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Dissertation
Genetic regulation of long-term non-progression in E-55+ murine leukemia virus infection
Doctor of Philosophy (Ph.D.), Allegheny University of the Health Sciences
Jan 1998
DOI:
https://doi.org/10.17918/00008686
Abstract
Certain inbred mouse strains display long-term survival after infection with E-55+ murine leukemia virus (E-55+MuLV) while others progress to lymphomas rather rapidly. This difference in disease progression occurs despite the fact that E-55+MuLV causes persistent infection in both BALB progressor (P) and C57BL long-term non-progressor (LTNP) mice. The goal of the studies in this thesis is to identify genetic loci and the functions mediated by these loci that are important in determining the LTNP phenotype. Immunosuppressed mice from P and LTNP strains develop lymphomas, indicating that LTNP is probably mediated by the immune system. Studies with bone marrow chimeras demonstrated that genes that determine the LTNP phenotype are expressed in donor bone marrow and not the recipient microenvironment. E-55+MuLV infection, in both the P and LTNP strains, is characterized by an acute and a persistent phase. During the acute phase, both P and LTNP mice demonstrate an initial increase in virus titer followed by a dramatic decrease in virus burden that occurs about two weeks after infection. Both P and LTNP mice require CD4+ T cells to mediate the decrease in virus burden but only P mice require CD8+ T cells as determined by in vivo depletion analysis. Moreover, during this phase of infection, both P and LTNP mice produce IFN-[gamma] whereas only P mice produce IL-4. IL-4 production in P strains results in the absolute requirement for CD8+ T cells to reduce the virus burden during the acute phase, whereas production of IFN-[gamma] is necessary for the development of the anti-virus CD8+ T cell response. On the other hand, LTNP strains do not produce IL-4 and do not require IFN-[gamma] to generate an effective immune response that reduces virus burden during the acute phase of infection. Backcross analysis of this phenotype suggests that more than one gene is responsible for these differences. Two candidate regions which may encode these genes, located on chromosome 7 and 19 respectively, were identified by recombinant inbred strain linkage analysis. During the persistent phase of infection, virus levels rise only in P strains and these mice progress to T cell lymphomas. Previous studies demonstrated that there is a difference in the cellular immune response between P and LTNP mice. Genetic studies on backcross mice show that there are two genes that regulate LTNP. Linkage analysis reveals that one of these genes is located on chromosome 15 (p = 0.00005) at the same region as the Rfv-3 gene. Rfv-3 is involved in recovery from Friend virus-induced leukemia and has been demonstrated to regulate neutralizing virus antibody titers. Previous studies, however, demonstrate that both P and LTNP strains produce similar titers of neutralizing anti-E-55+MuLV. Therefore, Rfv-3 may determine an influence on retrovirus infection that has not previously been described or these effects may be regulated by a closely linked gene.
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Details
- Title
- Genetic regulation of long-term non-progression in E-55+ murine leukemia virus infection
- Creators
- Vassiliki Panoutsakopoulou
- Awarding Institution
- Allegheny University of the Health Sciences
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Allegheny University of the Health Sciences; Philadelphia, Pennsylvania
- Number of pages
- xi, 161 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Allegheny University of the Health Sciences (1996-1998); School of Medicine (1996-1998); Pathology (and Laboratory Medicine) [Historical]
- Other Identifier
- 991021888781404721