4 ms·

> 2. chronic infection in a single immunosuppressed patient. We've seen this before (see, for example, this: https://www.nejm.org/doi/full/10.1056/NEJMc2031364

by etiam 5y ago

> 2. chronic infection in a single immunosuppressed patient. We've seen this before (see, for example, this: https://www.nejm.org/doi/full/10.1056/NEJMc2031364 https://www.nejm.org/doi/full/10.1056/NEJMc2031364 ) and southern africa has a lot of immunosuppressed people thanks to HIV. Additionally, there are some genetic markers that suggest evolution in a human. I speculated about this in another post recently. Might as well try putting it up for consideration here again: If it's in co-infection with HIV, then it isn't only the immune status that's abnormal in the physiology, and it might not even be the most significant circumstance with respect to what's happened here. They're not particularly closely related, but both coronaviruses and retroviruses apparently pack their genome as positive-sense, single-stranded RNA, so it doesn't seem wildly implausible to me that HIV's modifications to nucleic acid metabolism would operate on coronavirus RNA, and HIV is infamous for generating plenty of variability for itself. It copying sloppily and doing it on purpose, insofar as that can be ascribed to an organism like this. I never got particularly deep into viruses, so there may be certainly be known aspects about this I'm missing, but so far I haven't been able to find anyone to tell me a compelling reason why it wouldn't work. What are the markers that suggest evolution in a human? I'd be interested to see a reference.

robbiep 5y ago
Except SARS-CoV-2 also has a proof-reading lacking RNA Polymerase, and HIV infects CD4+ T cells whilst SARS-CoV-2 infects cells which express ACE2, which are numerous, but doesn’t necessarily mean a person with both infections is at all likely to have both viruses floating in the same cytoplasm. Basically, the mechanism you suggest is not necessary because the RNA Pol is just as shit as HIV’s
- etiam 5y ago
  Thanks for the input. The shared cytoplasm condition is perfectly reasonable requirement, certainly, but it's also not a terribly high bar to clear. HIV does indeed prominently infect CD4+ T lymphocytes, but that is by no means the only cell type it infects. At the very least, both species have been described to infect macrophages (and both may display tendencies to promote cell fusion, in which case I would expect many normal categorizations of what a cell type is, are off). As for the polymerases being roughly equivalent, I have a hard time believing that. As I've understood it, coronavirus RNA polymerase does perform proofreading, and over the course of the pandemic there has been plenty of media statements of relief and optimism about SARS-CoV-2 evolution not being such a big problem because the genome seems to be relatively stable as RNA viruses go. Many of the people making those statements may have had more hopes than facts to back that up, by all means, but simply grabbing a few highly ranked search result on mutation rates (I don't have time to do a more proper review now, sorry) does seem to suggest SARS-CoV-2 was estimated to have a low mutation rate (https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7387429/ https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7387429/) at least early after the introduction to human. Admittedly, it's also reported that mutations which should be suspected to reduce the proofreading effectiveness appeared early (https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8134885/ https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8134885/). But on the other hand, HIV is change virtuoso, and one of the first things you hit with a search engine on that topic currently (https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002251 https://journals.plos.org/plosbiology/article?id=10.1371/jou...) has the following very interesting piece in the abstract: "extremely high mutation rate of (4.1 ± 1.7) × 10^{−3} per base per cell, the highest reported for any biological entity. Sequencing of plasma-derived sequences yielded a mutation frequency 44 times lower, indicating that a large fraction of viral genomes are lethally mutated and fail to reach plasma. We show that the HIV-1 reverse transcriptase contributes only 2% of mutations, whereas 98% result from editing by host cytidine deaminases of the A3 family." Evidently those cytidine deaminases act on viral DNA sequences as a host defense mechanism, so that source of mutations at least, would be distinguishing for an RNA dependent DNA polymerase such as HIV reverse transcriptase (which, by the way, apparently really doesn't do any proofreading), as compared to a coronavirus RNA dependent RNA polymerase. Now I'd be curious to see if B.1.1.529 mutations appear preferentially at positions which would have cytidine after reverse transcription. I guess that would be the guanosines in RNA original?
  - robbiep 5y ago
    Thanks for the interesting reply. I was under the mistaken belief that SARS-CoV-2 lacked RNA Pol proof-reading, so that is my bad there and responsible for my equivocation between it and HIV. I completely accept that not only is it likely that there will be the viruses sharing the same cytoplasms on occasion, in large enough numbers, on long enough infections, etc etc - because one thing we know about biology is how slippery and stochastic things become, but the fact they dont generally share the same host does make this more of an interesting edge case I would imagine. Thanks for your interesting links and thoughtful reply!

