Wednesday, January 4, 2012

The human body actually has anti-retroviral defenses build in

The focus of this paper is a group of proteins every cell in your body has to defend themselves against retroviruses (want me to make an evolutionary guess, they protect us from wayward ERVs)-- APOBEC (Wikipedia page for a specific one, A3G). APOBEC is packaged in babby viruses, and then when the babby goes on to infect a new cell, APOBEC screws up their reverse transcription process and makes a ton of mutations in the new proviral DNA. …

So what happens is-- A retrovirus productively infects a cell. The infected cell produces lots of babby viruses. APOBEC stows away in those babby viruses, which go on to infect new cells... BUT! During reverse transcription, APOBEC introduces lots of unwelcome mutations. Which means even if that new cell is 'infected', the virus that inserts into its genome is crap. It cant make any more babby viruses.

APOBEC is like the retroviral version of Cockroach Hotel: Retroviruses can check in, but they dont check out.

An obvious observation is that XMRV has no apparent counter to human APOBEC, but it might. But previous experiments didnt seem to indicate there was one. ?

So... if XMRV is infecting humans... how is it getting around our APOBECs? If XMRV is not getting around our APOBECs... is XMRV infecting humans?

These folks started in cell lines. As Fraulein Maria would say 'A very good place, to start!' They infected 10 billion CEM cells (a T-cell line that expresses a lot of APOBEC3G and 3F) and 10 billion CEM-SS cells (a related T-cell line that expresses little/no A3G or A3F) with either 10^4, 10^5, 10^6, 10^7, 10^8, or 10^10 XMRV viruses (based off RNA copies/volume).

At 10^4, not a damn cell was infected, either line. But when they used more virus, the CEM-SS cells were infected and made lots and lots of baby viruses, while the CEM cells exposed to the same quantity of virus, were like 'Meh.' They got infected, they made *some* babby viruses... but those babby viruses didnt really go on to infect more cells to produce MORE babby viruses.
This result is consistent with the expectation that most of the proviruses in the CEM cells will be hypermutated and will be unable to produce viral particles.
CEMs, CEMs, a human T-cell line, Cockroach XMRV hotel.

But cell lines are not 'human'. So the next step was to isolate white blood cells from a few different people (one of the putative targets of XMRV, which express lots of A3G and A3F), made 10 billion cell aliquots of those cells, and did experiments with them.

The cells pretty much wanted nothing to do with XMRV. There's not much else to say.
A pity it doesn't work against HIV, but then again HIV is pretty well adapted to simians/primates.
If the cells are good targets, you expect to put on 'some' virus, and get out A TON OF VIRUS. Didnt happen here.

Furthermore, the few babby viruses that were made were mutated by APOBEC3G and 3F. They sequenced the babby viruses and saw A3G/A3Fs mutational signatures. Actually, they only sequenced a ~1200 nt region of the virus, and they saw more mutations in viruses we *know* came from a clonal stock than I see in the 'XMRV sequences' uploaded to Genbank, which theoretically come from 'wild type totally in nature' variants.

And I repeat: XMRV is NOT causing disease in humans.
So why the hell was I ranting about animal research in the beginning?

Because the data in this paper could have helped this paper. It could have made the deaths of those eight rhesus macaques most likely to yield the largest quantity of data/life. As is, the take-away message from that paper is "If you pump 10^6 XMRV IV into macaques (a dose that would leave you with a pile of dead monkey with SHIVs), pretty much nothing happens. No clinical symptoms. The XMRV gets in, but there isnt much (any?) productive infection." Where did the >10^6 number come from? What was the logic? Why not 10? Why not 10^10? 10^6 is a dead-monkey-dose with SHIV, but 10^6 XMRV on human isolated PBMC did jack shit. So why would you put 10^6 in an animal? Think of that this way-- lets say you put a few cells of algae in a fish tank, and they didnt take hold to make your fish tank gross. Why would you take that same 'dose' of algae and expect it to take hold in the Colorado River? And when the hell is any human exposed to >10^6 XMRV IV in real life? Wat? And Im looking at previous XMRV publications that indicated APOBEC is a Big Deal with XMRV restriction. At least with HIV-1, human APOBEC, human A3G is, what, 100-fold more potent than macaque A3G? Wheres the macaque in vitro data, like the data that is the topic of this post? They talk about APOBEC all over the place, but didnt feel it was necessary to investigate human vs macaque in vitro before they decided they made an animal model?? Wtf?

That paper is a rush job that gave us very little information in exchange for 8 dead monkeys, before basic bench research was done.

We can do better.

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