Imaging cancer viruses in vivo will provide new tools for studies of pathogenesis, potential tools for prognosis, as well as new ways to evaluate efficacy of therapeutic agents. We will evaluate two infectious agents that are closely associated with human malignancies. Human immunodeficiency virus type 1 (HIV-1), although probably not a direct cause of malignancies, is associated with a very high incidence of lymphomas and Kaposi's sarcomas as a result of interactions with herpesvirus infections. The methodology utilized in this proposal was first evaluated in HIV infected cells. Human T-cell leukemia virus type 1 (HTLV-1) is a cause of lymphoma in humans, as well as a neurological disorder known as HTLV-1 associated myelopathy (HAM), with which we have extensive molecular biology and animal models experience. The methodology developed for imaging will take advantage of a novel protein transduction system allowing efficient delivery of a wide range of proteins into all cell types that have been examined in tissue culture or in vivo, based on a peptide derived from the HIV-1 Tat protein. Recombinant fusion proteins are purified as polyhistidine-tagged proteins denatured in urea. Specific cleavage sites for HIV-1 or HTLV-1 proteases are inserted between the Tat sequence and the imaging compound to allow selective retention in infected cells.
The specific aims are to 1) develop chelation peptides or imaging proteins fused to the Tat permeation sequence and specific protease cleavage sites to detect HIV-1 and HTLV, 2) examine targeting of specific chelation peptides or imaging proteins to infected cells in tissue culture, and 3) examine targeting of specific chelation peptides or imaging proteins to infected cells in animal model systems. This project seeks to combine highly experienced investigators at Washington University with complementary skills to explore the use of novel molecular imaging techniques to study viral pathogenesis. These techniques will be critical to addressing issues of virus load and tissue targeting that are primary determinants of pathogenicity.
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