conference and Exhibition on VIROLOGY

5-7 September 2011 Baltimore, USA

Bradford K. Berges, Freddy S. Tumbaco, J. Nicholas Francis and Michael S. Kay

Scientific Tracks Abstracts: JAA

Abstract :

The new generation of humanized mice involves transplantation of human hematopoietic stem cells into highly immunodefi cient mouse strains, resulting in multi-lineage hematopoiesis and production of a large variety of human immune cell types. Human CD4+ T cells, monocytes/macrophages, and dendritic cells are detected in blood, lymphoid and nonlymphoid organs and these animals are highly susceptible to HIV-1 infection. Several FDAapproved anti-HIV-1 drugs have been examined for effi cacy in humanized mice and have been shown to reduce viral load and to prevent or reverse CD4+ T cell loss in various sites, and the development of viral resistance has also been documented. In the present study, we tested an experimental HIV-1 fusion inhibitor (PIE12-trimer) for effi cacy in blocking HIV-1 replication in humanized Rag2-/-c-/- mice. PIE12-trimer binds to a highly conserved hydrophobic pocket on gp41 and prevents fusion of viral and host cell membranes. Th is drug functions at picomolar concentrations in vitro, is eff ective against a broad array of HIV-1 isolates, is refractory to development of resistance mutations, and is composed of D-amino acids and thus is highly resistant to degradation. We have determined the pharmacokinetics of PIE12-trimer in mice, administered it to HIV-1+ humanized mice and monitored for changes in viremia and CD4+ T cell loss in peripheral blood relative to untreated HIV-1+ animals. Our results demonstrate the eff ectiveness of an investigational antiviral drug in vivo, and additionally show the utility of humanized mice to analyze the effi cacy of new drugs prior to clinical trials.

Biography :

Dr. Bradford K. Berges earned a Ph.D. from the University of Pennsylvania and did post-doctoral work at Colorado State University. He is currently an Assistant Professor of Microbiology and Molecular Biology at Brigham Young University. His research emphasis is on viral pathogenesis, using humanized mice as a model to study how human-specifi c viruses are transmitted and how they cause disease.