March 4, 2010
Category: Immunology • XMRV
Two things I didnt intend on writing about on ERV more than a few times, but turned into repeat guests: XMRV and Vpu.
Theyve finally come together.
Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors
Know how I was talking about
intrinsic immunity yesterday?
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?
Nope.
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...
It cant!
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.
But it still doesnt entirely make sense why the Reno group could find infectious XMRV in PBMCs. Evolutionarily, it shouldnt be there. Well, rather than screaming about how Judy Mikovits is a liar and a fraud, Harriet et al reacted in another normal, scientifically acceptable way-- by proposing some putative explanations, and excitedly waiting for future results. Their entire discussion was a pleasure to read.
In fact, the last author on this paper is Dr. Kate N. Bishop, also the last author on the second XMRV paper from the UK. Ignored the WPIs frantic wailing and claims everyone is incompetent but them, and kept doing science.
*tips hat to Dr. Bishop*
Neat science in this paper, Ma'am.
Posted by ERV at 6:00 PM • 3 Comments • 0 TrackBacks
March 3, 2010
Category: HIV/AIDS
Your immune system is like an onion ogre parfait.
Its has lots and lots of layers.
You have intrensic immunity-- Abilities every single one of your cells has to defend itself from viruses. VpuTetherin would be a good example of this, as would APOBEC and Trim5a. Pick a cell in your body-- it can make these proteins. Doesnt have to be a special immune cell.
Then you have innate immunity-- Certain immune cells are not specific for any particular pathogen, but they can identify patterns that are 'wrong'. They see things your body knows aint right, like double-stranded RNA (your body doesnt make that!) or unmethylated bits of DNA made up of mostly Cs and Gs (your body doesnt have that!), or bacterial proteins like flagellin (mammals dont have flagella that look like bacterial flagella!). These cells dont care what virus is making the double-stranded RNA (HIV-1, rotavirus, respiratory syncytial virus), it just knows that double-stranded RNA is wrong, and that happens to be a step in these viruses life-cycle. Only immune cells can see pathogens this way, and respond accordingly.
And then theres adaptive immunity-- This is the one you all are probably most familiar with. These immune cells evolve in the face of infection to be specific for that pathogen. Very generally, Cytotoxic T-cells evolve to specifically target and kill host cells infected with the pathogen, and B-cells evolve to make antibodies specific for the pathogen, to neutralize them or make them easier for your immune system to see-->kill.
All this specific immune response takes time to evolve (couple weeks). Viral vaccines use weak/dead viruses to prime your adaptive immune response. Thus when you are exposed to a real, harmful virus 'in the wild', your body has a cheat-sheet for how to get rid of the virus. Your response is stranger and faster than if you had never gotten the vaccine.
To bring this back to HIV-1, we might be screwed when it comes to making a CTL vaccine (or, if we dont do it quick we are screwed). HIV-1 is figuring out how to pick our locks at a population level.
Okay, well, what about antibodies, then? What about a vaccine that revs up B-cells instead of T-cells?
Well, a series of papers have been coming out of a lab in the Netherlands that makes me think we might be screwed on that front too.
And once again, its all evolutions fault.
Read on »
Posted by ERV at 11:00 AM • 36 Comments • 0 TrackBacks
March 1, 2010
Category: HIV/AIDS
HIV-1 deniers-- They love Orac. They love Tara. Even like haunting the Hoofnagle brothers a bit.
They dont like ERV.
Never have.
*sad face*
I really cant figure out why. (I bet its cause Im mean and kannut com00nicates scienz).
Three years ago, today, I posted a challenge to HIV-1 Deniers. A simple test of basic HIV-1 literacy and competency. Three years ago... and it only has three comments. One from a supporter, one from me, and one from an HIV-1 Denier... who didnt answer the question. Just linked to the nutty Perth Group and hoped something Perth said stuck (nothing on the linked page was related to The Challenge, sry).
