Entry of enveloped viruses into host cells is poorly understood. This is especially true for viruses which enter cells in a pH-independent manner. Included within this class is the human immunodeficiency virus and most other retroviruses. It appears however that similar mechanisms are utilized by many viruses based on the conserved features of the viral envelope proteins, suggesting a potential site for therapeutic intervention. Specific cellular receptors are utilized by the viral envelope proteins during infection. Only a few cellular proteins which mediate viral entry have been described, and there is at present no obvious common feature of these proteins which distinguishes them as viral receptors. Clearly use of a system in which there is genetic variability in the receptor such that functional and nonfunctional variants exist may permit the requisite features of a viral receptor to be defined. Rous sarcoma virus (RSV)represents such a system. In RSV there is not only genetic variation of the receptors but also a number of closely related envelope proteins (i.e. subgroups) which each interact with a different receptor. The receptor for one of the RSV subgroups has recently been isolated. It is an extremely small membrane glycoprotein consisting in its simplest form of a 72 amino acid glycosylphosphatidylinositol-liked glycoprotein. Within the extracellular region of this receptor is a protein motif closely related to the low density lipoprotein receptor (LDLR) ligand binding repeat. This motif has a role in protein-protein interaction in many of the other proteins in which it occurs. Therefore it is likely it may have a similar role in the receptor-envelope protein interaction. Given the extremely small size of this receptor it will be possible to perform a detailed molecular analysis of this receptor protein. The overall goal of this project is to define the specific sequences or features of the RSV subgroups A receptor protein which mediate retroviral entry into the host cell. To accomplish this goal, three specific aims will be pursued during the tenure of this rant. They are: 1) Characterize the gene, mRNA, and proteins in cells permissive and those restrictive for subgroup A RSV entry. 2) Define regions of the receptor which interact with the virus to facilitate entry. 3) Characterize the normal function or ligands for the RSV(A) receptor and determine if normal function relates to athe receptor's role in viral uptake.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29CA063531-01
Application #
2105442
Study Section
Experimental Virology Study Section (EVR)
Project Start
1994-05-01
Project End
1999-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Damico, R; Bates, P (2000) Soluble receptor-induced retroviral infection of receptor-deficient cells. J Virol 74:6469-75
Balliet, J W; Gendron, K; Bates, P (2000) Mutational analysis of the subgroup A avian sarcoma and leukosis virus putative fusion peptide domain. J Virol 74:3731-9
Wool-Lewis, R J; Bates, P (1999) Endoproteolytic processing of the ebola virus envelope glycoprotein: cleavage is not required for function. J Virol 73:1419-26
Balliet, J W; Berson, J; D'Cruz, C M et al. (1999) Production and characterization of a soluble, active form of Tva, the subgroup A avian sarcoma and leukosis virus receptor. J Virol 73:3054-61
Damico, R; Rong, L; Bates, P (1999) Substitutions in the receptor-binding domain of the avian sarcoma and leukosis virus envelope uncouple receptor-triggered structural rearrangements in the surface and transmembrane subunits. J Virol 73:3087-94
Rong, L; Gendron, K; Bates, P (1998) Conversion of a human low-density lipoprotein receptor ligandbinding repeat to a virus receptor: identification of residues important for ligand specificity. Proc Natl Acad Sci U S A 95:8467-72
Wool-Lewis, R J; Bates, P (1998) Characterization of Ebola virus entry by using pseudotyped viruses: identification of receptor-deficient cell lines. J Virol 72:3155-60
Bates, P; Rong, L; Varmus, H E et al. (1998) Genetic mapping of the cloned subgroup A avian sarcoma and leukosis virus receptor gene to the TVA locus. J Virol 72:2505-8
Damico, R L; Crane, J; Bates, P (1998) Receptor-triggered membrane association of a model retroviral glycoprotein. Proc Natl Acad Sci U S A 95:2580-5
Rong, L; Gendron, K; Strohl, B et al. (1998) Characterization of determinants for envelope binding and infection in tva, the subgroup A avian sarcoma and leukosis virus receptor. J Virol 72:4552-9

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