This proposal outlines a five year plan to systematically train the candidate for a career in academic Transfusion Medicine. The candidate is currently in his third year of formal residency training having completed twenty-one months of clinical training including one year as Chief Resident in Laboratory Medicine. He has spent the last year primarily in his mentor's lab but also collaborating in his comentor's lab generating preliminary data for this proposal. The candidate's basic research interests lie in the pathogenesis of HIV-1 infection, particularly as it relates to HIV- I associated hematodyspoiesis. The advent of AIDS caused by HIV has changed the nature and practice of Transfusion Medicine. Although strict screening programs have led to the marked decline in the number of transfusion-associated AIDS cases, the toll from the disease continues to rise. The beta-chemokine receptor CCR5 is the coreceptor for macrophage-tropic strains of HIV-1 that are responsible for blood-borne and sexual transmission of the virus and the alpha-chemokine receptor CXCR4 is the coreceptor for T-tropic strains of HIV- 1 that emerge years after infection. The concurrent realization that cognate ligands for these receptors play a role in normal hematopoiesis offers the possibility that studies into the biology of these chemokine receptors as viral coreceptors may also shed light on their role in hematopoiesis. These studies will utilize viral fusion and infection assays as well as a library of domain-specific monoclonal antibodies against cognate chemokine receptors to probe the structure-function correlates of chemokine receptors as they relate to viral entry and hematopoiesis. The respective expertise of the cosponsors, Dr. Robert Doms and Dr. Alan Gewirtz, in viral-chemokine receptor interactions and hematopoiesis respectively, will provide the candidate with the ideal environment in which to pursue his research training. Dr. Robert Doms has been a central figure in the discovery and characterization of HIV- 1 coreceptors. Dr. Alan Gewirtz is an internationally-respected authority in the field of hematopoiesis. The membership of the candidate's advisory committee includes Dr. Leslie Silberstein, who has recently established an NHLBI-funded Specialized Center of Research in Transfusion Medicine and Biology, and Drs. Ron Collman and Jim Hoxie, both well-respected authorities in the HIV/chemokine receptor fields. Together, this environment will allow Dr. Lee to gain the necessary technical and professional expertise to make the necessary transition to an independent clinical scientist in the field of academic Transfusion Medicine.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-Y (O1))
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Soilleux, Elizabeth J; Morris, Lesley S; Leslie, George et al. (2002) Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitro. J Leukoc Biol 71:445-57
Soilleux, Elizabeth J; Morris, Lesley S; Rushbrook, Simon et al. (2002) Expression of human immunodeficiency virus (HIV)-binding lectin DC-SIGNR: Consequences for HIV infection and immunity. Hum Pathol 33:652-9
Hong, Patrick W-P; Flummerfelt, Karen B; de Parseval, Aymeric et al. (2002) Human immunodeficiency virus envelope (gp120) binding to DC-SIGN and primary dendritic cells is carbohydrate dependent but does not involve 2G12 or cyanovirin binding sites: implications for structural analyses of gp120-DC-SIGN binding. J Virol 76:12855-65
Lee, B; Leslie, G; Soilleux, E et al. (2001) cis Expression of DC-SIGN allows for more efficient entry of human and simian immunodeficiency viruses via CD4 and a coreceptor. J Virol 75:12028-38
Blanpain, C; Wittamer, V; Vanderwinden, J M et al. (2001) Palmitoylation of CCR5 is critical for receptor trafficking and efficient activation of intracellular signaling pathways. J Biol Chem 276:23795-804
Soilleux, E J; Morris, L S; Lee, B et al. (2001) Placental expression of DC-SIGN may mediate intrauterine vertical transmission of HIV. J Pathol 195:586-92
Moonis, M; Lee, B; Bailer, R T et al. (2001) CCR5 and CXCR4 expression correlated with X4 and R5 HIV-1 infection yet not sustained replication in Th1 and Th2 cells. AIDS 15:1941-9
Lin, G; Lee, B; Haggarty, B S et al. (2001) CD4-independent use of Rhesus CCR5 by human immunodeficiency virus Type 2 implicates an electrostatic interaction between the CCR5 N terminus and the gp120 C4 domain. J Virol 75:10766-78
Puffer, B A; Sharron, M; Coughlan, C M et al. (2000) Expression and coreceptor function of APJ for primate immunodeficiency viruses. Virology 276:435-44
Pohlmann, S; Lee, B; Meister, S et al. (2000) Simian immunodeficiency virus utilizes human and sooty mangabey but not rhesus macaque STRL33 for efficient entry. J Virol 74:5075-82

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