Resistance to pathogenic agents such as retroviruses may be genetic or acquired. We propose studies of the erythroleukemic disease of mice induced by the complex Friend strain (FV) of mouse leukemia virus (MuLV) in which both types of resistance can be observed and appear to depend in part on similar underlying immunologic mechanisms involving the major histocompatibility complex of the mouse, H-2. Our findings may serve as models for the study of analogous aspects of HIV disease. Mice of certain genotypes that differ in the D region of H-2 show markedly different levels of genetic susceptibility or resistance to FV, but the mechanism of this presumably immunologic effect has never been definitively demonstrated. In particular, we will study the mechanisms whereby H-2 haplotypes that confer resistance to FV in homozygous mice no longer do so in congenic heterozygotes. We propose studies of this effect that will precisely identify the D region genes involved by the use of genetic mapping with recombinant and mutant H-2 haplotypes, by the analysis of relevant strains of transfected cells and of transgenic mice and by studies based on the known properties of genes mapping in this region. We will also study aspects of the cellular immune response to FV that appear critical in the development of acquired resistance to the virus. We will identify specific amino acid sequences in the viral gag/pol and env genes that, together with H-2D region gene products, constitute the structures seen by FV-specific cytotoxic T lymphocytes (CTL). We will develop virus-related RNA constructs that are defective for replication and nonpathogenic but enriched for the determinants of the epitopes recognized by CTL that we will have identified. We will package these epitope-enriched constructs in FV particles which should then be able to generate a strong immune response in host mice both by stimulation of the class II H-22 gene-restricted pathway for antigen presentation and by stimulation of the class I H-22 gene-restricted endogenous pathway. The efficacy of these agents as candidate vaccines will be determined.
| Ruan, K S; Lilly, F (1992) Approach to a retrovirus vaccine: immunization of mice against Friend virus disease with a replication-defective Friend murine leukemia virus. Proc Natl Acad Sci U S A 89:12202-6 |
| Ruan, K S; Lilly, F (1991) Identification of an epitope encoded in the env gene of Friend murine leukemia virus recognized by anti-Friend virus cytotoxic T lymphocytes. Virology 181:91-100 |
| Polsky, D; Lilly, F (1991) Suppression of H-2b-associated resistance to Friend erythroleukemia virus by a class I gene from the H-2d major histocompatibility complex haplotype. Proc Natl Acad Sci U S A 88:9243-7 |
| Hoatlin, M E; Kozak, S L; Lilly, F et al. (1990) Activation of erythropoietin receptors by Friend viral gp55 and by erythropoietin and down-modulation by the murine Fv-2r resistance gene. Proc Natl Acad Sci U S A 87:9985-9 |
| Holt, C A; Osorio, K; Lilly, F (1986) Friend virus-specific cytotoxic T lymphocytes recognize both gag and env gene-encoded specificities. J Exp Med 164:211-26 |
