Well, some scientists wondered how the heck XMRV was replicating in humans (especially human PBMCs), when other murine gammaretroviruses are restricted in humans because of our intrinsic immunity: Tetherin, APOBEC, Trim5. So they set out to investigate what effect (if any) these human antiretroviral proteins have on XMRV.
RECEPTOR: First things first. If a cell doesnt have the receptor XMRV needs, then it cant infect a cell. The cell doesnt have the right lock for XMRVs key. But what if you give XMRV the key to locks on every cell (VSV-G)? Can XMRV infect anything, then?
XMRVs can infect some cells a little better with the VSV-key, but it doesnt make a huge difference. This means that there is something else restricting infection and cell tropism. A greater pressure than something as simple as receptor, and present in every cell... Intrinsic immunity!
APOBEC3G: This protein does not prevent the production of babby viruses. But, the babby viruses are mutated beyond repair, and are thus noninfectious. But not every APOBEC works on any retrovirus, and some retroviruses have figured out ways to interfere with APOBEC (HIV-1 Vif).
Well, human APOBEC3G does not like MLV (XMRVs ancestor). It shuts that mo-fo down. Weirdly, though, APOBEC3G is found in high levels in human PBMCs... but infectious XMRV was found in human PBMCs... The resulting viruses should have been duds.
So, they tested whether human APOBEC3G can mess up XMRV. Um... it could. Human APOBEC3G knocked XMRV infectious offspring levels down to MLVs crappy levels. Hmm.
TETHERIN: These experiments are so cool! Okay, first of all, XMRV is restricted by tetherin. That is, you get really really shitty viral production off of infected cells that express human tetherin (or tetherin from a couple non-human primates). Now, HIV-1 has Vpu to counteract tetherin, right? So they added Vpu to XMRV infected cells, and voila! Tons of XMRV.
Furthermore, XMRV does not appear to have any obvious way of countering this host restriction. Yes, HIV-1 has Vpu. But viruses related to HIV-1 (HIV-2, SIVs) counter tetherin a different way-- with the envelope protein. Well, you dont need a complex retrovirus for Env, maybe XMRV counters tetherin that way?
Nope. HIV-1 with Vpu deleted replicates really shitty in human cells. If you add in XMRV envelope... HIV-1 with Vpu deleted still replicates shitty. Hmmm.
TRIM5alpha: Human TRIM5alpha messes up the structural proteins of regular MLV so it doesnt uncoat properly. So, they wanted to see if human (and twelve non-human primate) TRIM5alpha can screw with XMRV too...
This is the one innate immunity hurdle that XMRV can clear, while MLV cannot. Its odd, because XMRV-MLV structural amino acid sequences are super similar (95%), and TRIM5alpha has to interact with specific amino acids to work, but, eh, XMRV can do it.
Saturday, January 28, 2012
"The one innate immunity hurdle that XMRV can clear, while MLV cannot"
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