The murine leukemia viruses (MuLVs) are gammaretroviruses that have been important in the study of retroviral pathogenesis, oncogenesis, viral integration, transcriptional regulation and gene therapy. Now they are important in the study of the MuLV related human retroviruses, including XMRV and the newly identified polytropic variants.
Sandra Ruscetti, a collaborator on the Science paper, has been studying mouse retroviruses for more than thirty years. She is the head of the Retroviral Pathogenesis Section, Laboratory of Cancer Prevention at the NCI. Her work is now highly relevant to the study of gammaretroviral disease in humans. Dr. Ruscetti is an author on over 120 papers listed on PubMed. From her NCI profile webpage (link):
“The focus of our research is devoted to understanding the molecular basis for the pathogenesis of retrovirus-induced diseases. We have been studying retroviruses that cause leukemia or neurological disease in rodents to obtain basic information on how molecular changes in normal cells can result in pathological consequences. Our current studies are focused on determining whether similar mechanisms may be utilized by the human retrovirus XMRV to cause cancer and neuroimmune diseases in man. Overall, we hope to use the information gained from our studies to design and test rational strategies to counteract the retrovirus-induced molecular events that are responsible for these diseases.”
PVC-211 MuLV models neuroimmune disease in rats. It was derived by passage of the Friend virus complex (both F-MuLV and SFFV) through rats. It is an ecotropic virus that contains point mutations in its envelope gene which allow it, unlike Friend MuLV, to infect brain capillary endothelial cells and to cause neurodegeneration in rats. Microglia are activated macrophages in the CNS recruited from peripheral monocytes. They are activated by vascular damage, leakage of vessels, causing elevation of VEGF, a vascular permeability factor, in the rat cerebellum. Activated microglia cause upregulation of proinflammatory cytokines and chemokines, e.g. MIP-1a. There is an increase in iNOS, an enzyme involved in response to oxidative stress, increasing NO. So the result of activation of microglia, not a direct result of the virus. The cascade damages neurons indirectly. This paper also reports the use of clondrate-containing liposomes, which kill microglia, to block the neurogenerative effects of the virus.
J Virol. 2009 May;83(10):4912-22. Epub 2009 Mar 11. Neurodegeneration induced by PVC-211 murine leukemia virus is associated with increased levels of vascular endothelial growth factor and macrophage inflammatory protein 1 alpha and is inhibited by blocking activation of microglia. Li X, Hanson C, Cmarik JL, Ruscetti S. (full text pdf)
Another important murine model for human disease, SFFV has been studied for it’s oncogenic effects in mice. It was derived by recombination of the ecotropic Friend MuLV with endogenous polytropic envelope gene sequences and then underwent specific deletions throughout its genome to generate a replication defective MLV that encodes a unique envelope protein that is responsible for its pathogenicity. The unique SFFV envelope protein is responsible for the Epo-independent erythroid hyperplasia caused by the virus. It does this by activating a cellular tyrosine kinase (sf-Stk) that activates proliferative signals in erythroid cells. Because these proliferating SFFV-infected erythroid cells can still differentiate into red blood cells, they become immortal (transformed) only if SFFV has activated (by insertional mutagenesis) a cellular gene that blocks this differentiation. Inactivation of tumor suppressor genes in SFFV-infected erythroid cells also favors the outgrowth of transformed cells.
Int J Biochem Cell Biol. 1999 Oct;31(10):1089-109. Deregulation of erythropoiesis by the Friend spleen focus-forming virus. Ruscetti SK. (abstract)
Here are links to more light reading:), highly relevant papers about the neuropathogenic retrovirus, PVC-211 MuLV, by Dr. Ruscetti, going back in time:
Cell lines from wild mice (wild mice themselves apparently have not been studied much) are susceptible to exogenous xenotropic and polytropic MuLVs. Although cell lines from lab mice are not susceptible to xenotropic MuLVs, they are susceptible to polytropic MuLVs, as are the lab mice themselves. This is because lab mice carry a mutant Xpr1 receptor that doesn’t facilitate entry of xenotropic MuLVs but will allow entry of polytropic MuLVs.
A xenotropic virus may cause disease in a non-mouse species, but to qualify as a xenotropic virus, the virus need only use a particular receptor. So it may complete early events (cell entry and integration) in cultured cells but not be able to assemble new, infectious particles, much less pass from host to host. These issues seem very case-specific to a newbie like myself. If you want to know what a particular strain of MuLV does, you have to consult the published literature on that particular strain. There are many different strains and mutants, and they have their idiosyncrasies.
Here’s a mouthful that helped me understand, from the background section of a paper on an amphotropic MuLV that discusses the different designations of murine retroviruses according to their host ranges:
A large number of genetically transmitted endogenous murine leukemia viruses (MuLVs) and non-genetically acquired exogenous retroviruses have been classified on the basis of their in vitro host range, interference and neutralization properties. Regardless of their origin, the gammaretroviruses isolated from a wide variety of inbred or feral mouse strains have been designated as ecotropic (MuLV-E), xenotropic (MuLV-X), amphotropic (MuLV-A), polytropic, mink cell focus forming (MCF) and ‘modified polytropic’ viruses. The MuLV-E’s are the most common endogenous or exogenously acquired retroviruses of mice and they grow well in mouse or rat cells but not in cells derived from higher primates, humans or other mammals. All MuLV-E strains induce syncytia in a Rous Sarcoma virus transformed, non-producer XC rat cells. The xenotropic viruses (MuLV-X) are the genetically transmitted endogenous retroviruses of mice that do not replicate well in mouse cells which produce these viruses, but they grow preferentially in cells of heterologous species, including human and other primate cells. The polytropic and ‘modified polytropic’ viruses are endogenous nonecotropic MuLVs that grow in mouse, human and other mammalian cell types. Most of the polytropic viruses are expressed during leukemogenesis in various inoculated mice and they are called mink cell focus forming (MCF) as they induce syncytia in the replication defective Kirsten mouse sarcoma virus transformed non-producer, mink cells. In contrast, the amphotropic retroviruses do not induce foci in transformed mink cells (i.e. not related to MCF viruses) and they display distinct interference, host range and neutralization patterns from all other endogenous or exogenously acquired, ecotropic, nonecotropic, xenotropic, polytropic or MCF MuLV strains. (Virology Journal 2006, 3:101)
Most studies on MuLVs are carried out by injecting mice with ecotropic MuLVs (another class of exogenous MuLVs), which recombine with endogenous polytropic envelope gene sequences to generate pathogenic polytropic MuLVs, or by infecting mice with a virus like SFFV, which carries its own pathogenic envelope gene.
Yes folks, it is harder than rocket science. But I think it is important for us, trying to understand what is wrong with us and what to do about it, to consider the science and learn the terminology. If things take off as they should with the research, understanding these concepts will be necessary to integrate the scientific literature into our clinical thinking going forward. The uninitiated might think that this post is completely over the heads of most readers. But, due to extreme neglect by the medical profession, the patients in this group have been forced to read difficult science before.
Look at how far science has come in characterizing retroviral diseases in mice! Bodes well for us for the future, now that they finally know what they are looking for.