Department Affiliation: Primary: Pharmacology and Molecular Sciences
Degree: Ph.D., Oxford University, England; M.D. Johns Hopkins University
Rank: Adjunct Professor, Pharmacology and Molecular Sciences
Telephone Number: 615-327-5754
Fax Number: 615-327-6929
E-mail address: jhildreth@mmc.edu
Meharry Medical College Address: 1005 Dr. D.B. Todd, Jr. Blvd., 21st Avenue and Meharry Blvd., Room 4200, Nashville, TN 37208
Mechanisms of Transmission and Pathogenesis of Human Retroviruses HIV-1 and HTLV-1
Our laboratory is interested in the role played by host non-receptor molecules on host cells in the biology of human retroviruses HIV and HTLV-1. In past studies we have shown that these viruses acquire in their membranes host cell adhesion receptors including integrins and integrin ligands such as LFA-1, VLA-4, ICAM-1 and VCAM-1. Additional studies confirmed that these molecules fully retain their function and contribute significantly to virus-cell interactions and substantially increase the infectivity of the viruses. In studies to determine the mechanism by which HIV selectively incorporates some host proteins while excluding others we demonstrated for the first time that HIV buds selectively from specialized regions of cell membranes called lipid rafts. These membrane domains that play important roles in cell signaling are characterized by high concentrations of cholesterol and sphingolipids and by the clustering of lipid-modified membrane proteins. Our recent studies in this area have focused on the role of cholesterol in the biology of HIV and HTLV-1. We have shown that the cholesterol-sequestering agent beta-cyclodextrin (BCD) blocks infection of cells by HIV and HTLV-1 at many levels, including that of the virus-producing cell. This natural product has an extensive base of safe use in humans and we are currently conducting in vitro and animal studies evaluating the potential of this moleculae as a chemical condom (microbicide) to block the sexual transmission of HIV, herpes simplex virus, and other STD pathogens.
Another current major focus of the laboratory is the Trojan Exosome model of retrovirus biology. Much of our work and that of others has shown that the biology of HIV is more complex than would be anticipated from the genes present in its genome. Furthermore, the large number of host proteins associated with the virus suggest that HIV probably utilizes a cellular pathway for biogenesis and release. Recently, a number of investigators have shown that gag proteins of retroviruses directly interact with host proteins involved in formation of or trafficking of late endosomes. In addition, HIV budding in macrophages occurs in large class II MHC loading compartments or multivesicular bodies (MVBs). These compartments serve as sites for formation of exosomes, virus-sized vesicles formed within MVBs and released into the extracellular space. In collaboration with Dr. Stephen Gould of Johns Hopkins University we have proposed that HIV and other retroviruses are cargo of this pathway (the Trojan Exosome Hypothesis). In a recent paper, we presented evidence that HIV budding in macrophages occurs through the exosome release pathway and similar observations have been made for HTLV-1. The Trojan Exosome model has important implications for retrovirus transmission, pathogenesis, and vaccine development. Ongoing and future studies will focus on the molecular mechanisms of exosome release and uptake as they relate to retrovirus biology and on studies in animals that test the predictions made by the hypothesis.
Dr. Hildreth’s laboratory has extensive expertise in the production and characterization of monoclonal antibodies and his laboratory serves as the Monoclonal Antibody Core for the NIH-sponsored Johns Hopkins University Center for AIDS Research. The Core assists investigators both in AIDS-related and non-AIDS-related fields with the production of antibody reagents that are not available commercially or are too expensive for the studies planned. All aspects of hybridoma generation and antibody production are covered. Dr. Hildreth’s laboratory has produced hundreds of monolconal antibodies against cellular and viral molecules all of which are available either commercially, through repositories, or directly from the Hildreth laboratory. The Genentech drug RAPTIVA recently approved by the FDA for treatment of psoriasis is based on a monoclonal antibody (MHM.24) produced by Dr. Hildreth.
Representative Publications:
- Hildreth, J.E.K. and Orentas, R.J. Involvement of a leukocyte adhesion receptor (LFA-1) in HIV-induced syncytium formation, Science 244:1075-1078, 1989. Pub Med Reference
- Orentas, R.J. and Hildreth, J.E.K. Association of host cell-surface adhesion receptors and other membrane proteins with HIV and SIV,. AIDS Res. Human Retroviruses 9:1157-1165, 1993. Pub Med Reference
- Guo, M.M.L. and Hildreth J.E.K.. HIV acquires functional adhesion receptors from host cells, AIDS Research and Human Retroviruses, 11:1007-1013, 1995. Pub Med Reference
- Hildreth, J.E.K., Subramaniam, A., and Hampton, R.A. HTLV-1-induced syncytium formation mediated by vascular cell adhesion molecule-1 (VCAM-1): Evidence for involvement of cell adhesion molecules in HTLV-I biology, J. Virol. 71:1173-1180, 1997. Pub Med Reference
- Nguyen, D.H. and Hildreth, J.E.. Evidence for budding of HIV-1 selectivity from glycolipid-enriched membrane lipid rafts, J. Virol, 74:3264-3272, 2000. Pub Med Reference
- Niyogi, K. and Hildreth, J.E.K. Characterization of new syncytium-inhibiting monoclonal antibodies implicate lipid rafts in HTLV-1 infection. J. Virol. 18:7351-7361, 2001. Pub Med Reference
- Liao, Z., Cimakaski. L., Nyugen, D., Hampton, R., and Hildreth, J.E.K. Lipid rafts and HIV pathogenesis: cholesterol is required for HIV-1 infection, AIDS Res. Hum. Retroviruses 17:1009-1019, 2001. Pub Med Reference
- Liao, Z., Graham, D.R., and Hildreth, J.E.K. Lipid rafts and HIV-1 pathogenesis: Virion-associated cholesterol is required for fusion and infection of susceptible cells, AIDS Res. Human Retroviruses 19:675-687, 2003. Pub Med Reference
- Graham, D.R., Chertova, E., Hilburn, J., Arthur, L.O., and Hildreth, J.E.K. Cholesterol depletion of HIV-1 and SIV with beta-cyclodextrin inactivates and permeabilizes the virions: Evidence for virion-associated lipid rafts, J. Virol. 77:8237-8248, 2003. Pub Med Reference
- Gould, S.J., Booth, A.M. , and Hildreth, J.E.K. The trojan exosome hypothesis, Proc. Nat. Acad. Sci. USA 100:10592-10597, 2003. Pub Med Reference
- Nguyen, D.G., Booth, A.M. , Gould, S.J., and Hildreth, J.E.K. Evidence that HIV Budding in Primary Macrophages Utilizes the Exosome Release Pathway. J. Biol. Chem., October 14, In Press. Pub Med Reference
Other graduate programs in which Dr. Hildreth participates:
BCMB Program
Cellular and Molecular Medicine Graduate Program
Immunology Graduate Program
Anti-Cancer Drug Development Program
Also Pathology and Pediatric Oncology
