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Hello TWiV hosts,
I'm currently working as a technician in the biochemistry and molecular biophysics department at Columbia, having just received my BA from here in the Spring. First of all, I'd like to join the chorus of praises for your dedication to doing this podcast. I first heard about it this past Spring when I took the virology class as an undergrad and have always found it to be a very entertaining and informative discussion of a topic which I find very interesting. If I may, I'd like to ask if you could touch on two subjects that I've recently read about. The first is one that I think you've talked a little about before, and that is the subject of CRISPRs. Specifically, I would love to hear a bit more about the mechanisms by which they help defend bacteria against phage and how they could have gotten into the genome (perhaps these things are not very well understood yet, but even some speculation would be interesting).
The second is an article in the July issue of PLoS Pathogens entitled, Unexpected Inheritance: Multiple Integrations of Ancient Bornavirus and Ebolavirus/Marburgvirus Sequences in Vertebrate Genomes. The authors find several sequences in vertebrates including humans that seem to have been integrated from viruses in the two virus families mentioned in the title. Not only are there long ssRNA viral sequences integrated into a dsDNA genome, but they seem to be conserved and even expressed in some cases. One big question that I have is regarding the mechanism by which a single stranded RNA virus's genome could be integrated into the genome of its host (they go into a possible mechanism involving LINE elements in the paper, but I'm not sure if I fully understood the details). I believe Bornaviruses go into the nucleus, which is unusual for an RNA virus, but does the same go for the other two? Are these integrations a result of an error in a pathway, and if so, is it a viral or a host pathway? I happened to read this article shortly after listening to your ASV episode where one of your guests mentioned that there is a potential for using viral proteins as drugs which could interfere with the formation of viable virus particles when a virus infects a cell. Could this be a case of nature already having used this idea?
Thanks again for the wonderful podcasts.
PS: Although from my understanding it's not really relevant to humans disease, could Dick talk about the liver fluke worm, dicrocoelium dendriticum on TWiP? I recently heard about it, and it's life cycle seems absolutely fascinating.
I recently developed a science obsession that led me to learning about viruses and ERVs. I found your show in the search, and although most of the terminology is unfamiliar to me, my progression through your virology 101 podcasts, as well as some serious web searching is helping to bring me up to speed. I listened to your podcast on ERVs - and I've read numerous articles and scientific papers.
In all of that, I've never heard a comprehensive description of how an ERV enters the germline.
In those regards, I have some specific questions:
1.) How does a retrovirus bypass the blood-testes barrier to reach the germ cells? I understand that HIV does so by "hiding" in white blood cells. Are any other retroviruses capable of doing this (i.e.: they must be able to bind to CD4 receptors)?
2.) Of the 5 types of ERVs: Alpharetroviruses, Betaretroviruses, Gammaretroviruses, Lentiviruses, and Spumaviruses, is it known that any of them have the correct surface proteins to bind to germ cell specific binding sites? I read that the common sperm cell binding sites are heparan sulfate and mannose receptors. I'm not sure if those are the same for spermatagonia.
3.) Once inside a germ cell, how does a retrovirus successfully integrate its DNA into the host DNA? I read some HIV studies where the sperm of deceased HIV patients were examined - as well as studies where HIV was introduced to sperm in vitro. In no case was the viral DNA inserted into the host's chromosomes - even though the virus was found within the germ cells. One study suggested that a low hydrolytic activity in the cytosol of sperm prohibited viral uncoating. Could the tightly wound structure of sperm chromatin also hinder viral DNA insertion?
4.) My guess is that a retrovirus would have more success inserting its DNA in a spermatagonia stem cell than in a developed sperm. How would the spermatagonia be able to survive such an infection? Wouldn't the viral infection and subsequent release of new viruses eventually destroy the stem cell? It if survived, would the host produce sperm cells with the retrovirus insert for the rest of host's life? Or would the host have to reproduce while actively infected with the retrovirus before the immune system wipes it out?
5.) Lastly, if the retrovirus was able to jump through the previously mentioned hoops and a provirus infected sperm fertilized an egg, how would the forming baby be able to survive having a provirus in every cell of its body? It's my understanding that the majority of modern day exogenous retroviruses cause cancers, lymphomas, and leukemia. How does any child survive long enough to reproduce when these pathogenic forces are at work in every cell of its body?
I appreciate any help you can lend. I'm also wondering if I will have to listen to a podcast to hear my answers read to me, or if you will respond via email?
A fan of your show….. I would like to hear your comments upon reading this relatively recent publication in the Journal of Virology:
Isolation of an Infectious Endogenous Retrovirus in a Proportion of Live Attenuated Vaccines for Pets ….J Virol. 2010 April; 84(7): 3690–3694. Published online 2010 January 27. doi:10.1128/JVI.02715-09.