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. Currently, we are using a novel in vivo model that recapitulates mucosal HIV infection to determine the in vivo relevance of the in vitro activities associated with Nef.
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.
Cancer Immunology. Lymphotropic viruses are responsible for a vast number of human cancers. Unfortunately, their study has been severely limited due to the fact that the majority of these viruses do not infect other mammals. Thus, the lack of animal models susceptible to infection by these human viruses has severely limited our ability to develop novel treatments and effective vaccines. Our laboratory has established novel animal models that recapitulate key aspects of infection by human-specific viruses such as EBV, HIV, HHV-8 and dengue virus. We are currently using these systems to evaluate novel interventions to treat and/or prevent the devastating diseases caused by these pathogens.
RESEARCH INTERESTS
Stem Cells
HIV/AIDS
Vaginal/Rectal HIV Transmission
Regulation of Nef Activities
Gene Transfer/Gene Therapy
RECENT PUBLICATIONS
Denton PW, Estes JD, Sun Z, Othieno FA, Wei BL, Wege AK, Powell DA, Payne D, Haase AT, Garcia JV, "Antiretroviral Pre-exposure Prophylaxis Prevents Vaginal Transmission of HIV-1 in Humanized BLT Mice" PLoS Medicine, 5(1):e16:doi:10.1371/journal.pmed.0050016, January 2008
Sun Z, Denton PW, Estes JD, Othieno F, Wei B, Wege AK, Melkus MW, Padgett-Thomas A, Zupancic M, Haase AT, Garcia JV, "Intrarectal Transmission, Systemic Infection and CD4 T Cell Depletion in Humanized Mice Infected with HIV-1" Journal of Experimental Medicine, 204:705-714, 2007
Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW, Othieno F, Wege AK, Haase AT, Garcia JV, "Humanized Mice Mount Specific Adaptive and Innate Immune Response to EBV and TSST-1" Nature Medicine, 12:1316-1322, 2006
Hamra FK, Gatlin JE, Chapman KM, Grellhesl DM, Garcia JV, "Production of Transgenic Rats by Direct Germline Transmission" Proc. Nat. Acad. Sci. USA, 99:14931-14936, 2002
Wei BL, Denton PW, O’Neill E, Luo T, Foster JL, Garcia JV, "Inhibition of Lysosome and Proteasome Function Enhances Human Immunodeficiency Virus Type 1 Infection" Journal of Virolgy, 79:5705-5712, 2005
SIGNIFICANT PUBLICATIONS
Denton PW, Estes JD, Sun Z, Othieno FA, Wei BL, Wege AK, Powell DA, Payne D, Haase AT, Garcia JV, "Antiretroviral Pre-exposure Prophylaxis Prevents Vaginal Transmission of HIV-1 in Humanized BLT Mice" PLoS Medicine, 5(1):e16:doi:10.1371/journal.pmed.0050016, January 2008
Sun Z, Denton PW, Estes JD, Othieno F, Wei B, Wege AK, Melkus MW, Padgett-Thomas A, Zupancic M, Haase AT, Garcia JV, "Intrarectal Transmission, Systemic Infection and CD4 T Cell Depletion in Humanized Mice Infected with HIV-1" Journal of Experimental Medicine, 204:705-714, 2007
Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW, Othieno F, Wege AK, Haase AT, Garcia JV, "Humanized Mice Mount Specific Adaptive and Innate Immune Response to EBV and TSST-1" Nature Medicine, 12:1316-1322, 2006
Binck BW, Tsen MF, Islas M, White JD, Schultz RA, Willis MS, Garcia JV, Horton JW, Thomas JA, "Bone marrow-derived cells contribute to contractile dysfunction in endotoxic shock" Am. J. Phys., 288:577-583, 2005
Bente DA, Melkus MW, Garcia JV, Rico-Hesse R, "Dengue Fever in Humanized NOD/SCID Mice" Journal of Virology, 79:13797-13799, 2005
Point and right click (click and hold for Mac users) your mouse onand select "Save this link (or target) as..." option to save the file to your local computer.
and select "Save this link (or target) as..." option to save the file to your local computer.