Pathogenic retroviruses are widely distributed across the species, including man, with retroviruses that cause immunodeficiency, leukemia, or other diseases. Several properties of the retroval life cycle enable retroviruses to be formidable pathogens, difficult for the immune system to eliminate from the host. Among possible retroviral """"""""escape mechanisms"""""""" retroviruses may vary in the viral epitopes recognized by T lymphocytes. Here, a mouse retroviral system is proposed to study the mechanisms of retroviral variation and their consequences for protective T cell- mediated immunity via direct in vivo assessment of the physiological relevance of precise retroviral variations. The spontaneously occurring T cell lymphomas/leukemias of high incidence in certain mouse strains such as AKR are caused by endogenous murine leukemia viruses (MuLV) of the AKR/Gross type. Although the proximal leukemogenic MuLV are recombinant mink cell cytopathic focus-inducing (MCF) retroviruses generated at several months of age, the early-arising ecotropic MuLV of low leukemogenicity are also required. First, the ecotropic MuLV contribute the vast majority of the gag and pol gene sequences for the MCF viruses. Second, the early ecotropic MuLV viremia is required for maximal leukemia incidence. Although some virological aspects of this system are different from the Adult T-cell Leukemia (ATL) of man caused by HTLV-I, AKR/Gross MuLV induced leukemia is similar with regard to the T cell tropism and replication competent, viral oncogene negative nature of the retroviruses, and the delayed kinetics of disease development which allow the immune surveillance system to respond to emerging neoplastic cells. Because cytolytic T lymphocytes (CTL) are considered to be particularly effective in host elimination of virus infected cells and tumor cells, the focus is on AKR/Gross MuLV specific CTL, their recognition of virally-encoded epitopes presented by class I major histocompatibility complex molecules, and retroviral variations that affect CTL recognition of these epitopes.
The specific aims are to: 1) determine the in vivo relevance of the major immunodominant epitope located in the p15E transmembrane viral envelope protein, to compare the importance of this epitope to that of two distinct minor CTL epitopes, and to define the importance of retroviral variations in these epitopes; 2) determine the basis for the inability of anti-AKR/Gross MuLV CTL to recognize MuLV that have variations either within or adjacent to the major immunodominant epitope; 3) define antiviral CTL responsiveness in high- vs low-incidence leukemic mouse strains, particularly the AKR.H- 2b:Fv 1b congenic, which converts from an antiviral CTL responder to nonresponder at about 9 weeks of age; and 4) generate and characterize CTL to MCF MuLV that do not encode the immunodominant CTL epitope. Information gained will advance the understanding of AKR/Gross MuLV- induced leukemogenesis and may have relevance to tumors in higher species, including ATL/HTLV-I in man.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA069525-02
Application #
2330963
Study Section
Virology Study Section (VR)
Project Start
1996-04-01
Project End
2001-01-31
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755