Alllllll those HIV-1 Deniers stalking Silvia... allllll those HIV-1 Deniers blabbing on other science blogs... they have no idea what that picture is. Dont know what it is, so cant figure out what it means. Stock-standard image that is in a million HIV-1 publications, they dunno what it is.
But they know HIV-1 doesnt cause AIDS. Or it doesnt exist. Or something.
Maybe expecting people with such passionate opinions be even modestly educated on the topic they are so passionate about is too much to ask.
So here is an even easier challenge. Ill even include some links to make this really, really fucking easy.
HIV-1 DENIERS! EXPLAIN THIS:
293T cells were transfected with an infectious molecular clone of HIV-1, where EGFP was inserted between env and nef. The resulting viruses contain genomes that contain the EGFP gene, thus the EGFP gene is permanently inserted in the host genome after infection.
This is what happens to cells 'infected with HIV-1' (raw image)
This is what happens to cells that only get media off untransfected 293Ts (raw image)
If HIV-1 does not exist:
- How did the EGFP gene get into the PBMCs genome?
- Why are these cells now producing EGFP, as well as progeny virions that can go on to infect new cells and turn them green?
- Why are all those EGFP positive cells going to be dead tomorrow, while the not-green cells are snug as bugs in rugs?
Posted by ERV at 6:00 PM • 38 Comments • 0 TrackBacks
February 26, 2010
Category: Douchebaggery! • Science Outreach
Boy, do I have egg on my face!
After I just made fun of the absurdity of Chris Mooneys 'building bridges with antivaxers' or 'ladders to heaven' or 'rope swings to Creationists' or whatever strategy, Mooney is named a Templeton Foundation 'fellow'.
Like most of you, my initial response was "What a douche."
But then I realized-- This is THE answer to my prayers.
All these years I have been so goddamn frustrated with the level of stupidity coming out of religious institutions regarding HIV-1.
But there was nothing I could do about it because Im not nice and Im a stoopid scientest tat dunt commoonikates gud.
Now that The Master Science Communicator and Bridge Engineer is in A Position of Power, Mooney can solve all of my problems!!!!!
The GameMaster Pope will start telling everyone to use condoms to stop the spread of HIV-1!
Fundamentalist Christians in the US will stop trying to kill HIV(+) homosexuals in Africa!
Fundamentalist Christians will stop holding up Anti-HIV funding because it might go towards family planning clinics or needle exchange programs!
Fundamentalist Christians will stop promoting their failed 'abstinence only' anti-HIV plan, recognizing that their 'moral authority' has limited real-world applications.
Fundamentalist Muslims will stop killing HIV-1 advocates in Africa!
The Red Sea will part, manna will fall from the heavens, bridges will be built between the real world and lunatics, now that Chris Mooney is a Templeton Fellow!
He can now show us all how its done!
*grins like a Cheshire cat and waits*
Posted by ERV at 4:30 PM • 41 Comments • 0 TrackBacks
Category: XMRV
Study from the Netherlands:
Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort
CFS/ME patients plus age/sex/neighborhood matched controls (patients brought in friends that lived in the same area-- environment might play a role).
32 ME/CFS patients
43 controls
0 XMRV present in PBMC, using reagents verified in this paper (integrase) and this paper (gag- the same ones WPI used).
Cut/Paste summary:
A limitation of our study is that the numbers of patients and controls in our study were relatively small. Based on these low numbers, the upper limit of the 95% confidence interval is a prevalence of 9% for the patient group and 7% for the control group, as calculated according to Eypasch et al (by the formula p=3/n).18 Although we cannot formally rule out a role of XMRV, our data cast doubt on the claim that this virus is associated with chronic fatigue syndrome in the majority of patients...
... Technical aspects are unlikely to explain the difference in XMRV positivity rate between our data and their data...
... It is possible that the study of Lombardi et al has unravelled the viral cause of the chronic fatigue syndrome outbreak, but it seems unlikely that their study demonstrates a viral association for sporadic chronic fatigue syndrome cases, such as those we tested, or represents the majority of patients.
