Friday, 14 October 2011

At least two sides to every story

This is a blog predominantly about autism research but now and again I have been known to wander. One topic which I wander off into quite a bit is Chronic Fatigue Syndrome (CFS) / Myalgic Encephalomyelitis (ME)  as exemplified by posts like this and this. I wander into CFS/ME because, like autism, here is a spectrum of conditions asking more questions than answering them. One of the more 'heated' areas of questioning in CFS/ME has been around the various twists and turns of the XMRV story.

I'm not going to rehash the same stuff in this post but the main points focus on the almost operatic battle on the question of detecting XMRV: yes I can, no you can't. Yes we can find it in some samples from people with CFS/ME according to this article published in 2009*. No we can't, in this recent paper** which has gone hand in hand with a partial retraction and some discussions on various Internet sites which I am not going to cite in this post.

Up until a few days ago I didn't know all that much about the work coming out of the Whittemore Peterson Institute (WPI) led by Dr Judy Mikovits aside from what I read in cyberspace. I knew a little bit about the backstory: Dr Mikovits asked to leave and the continuing debate about why and what will happen to various research and grants. I know a little bit more now after seeing Dr Mikovits present some of her data and answer some of the questions about this whole story and where it might go next. As in the title of this post, there are always at least two sides to every story. Let me elaborate.

It was a fresh clear Autumnal Friday evening when Dr Mikovits made a presentation at the Education Centre of Sunderland Royal Hospital at the behest of the Sunderland & South Tyneside ME/CFS Support Group. The first impression I got about Dr Mikovits is that she knows her stuff. She is no stranger to research after all with a quite impressive publication record spanning her varied career, covering areas of HIV, product formulation and drug discovery and cancer research. Her work in HIV and retroviruses potentially tied into DNA methylation is perhaps most interesting alongside the now pretty well established link between some viruses and some cancers.

Her presenting style was slick, quick and pretty technical, going through the various stages of the XMRV story and some elaboration of the saga behind the headlines. A few points that I managed to jot down from her presentation:

  • Whilst ME/CFS is a focus for the current virology work, she is interested in various other conditions under the umbrella of 'neuro-immune' which potentially share some overlapping features such as cytokine and chemokine abnormalities, inflammation, allergy and intolerances and oxidative stress. Epigenetics (changes in gene expression not involving alterations to the genetic code) was also mentioned. You guessed it; that also includes autism.
  • We were given a crash course in human gammaretroviruses (HGRVs). Part of that focused on how these viruses might be involved in all manner of things including potentially interacting with other viruses. One or two interesting primate studies were also discussed including this one by Onlamoon and colleagues*** on disappearing viral and proviral signals in blood after a month of XMRV infection (latency and activation). Work by Makarova and colleagues**** on the low immunogenicity of the virus was also detailed.
  • There was some suggestion of a signature 'footprint' cytokine and chemokine profile present in cases of CFS/ME positive for XMRV. This included: IL-8, IL-13, MIP-1alpha and MIP-1beta, TNF-alpha, IL-7, INF-alpha, IL-6, and GM-CSF. I can't readily verify this compound set, the numbers of participants it was based on and whether all were increased or decreased. I would imagine 'increased' given the functions of many being in response to viruses (and bacteria and parasites).
  • Mention was also made of nagalase activity being elevated. I remember reading recently about some similar findings of nagalase being reported in cases of autism (here) albeit not formally published on. I'm not going too much further into this area because it is frighteningly outside of my competence and indeed takes CFS/ME and autism into some very unusual territory.
  • The 'contamination' debate which is being widely discussed was also presented on. I can't claim to understand everything but I have the words 'plasmid contamination' and 'junction primer' scribbled in my notes if that makes sense to anyone.

The general impression I got, as a non-virologist, about the detection of XMRV and related viruses (as with any virus) is that it is complicated. It's not like saying we can detect this virus or other viruses like we can measure blood glucose levels for example. You need to avoid contamination (as we have seen recently in other areas of forensic science). You need to make sure your are using the right targets to detect the virus. You also need to think about where the virus is and how 'active' it might be (or not) and onwards whether you need to 'provoke' the activation of a virus ('provocation' can be construed in many different ways). In short it is a complicated procedure; much more complicated than I originally thought.

Dr Mikovits accepted that XMRV is probably not going to be the 'be all and end all' of CFS/ME as per the partial retraction of the Science paper. She did however stick to her guns about the potential involvement of other gammaretroviruses as perhaps a source of further investigation.

I don't claim to be an expert in this area of investigation (and speculation). Neither do I offer any view on who is right or wrong in this complicated area. What I do perhaps want to see more of is continued research done in this area as suggested by Lo and colleagues***** and their suggestions of a related polytropic family of viruses, related but not necessarily XMRV, which might be applicable to many more conditions outside of just ME/CFS. Just because the technology and methods might not be suitably honed to detect these complicated viruses, does not mean that they may not be there. The chicken and egg question is what came first: CFS/ME or virus?

As we have seen recently in Alzheimer's disease, there is a lot not known about the viruses we share our little rock with and how we interact with them and them with us.

P.S. I am only reporting what I heard. Don't shoot the messenger.

* Lombardi VC. et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science. 2009. 326: 585-589.

** Simmons G. et al. Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: a multi-laboratory study. Science. 2011. September 2011.

*** Onlamoon N. et al. Infection, viral dissemination, and antibody responses of rhesus macaques exposed to the human gammaretrovirus XMRV. J. Virol. 2011. 85: 4547-57.

**** Makarova N. et al. Antibody responses against xenotropic murine leukemia virus-related virus envelope in a murine model. PLoS ONE. 2011. 6: e18272.

***** Lo SC. et al. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. PNAS. 2010. 107: 15874-9.