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Biologic and molecular genetic characteristics of a unique MCF virus that is highly leukemogenic in ecotropic
S K Chattopadhyay1, B M Baroudy, K L Holmes
1Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892.
Abstract:
California wild mouse-derived ecotropic virus Cas-Br-M induces a spongiform encephalopathy and a wide variety of hematopoietic neoplasms on inoculation of neonatal mice. We isolated a MCF virus [Ns-6(186) MCF] from a thymic T-cell lymphoma developing in a NFS mouse inoculated with Cas-Br-M virus. Biologically cloned NS-6(186) MCF virus, in contrast to previously studied MCF viruses, was found to induce thymic or nonthymic T-cell lymphomas with high efficiency in the absence of ecotropic helper virus. Comparison of the restriction endonuclease maps derived from Cas-Br-M and NS-6(186) MCF revealed differences only in the env region, between 5.8 and 7.8 kb from the 5' end. Two biologically active molecular clones of the NS-6(186) MCF (clone 15 with two LTRs and clone 19 with 1 LTR) were studied. Although both clones exhibited similar in vitro activities, clone 15-derived virus induced only T-cell lymphomas with short latency whereas clone 19-derived virus induced a wide variety of neoplasms with a significantly longer latency. Nucleotide sequence analysis established that the U3 region of each of the two LTRs of clone 15 has a 53-bp duplication which includes "enhancer elements," but that the single LTR of clone 19 has no such duplication.
Insights
California wild mouse virus Cas-Br-M causes neurological disease and hematopoietic neoplasms. A novel MCF virus derived from a lymphoma efficiently induced T-cell lymphomas independently of helper virus.
Area of Science:
- Virology
- Oncology
- Immunology
Background:
- Cas-Br-M, a California wild mouse virus, induces spongiform encephalopathy and hematopoietic neoplasms in neonatal mice.
- MCF (Multiple-Coping-Factor) viruses are known to be involved in lymphomagenesis, often requiring helper viruses.
Purpose of the Study:
- To characterize a novel MCF virus isolated from a Cas-Br-M-induced lymphoma.
- To investigate the oncogenic potential of this MCF virus and its molecular clones independently of helper viruses.
- To identify genetic differences contributing to distinct oncogenic properties.
Main Methods:
- Isolation and biological cloning of a novel MCF virus (Ns-6(186) MCF).
- Inoculation of neonatal mice with the cloned MCF virus and its molecular clones.
- Restriction endonuclease mapping to compare viral genomes.
- Nucleotide sequence analysis of LTRs (Long Terminal Repeats) and U3 regions.
Main Results:
- The Ns-6(186) MCF virus efficiently induced T-cell lymphomas in mice without helper virus.
- Restriction mapping revealed differences in the env region between Cas-Br-M and Ns-6(186) MCF.
- Two molecular clones (clone 15 and clone 19) showed differential oncogenic potential: clone 15 induced T-cell lymphomas rapidly, while clone 19 induced diverse neoplasms with longer latency.
- Clone 15 possessed a duplicated U3 region in its LTRs containing enhancer elements, absent in clone 19.
Conclusions:
- The isolated MCF virus possesses intrinsic oncogenic properties, capable of inducing lymphomas without helper virus.
- Differences in the env region and LTR U3 duplications contribute to the distinct oncogenic profiles and latency of MCF virus clones.
- This study highlights the complex interplay between viral genetics and oncogenesis in retroviral lymphomagenesis.