Now, this paper demonstrates the scientifically acceptable, normal way scientists bitch-slap one another (SPOILER: It doesnt involve calling other scientists frauds):
In conclusion, we found no evidence for a role of XMRV in the cause of chronic fatigue syndrome in Dutch patients. Over the past decades we have seen a series of papers prematurely claiming the discovery of the microbial cause of chronic fatigue syndrome. Regrettably, thus far none of these claims has been substantiated.
Still no XMRV in Europe.
Posted by ERV at 12:00 PM • 20 Comments • 0 TrackBacks
February 25, 2010
Category: HIV/AIDS
From building bridges with anti-vaxers to building bridges with animal liberation maniacs, Chris Mooneys 'building bridges' plan is revolutionizing the way scientists interact with insane people!
Its even changing the playing field with HIV-1 Deniers.
Long-time readers know I have relatively little patience with HIV-1 Deniers. Everyone involved with HIV Denial, from the 'professional scientists' to the 'Average Joe snake-oil salesman' are complete and utter morons. So, frankly, they are only good for one thing: lulz.
So while I like writing about the latest HIV-1 findings on ERV, I rarely actively engage HIV Deniers. I just laugh at them.
Now, that is a Very Bad Move, according to Mooney. HIV-1 researchers should be building bridges with HIV Deniers:
Instead, I believe we need some real attempts at bridge-building between medical institutions--which, let's admit it, can often seem remote and haughty--and the leaders of the anti-vaccination HIV Denial movement. We need to get people in a room and try to get them to agree about something--anything. We need to encourage moderation, and break down a polarized situation in which the anti-vaccine HIV Denial crowd essentially rejects modern medical research based on the equivalent of conspiracy theory thinking, even as mainstream doctors just shake their heads at these advocates' scientific cluelessness. VaccineHIV skepticism is turning into one of the largest and most threatening anti-science movements of modern times. Watching it grow, we should be very, very worried--and should not assume for a moment that the voice of scientific reason, in the form of new studies or the debunking of old, misleading ones, will make it go away.
This is what happens when you try to build bridges with HIV Deniers:
Read on »
Posted by ERV at 2:00 PM • 98 Comments • 0 TrackBacks
February 22, 2010
Category: XMRV
When scientists are creating tests to detect viruses, they need to balance two factors:
A 'sensitive' test is no good if it cross-reacts with other proteins/viruses/antibodies. A test with high 'specificity' is no good if you miss 3 out of 10 infections.
Of course, then you need to worry about cost (a perfect test is unusable if no one can afford it) and speed (acute diseases need fast diagnoses, and who wants to wait 3 months to find out if they have a life-altering chronic disease?), and other factors.
So scientists normally use tests that view a putative disease from lots of angles, reducing the odds we are making mistakes by looking for one thing the wrong way--
- Look for antibodies to the virus
- Look for viral antigens
- Look for viral RNA and/or DNA
Each of these tests have variations (antibodies to what? what viral protein? viral genomes? proviruses? which part?), and when you put them all together, the odds of someone being falsely labeled 'POSITIVE' (or 'negative') drop lower and lower and lower.
One thing about these XMRV 'tests' and their reported 'results' is that some of the scientists reporting 'positives' are not thinking critically, at all, about what they are saying regarding the sensitivity and specificity of their tests.
Prime example, the WPIs latest bitchfest press release regarding other labs findings (or lack thereof):
Read on »
Posted by ERV at 1:30 PM • 35 Comments • 0 TrackBacks
February 20, 2010
Category: Creationism • Humor
Creationism is so boring.
Creationist: BIOLOGICAL FEATURE ___ IS IMPOSSIBLAH!
Scientist: Um, Dude, theres like 65 years of research explaining how feature ___ evolved.
Creationist: NO THAT RESEAERCH SUPPORTS JESUS! EVIDENCES OF CREATION!
