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FRISC: The Faculty Research Interests Science Comparator |
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Associate Professor of Internal Medicine
Immunology
Molecular Microbiology
Office: (214) 648-9970
FAX: (214) 648-0231
Building Y, Room 9.206
Mail Code 9113
Email: victor.garcia@email.swmed.edu
HIV, AIDS and Virus Pathogenesis
Throughout evolution, humans have been challenged by pathogens new to the species.
For the most part, our immune system mounts an adequate response that protects us
from the fatal consequences of infection. However, in some instances viruses can
circumvent the immune system and cause fatal diseases such as hemorrhagic fever (Ebola
virus) and AIDS (HIV). Understanding the host pathogen relationship at a molecular
level provides rational approaches to therapy and vaccine development. In addition,
it also provides a better understanding of human biology. We are interested in how
the HIV causes AIDS and why the immune system is not able to control this infection.
Our working hypothesis is that the ancillary genes of HIV, nef, vpu, vpr, and vif,
are the determinants of HIV pathogenesis. To evaluate the role of these genes in
disease progression, we have developed in vitro and in vivo models that recapitulate HIV
infection. Our emphasis has been placed on the nef gene because of its ability to
enhance virus replication in vivo. We have demonstrated that Nef is a
multifunctional protein that 1) downregulates cell surface expression of CD4 and MHC I; 2)
binds and activates PAK, a serine/threonine kinase; and 3) enhances the intrinsic
infectivity of HIV particles. Our long-term goals are to elucidate the molecular
basis of Nef function and to develop specific inhibitors with clinical applications.
Cell and Gene Therapy
Mutations in the human genome can cause alterations in gene expression that result in
inherited diseases such as cystic fibrosis, hemophilia, sickle cell disease, inborn errors
of metabolism etc. Currently, there are no cures for many of these diseases.
We therefore have been exploring the possible correction of defective phenotypes by gene
addition. This approach, generally known as somatic gene therapy, consists of introducing
the correct gene into the patient cells. Our laboratory has developed highly
efficient gene transfer systems that permit the introduction of genetic material into a
variety of human cell types. Our primary target has been the human hematopoietic
stem cell. This cell has very high differentiation and proliferative potential in
vivo. Using our gene transfer vectors and human hematopoietic stem cells we have
developed a xenograft model in which we can reconstitute the human hematopoietic system in
immune deficient mice. This system provides an excellent way to evaluate gene
therapy approaches prior to clinical implementation. These gene transfer vectors have also
allowed us to address fundamental questions such as intrathymic T cell differentiation, B
cell homeostasis, and the regulation of signal transduction pathways in human primary
hematopoietic cells.
Selected Publications:
S.C. Barry, J. Seppen, J.L. Foster, H. Ochs, J.V. Garcia, and Osborne W.R.A. (2000)
Lentiviral and Murine Retroviral Transduction of T-Cells for Expression of Human CD40
Ligand. Human Gene Therapy 11:323-332
Evans, JT, Kelly, P, O’Neill, E and
Garcia, JV. (1999) Human CD34+CD38- cell transduction via lentiviral-based gene transfer
vectors. Human Gene Therapy 10:1479-1489
Douglas, J, Kelly, P, Evans, JT and
Garcia, JV. (1999) Efficient Transduction of Human Lymphocytes and CD34+ Cells Via
HIV-Based Gene Transfer Vectors. Human Gene Therapy 10:935-945
Kechli, AM, Freiden PJ, Rossi JJ, Brenner
MK, Choueiry MA, Garcia JV, and Slobod KS. (1998) Overexpression of the HIV-1 primer
binding site inhibits HIV-1 replication. Human Gene Therapy 9:587-590
Luo L, Douglas JL, Livingston, RL, and
Garcia JV. (1998) Infectivity enhancement by HIV-1 Nef is dependent on the pathway of
virus entry: implications for HIV-based gene transfer systems. Virology
241:224-233
Luo T, Livingston RL and Garcia JV.
(1997) Infectivity enhancement by HIV-1 Nef is independent of its association with a
serine/threonine kinase. J. Virology 71:9524-9530
Luo T, Downing JR, and Garcia JV. (1997)
Induction of phophorylation of human immunodeficiency virus type 1 Nef and enhancement of
CD4 downregulation by phorbol myristate acetate. J. Virology 71:2535-2539
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Last updated: 13 Feb 2001
Extraction Method: Expand using Medical Synonyms-
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