Murine Leukemia Virus (MLV) and mammalian gamma retro viruses
Aaronson et al in 1969 observed spontaneous release of MLV from uninfected murine cell cultures. At the same time when Dr. Weiss found the induction of virus production from chick embryo cells, similar experiments were reported for MLV activation by halogenated pyrimidines. The genetic mapping and analysis of gene expression of endogenous MLV was studied in great detail in 1970s and 1980s. As observed in case of endogenous ALVs, many of the genomes of endogenous MLV were defective, while others contained ORFs or complete, potentially infectious genome.
With this discovery of endogenous ALV, many investigators in the 1970s began to examine cells from other species for similar viruses. Many mammalian species including non-human primates were found to harbor MLV related gamma retro viruses.
Murine Mammary Tumor Virus (MMTV)
Earlier, it was thought that the susceptibility to breast cancer in mice was genetic. However, J.J. Bittner made an important observation in 1936. He observed that foster nursing of a low-incidence strain of new born mice on a high-incidence mother, caused the females to develop breast cancer as adult. Further, in 1949, Dr. Dmochowski observed a filterable oncogenic agent in the milk, which led to the identification of MMTV.
The finding that MMTV is endogenous was made at the same time when endogenous ALV was described. As with ALV and MLV, mice carry numerous MMTV ERVs in their chromosomes.
Xenotropism and Xenotransplantation
It has been observed that many endogenous retroviruses do not readily re-infect their own host cells but can infect other species in vitro or in vivo. Thus the endogenous ALV of chickens infects cells of quail, pheasants and turkey more readily than the
chicken. Jay Levy coined the term ‘xenotropic’ for viruses that only infect foreign species. The host has a selective advantage for being insusceptible to re-infection by a potentially pathogenic ERV. This ERV can not be amplified to reach a high viral load in its host. Resistance mechanisms for re-infection include mutation of receptors, blocking of receptors by endogenous Env expression, and intracellular restriction factors. Murine hybridomas can also release xenotropic MLV, so it is important to ensure that biologic medicines such as therapeutic monoclonal antibodies are not contaminated by retroviruses.
Evolutionary Perspectives
There are many questions on these ERVs. Do they represent junk DNA or do they play important roles in genetic regulation of the host? Do retroviruses serve as vectors for horizontal gene exchange? Do ERVs always become defective over time?
There are evidences that suggest that MLV-related gamma-retroviruses may reside for million of years in the germ line of its hosts and yet remain replication competent. Maintenance of functional genomes with ORFs probably requires retrotranspositions. This might be the reason that the ERVs with the complete genomes are recently recycled ones. Colonization of a new host presumably goes via an infectious phase before insertions occur in its germ-line.
Retroviruses could serve as a horizontal means of exchange of genetic information. However, other than transporting themselves, ERV do not appear to be a career of genes.
At the end I would like to quote the last paragraph from this review which talks about the lacunae in information and the future directions.
“ Finally, one may ask why DNA viruses that have a capacity to integrate into host DNA have not been detected in the germ line. Although integration is not an obligate step in their replication cycles, polyoma viruses, papilloma viruses, hepadnaviruses, adenoviruses and parvoviruses could each have gained a free ride to the next host generation, provided they were able to infect primordial germ cells or early embryo cells before segregation of the germ line. Adeno-associated virus has a preferred integration site on human chromosome 19 but has apparently not become inherited at this locus. Like MLV, the polyoma virus, SV40, can infect embryonal stem cells in vitro, and become latent in them. This would be a good way to endogenize yet there is little evidence that it has happened. I am aware of only one example of a Mendelian DNA virus, that of human herpesvirus 6, and this is not universal in the human population. It will be fascinating to work out why HHV-6 but not other herpesviruses
endogenize, and whether other non-retroviral endogenous genomes will be discovered.”
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