Scientist: What? No, we have a pretty good idea the evolutionary steps between ___ and ___. Theres no way this research supports special creation. I mean, its actually taught in undergrad biology classes now.
Creationist: NO. I CALCULATED IMPOSSIBLAH. JESUS LOVES ME!
Scientist: ... Youre just mashing the keys of your calculator. Thats not a 'calculation'.
Creationist: EXPELLED! EXPEEEEEEELLLED! YOU ARE BE PURSEICUTING MEH!!! NAZI!! *runs to a school board to get their 'calculations' taught in public school science classes*
Thats it. Same thing from YECs, to OECs, to IDCs, decades and decades of that.
We finally have something new.
Creationists propose "Intelligent Recall" theory to explain extinction of species--
Hawkins further revealed that God had decided to recall the dinosaurs after rescuing them from the global flood. Hawkins didn't specify the factors that God considered before recalling any species, proclaiming it to be beyond the capacity of human intelligence.
AHAHAHAHAHAHAHA! Parody writers: More creative than Creationists.
Posted by ERV at 11:49 AM • 20 Comments • 0 TrackBacks
February 19, 2010
Category: Virology
Antibodies are normally a good thing. Neutralize viruses and bacterial toxins, tag bacteria for complement so they get blown up, tag invading parasites/worms/ew so your immune cells can kill them, antibodies even make nice cancer therapies.
One of the great things about antibodies is that the cells that make them? They 'remember' what theyve seen before. Thats how vaccines work-- you expose someone to a crappy polio virus, your body figures out how to neutralize it, and if youre exposed to Real Virulent Polio, your body has a cheat-sheet. Your body already has memory B-cells that know how to neutralize the virus, it doesnt have to scramble to figure out a right answer while the Real Virulent Polio is causing disease. Thus, if you get your polio vaccine, you will never experience disease caused by the polio virus, even if youre exposed to it.
But things dont always go according to plan, like with Dengue viruses:
Enhanced Infection of Liver Sinusoidal Endothelial Cells in a Mouse Model of Antibody-Induced Severe Dengue Disease
Normally, the more you are exposed to a virus, the milder the disease gets, if you get a 'disease' at all.
The exact opposite happens with dengue.
There are four 'flavors' of dengue. The first time youre exposed, you have very mild symptoms, or you might be totally asymptomatic. The second time youre exposed to dengue, if its a different flavor, you start getting the severe symptoms-- fever, aches/pains, rash, and potentially death.
That makes no sense, right? Youre supposed to get sick the first time youre exposed, and not sick the second/third/fourth time your exposed. Whats going on?
The four flavors of dengue are closely related, but they are still different. Your body keeps making antibodies to the 'same' parts (antigenic sin), when its the different parts that mediate infection. So after your second infection, your body is making antibodies that cant neutralize the viruses anymore.
Furthermore, the non-neutralizng antibodies sticking to the viruses give the viruses an advantage: before, they could only infect cells that had just the right attachment molecules on the host cell surface. Non-neutralizing antibodies attached to viruses cause them to 'stick' to cells they normally couldnt infect... and the cell the virus is stuck to is now susceptible to infection.
Antibody-Dependent Enhancement.
... So what does this mean for vaccine design??
Anything but a 'perfect' vaccine could cause more severe disease after exposure, instead of preventing infection! It might mean we need to avoid making vaccines that elicit an antibody response, and shoot for a CTL vaccine instead.
What Zellweger et al have done is create a small animal model we can use for studying that very question. Their mouse model exhibits the same symptoms/pathology of dengue fever in humans. Theyve not only provided a means for collecting data that would otherwise only be available via autopsy, but a model for studying potential dengue vaccines and potential therapies for patients suffering from dengue fever. Sweet!
Posted by ERV at 1:00 PM • 12 Comments • 0 TrackBacks
I'm a graduate student studying the molecular and biochemical evolution of HIV within patients and within populations. I also study epigenetic control of ERVs.
