The overall goal of this comprehensive National Cooperative Drug Discovery Group [""""""""Toward Gene Therapy for AIDS""""""""] is to evaluate gene therapy as an alternative, less conventional approach to the treatment of infections by human immunodeficiency virus (HIV). Classical gene therapy aims to correct a mutant somatic gene; gene therapy applied to AIDS will be designed to block a step in virus replication or disease pathogenesis. The basic concept is to engineer hematopoietic stem cells to be resistant to HIV in order to provide the donor with protected cells. In this Group, tissue culture cells will be used initially to assess the potential effectiveness of an inhibitory strategy on HIV replication. Promising treatments will be tested in vivo in a mouse/human chimera animals model. Specific HIV gene products (gp120, Nef, Tat) will be explored as potential inhibitory factors that might form the basis of gene therapy approaches. Targeted steps in the virus life cycle will be attachment and expression of regulatory genes. Inhibitory strategies focus on: (1) Receptor blockade by fragments of gp120 or soluble CD4; (2) Potential effect of overexpression of nef on HIV replication or latency; and (3) Block of transactivation by tat by overproduction of transactivator regulatory (TAR) element RNA. Gene therapy success requires knowledge of the pathophysiology of disease. Components in this Group address pathogenesis- related processes that impact on planning and evaluation of gene therapy approaches: (1) Role of gp120 in cytopathology and T-cell depletion (tested using recombinants between HIV and murine retroviruses and by creating transgenic mice encoding human-mouse chimeric CD4 able to bind HIV gp120); (2) Effects of expression HIV genes on T-cell immune functions in cells engineered to test a gene therapy approach; and (3) Functional significance of variation in HIV DNA sequences in the infected host and in response to a gene therapy approach (determined using PCR and automated DNA sequencing technology). All five projects will rely heavily on service functions provided by three core facilities: A - Specimen handling, flow cytometry and immune function core (patient materials will be obtained from HIV-positive males seen at the Houston Veterans Affairs Medical Center); B- Nucleic acid service facility (oligonucleotides, DNA sequencing, PCR technology); and C - Gene therapy mouse facility (mutant mice strains will be maintained, bone marrow transplanted, mouse/human chimeras infected with HIV, and gene therapies tested). Although many hurdles remain before gene therapy becomes a reality, it is timely to assess its applicability to the treatment of AIDS. This Group draws together two areas of strength at Baylor - animal virology and gene therapy for human disease. Close interaction between individuals in these areas maximizes the likelihood of significant progress in this Group effort.
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