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Dusty Miller said: ↑
I don't agree with the statement that "MLV latency is easily established. Of course, it depends on your definition of latency. I just spoke with some other virologists here at my institute, and the definition that seems most reasonable is the persistence of a virus genome in the absence of virus production, but with the potential for production of fully-infectious virus at a later time. Herpes viruses do this quite well. The herpes virus genome can persist in neuronal cells for long periods without making infectious virus, but can 'reactivate' at a later time and produce fully-infectious virus. During this period of latency, some proteins are made by the virus genome, and these regulate the latent state. In this way, the virus can avoid detection by the immune system for prolonged periods, only to re-emerge later. Shingles, caused by herpes zoster, is a good example of such re-emergence from virus latency.
Back to the question of MLV latency, the publications quoted above don't show that MLV latency is easily established.
For http://www.ncbi.nlm.nih.gov/pubmed/3871491, the statement in the Abstract that "NFS/N mice inoculated with Moloney murine leukemia virus (M-MuLV) developed T-cell lymphoma after a 10-week latent period" only means that it took 10 weeks for the lymphoma to be apparent. I couldn't get the full paper without paying an exorbitant fee, but it is likely that these mice were injected with virus at birth, such that the virus was continuously replicating during the 10-week period after injection and before the lymphoma became apparent.
For http://www.ncbi.nlm.nih.gov/pubmed/187773, the statement in the Abstract that "These [data] suggested that MuLV (Scripps) could exist either as a productive persistent or nonproductive latent infection in C57BL/St mice" doesn't say which possibility the data support, and therefore, does not provide data that an MLV can indeed become latent.
For http://www.nature.com/nature/journal/v283/n5745/abs/283404a0.html, the statement that "In such cases, lymphomagenesis seemed to operate through the agency of activated murine leukaemia viruses (MuLV) and occurred only after very long latent periods, and most (but not all) lymphomas were of host origin" again refers only to a "latent" period before the lymphoma was detected, and does not address whether the virus was latent or not. Same for the last paper cited above. Thus, the question of possible MLV latency has not been resolved by these reports.
Regardless, what I think most people on this forum are interested in is whether humans can be infected by an MLV-like retrovirus, which is later undetectable in the blood but remains hidden in either an inactive "latent" state, only to re-emerge later and cause additional damage, or in a slowly replicating "persistent" state, where it may cause hidden damage. Such hidden damage might occur in the brain while the virus is undetectable in blood, and biopsy of the brain to find the virus is problematic. On the other hand, MLV-like viruses poorly infect nondividing cells, such as neural cells, and the data from XMRV-infected monkeys support this prediction (Onlamoon et al. Table 1, showing little if any infection of brain).
Interesting questions. My understanding is that these simple retroviruses have no easy way to go latent. Unlike herpesviruses, for example, which have complex genetic machinery to regulate their active versus latent states, simple retroviruses like XMRV and MoMLV are always 'on'. They have strong enhancers and promoters of transcription that appear to be designed for maximum gene expression under all circumstances.
However, it is true that retrovirus expression can be suppressed by the host cell after integration of the virus, and this might be considered a form of latency. I don't know whether experiments have been done to look at the fate of such integrated but inactive viruses in animals. Certainly, it would be difficult to obtain funding to explore these issues in primates, our closest relatives, for 30 years under many different conditions, given the fact that there is little evidence that these viruses are present or cause disease in humans. In contrast, a huge and well-funded effort to understand HIV, a known human pathogen, is underway. Obviously, researchers and funding agencies must make choices about where to focus their efforts for maximum benefit.
However, it is true that retrovirus expression can be suppressed by the host cell after integration of the virus, and this might be considered a form of latency. I don't know whether experiments have been done to look at the fate of such integrated but inactive viruses in animals. Certainly, it would be difficult to obtain funding to explore these issues in primates, our closest relatives, for 30 years under many different conditions, given the fact that there is little evidence that these viruses are present or cause disease in humans. In contrast, a huge and well-funded effort to understand HIV, a known human pathogen, is underway. Obviously, researchers and funding agencies must make choices about where to focus their efforts for maximum benefit.
I don't agree with the statement that "MLV latency is easily established. Of course, it depends on your definition of latency. I just spoke with some other virologists here at my institute, and the definition that seems most reasonable is the persistence of a virus genome in the absence of virus production, but with the potential for production of fully-infectious virus at a later time. Herpes viruses do this quite well. The herpes virus genome can persist in neuronal cells for long periods without making infectious virus, but can 'reactivate' at a later time and produce fully-infectious virus. During this period of latency, some proteins are made by the virus genome, and these regulate the latent state. In this way, the virus can avoid detection by the immune system for prolonged periods, only to re-emerge later. Shingles, caused by herpes zoster, is a good example of such re-emergence from virus latency.
Back to the question of MLV latency, the publications quoted above don't show that MLV latency is easily established.
For http://www.ncbi.nlm.nih.gov/pubmed/3871491, the statement in the Abstract that "NFS/N mice inoculated with Moloney murine leukemia virus (M-MuLV) developed T-cell lymphoma after a 10-week latent period" only means that it took 10 weeks for the lymphoma to be apparent. I couldn't get the full paper without paying an exorbitant fee, but it is likely that these mice were injected with virus at birth, such that the virus was continuously replicating during the 10-week period after injection and before the lymphoma became apparent.
For http://www.ncbi.nlm.nih.gov/pubmed/187773, the statement in the Abstract that "These [data] suggested that MuLV (Scripps) could exist either as a productive persistent or nonproductive latent infection in C57BL/St mice" doesn't say which possibility the data support, and therefore, does not provide data that an MLV can indeed become latent.
For http://www.nature.com/nature/journal/v283/n5745/abs/283404a0.html, the statement that "In such cases, lymphomagenesis seemed to operate through the agency of activated murine leukaemia viruses (MuLV) and occurred only after very long latent periods, and most (but not all) lymphomas were of host origin" again refers only to a "latent" period before the lymphoma was detected, and does not address whether the virus was latent or not. Same for the last paper cited above. Thus, the question of possible MLV latency has not been resolved by these reports.
Regardless, what I think most people on this forum are interested in is whether humans can be infected by an MLV-like retrovirus, which is later undetectable in the blood but remains hidden in either an inactive "latent" state, only to re-emerge later and cause additional damage, or in a slowly replicating "persistent" state, where it may cause hidden damage. Such hidden damage might occur in the brain while the virus is undetectable in blood, and biopsy of the brain to find the virus is problematic. On the other hand, MLV-like viruses poorly infect nondividing cells, such as neural cells, and the data from XMRV-infected monkeys support this prediction (Onlamoon et al. Table 1, showing little if any infection of brain).