by etiam 5y ago

robbiep 5y ago

Except SARS-CoV-2 also has a proof-reading lacking RNA Polymerase, and HIV infects CD4+ T cells whilst SARS-CoV-2 infects cells which express ACE2, which are numerous, but doesn’t necessarily mean a person with both infections is at all likely to have both viruses floating in the same cytoplasm. Basically, the mechanism you suggest is not necessary because the RNA Pol is just as shit as HIV’s

etiam 5y ago
Thanks for the input. The shared cytoplasm condition is perfectly reasonable requirement, certainly, but it's also not a terribly high bar to clear. HIV does indeed prominently infect CD4+ T lymphocytes, but that is by no means the only cell type it infects. At the very least, both species have been described to infect macrophages (and both may display tendencies to promote cell fusion, in which case I would expect many normal categorizations of what a cell type is, are off). As for the polymerases being roughly equivalent, I have a hard time believing that. As I've understood it, coronavirus RNA polymerase does perform proofreading, and over the course of the pandemic there has been plenty of media statements of relief and optimism about SARS-CoV-2 evolution not being such a big problem because the genome seems to be relatively stable as RNA viruses go. Many of the people making those statements may have had more hopes than facts to back that up, by all means, but simply grabbing a few highly ranked search result on mutation rates (I don't have time to do a more proper review now, sorry) does seem to suggest SARS-CoV-2 was estimated to have a low mutation rate (https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7387429/ https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7387429/) at least early after the introduction to human. Admittedly, it's also reported that mutations which should be suspected to reduce the proofreading effectiveness appeared early (https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8134885/ https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8134885/). But on the other hand, HIV is change virtuoso, and one of the first things you hit with a search engine on that topic currently (https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002251 https://journals.plos.org/plosbiology/article?id=10.1371/jou...) has the following very interesting piece in the abstract: "extremely high mutation rate of (4.1 ± 1.7) × 10^{−3} per base per cell, the highest reported for any biological entity. Sequencing of plasma-derived sequences yielded a mutation frequency 44 times lower, indicating that a large fraction of viral genomes are lethally mutated and fail to reach plasma. We show that the HIV-1 reverse transcriptase contributes only 2% of mutations, whereas 98% result from editing by host cytidine deaminases of the A3 family." Evidently those cytidine deaminases act on viral DNA sequences as a host defense mechanism, so that source of mutations at least, would be distinguishing for an RNA dependent DNA polymerase such as HIV reverse transcriptase (which, by the way, apparently really doesn't do any proofreading), as compared to a coronavirus RNA dependent RNA polymerase. Now I'd be curious to see if B.1.1.529 mutations appear preferentially at positions which would have cytidine after reverse transcription. I guess that would be the guanosines in RNA original?
- robbiep 5y ago
  Thanks for the interesting reply. I was under the mistaken belief that SARS-CoV-2 lacked RNA Pol proof-reading, so that is my bad there and responsible for my equivocation between it and HIV. I completely accept that not only is it likely that there will be the viruses sharing the same cytoplasms on occasion, in large enough numbers, on long enough infections, etc etc - because one thing we know about biology is how slippery and stochastic things become, but the fact they dont generally share the same host does make this more of an interesting edge case I would imagine. Thanks for your interesting links and thoughtful reply!