Phoenix Rising - Cort Johnson's Column
...Presenting complex chronic fatigue syndrome (ME/CFS) research in a way we can all understand.
XMRV in the Spotlight
by Cort Johnson
XMRV was next up at the mike at the CFSAC meeting. First Dr. Peterson went over the published research one more time. Hearing it again simply reinforced what an extraordinary discovery XMRV may be. His presentation was, in some ways, though, really just a prelude to Dr. Coffin’s presentation. The co-author of the major text in the field, Dr. Coffin represents the upper tier of world class researchers that we’ve been wanting to attract for so many years. He was basically our toughest test case; if he was excited about this virus then everyone in his field is.
Good Science! - He was excited. There have been some questions about the demographics side of the study but the science side was better than we patients could tell. Annette Whittemore said that the Science paper didn’t get easily; Science wanted the virus story but not the CFS part of it. After the WPI dug in their heels and said you’re not going to get one without the other Science made them jump through hoop after hoop. Their ability to do what they did surprised alot of people.
“This is a remarkable finding. Everybody recognizes this is potentially of extraordinary importance” Dr. John Coffin
A Remarkable Finding - The prostate cancer association with XMRV interested the field in the virus; the Science paper apparently blew the lid off of it. Already the WPI (and NCI and Cleveland Clinic) researchers have accomplished something that its very difficult, even now, to do in HIV which is target the virus in the plasma. Apparently its not difficult to find HIV in cells but its still very difficult to actually capture it in plasma.
The fact they were able to isolate a virally infected cell and put it next to a prostate cancer cell and watch the virus infect the prostate cancer cell was a huge win for them. The fact that Dr. Peterson was able to thaw out some samples that had been frozen for 25 years and then grow virus out of them apparently just blew the virologists minds.
When they looked for it in the ‘activated’ immune cells they found it in a very high percentage of them - which suggests an active infection. (Immune cells become ‘activated’ - basically put themselves into overdrive - once they encounter a pathogen. ) They’ve also been able to induce the virus to grow in a number of cell lines (prostate cells, B and T cells).
None of these steps should be taken for granted. Getting a pathogen to grow in cell lines is a very important step in studying it. Not only can you grow alot of virus when you do that but you can study the virus intimately. It’s often, however, difficult to put viruses in a test tube and get them to actually grow in cell lines. For instance, decades later, hepatitis C virologists have still never isolated the hepatitis C virus (they sequenced its genome instead) and have never been able to grow it in a culture. Because of this essential elements of its biology have escaped them. (VIPdx began offering a culture test for XMRV a week ago).
The Bad Virus on the Block? - Nobody knows what effects XMRV does or does not have but its clear that the family of retroviruses it belongs to is a nasty one. These gamma retroviruses are known to cause a slue of cancers in animals including lymphoma (aka Incline Village) and leukemia. This is part of what’s fascinating to researchers about the virus; could it set the stage for all sorts of cancers? Annette Whittemore said breast, leukemia, lymphoma, etc. researchers are all going to take their shot at this virus. Over the next couple of years its possible this virus shoot from near obscurity to being very well understood in the scientific community.
Not HIV! - XMRV is about as different from HIV as a retrovirus can be in several ways. XMRV doesn’t appear to replicate rapidly which means it has a low mutation rate and suggest it might be relatively easy to create a vaccine for but also gives researchers less of a window on the treatment end to knock it down.
“The potential pathogenecity of this virus should not be underestimated” Dr. John Coffin
Treatments - Its unclear whether HIV drugs are going to work. (The WPI is reportedly testing them and antivirals including Ampligen in the lab). Interestingly AZT, which had been sitting on the shelf for 20 years before the HIV epidemic hit, was developed against a gamma retrovirus (like XMRV). Even more interesting the drug developers apparently have a good number of anti- retroviral drugs sitting on the shelves that didn’t appear to work well enough against HIV but could find some promise with XMRV.
Vaccine Yes, Treatment? - It may not be easy, though. Dr. Coffin reiterated the fact that the viruses remarkable genetic similarity from person to person (even between people located across the country) meant that chances for finding a vaccine were pretty good and, in fact, one has been developed for a similar virus. The low replication rate, however, apparently make it more difficult to target treatments against this bug. (Different HIV treatments target different stages of its replication process).
(Genetic diversity is essentially a function of replication; the more a virus replicates the more small changes in its DNA accumulate. The fact that genetic diversity is so low in this bug suggests that it is not replicating very much. It could also suggest that a contaminant got into the samples but the researchers appear to have discarded this scenario. )
In key ways HIV is the exact opposite of XMRV; it replicates rapidly and demonstrates high rates of genetic variability. Dr. Coffin noted that the HIV virus will mutate more simply living in a person’s body over several months than XMRV has between people living different parts of the country. What we have with HIV, of course, are alot of treatment options (@30 drugs) and, despite years of enormous effort and money - almost zero advance on the vaccine front.
Hopefully the opposite scenario will not prove true with XMRV. Dr. Coffin reported some antiretrovirals were proving effective at least in the lab against the virus. (Ampligen was reportedly working in at least some patients cells.) Translating the results from the lab to an actual patient is, often difficult to do, however.)
Does Low Replication Mean Little or No Disease? - Not necessarily. A virus doesn’t need to replicate in order to effect the body; it simply needs to be alive and pumping out injurious proteins. The idea of a kind of smoldering infection with low replication rates has caught on in some parts of the research community. Dr. Glazer has,for instance, identified enzymes produced by EBV that can cause a number of negative effects.
Add to that the fact that a large percentage of ME/CFS patients T-cells are typically ‘activated’ (turned on by a pathogen) and then throw in Dr. Coffin’s statement that a large percentage of activated cells carry the virus and you get the picture of a virus that may be very prevalent in the body; i.e., it might not need high levels of replication to do its work.
"I’ve had many people come up to me and ask how I can get involved" - Dr. John Coffin
XMRV and ME/CFS - How to explain the high apparent rate of infection in the ME/CFS patients but not the healthy controls? Dr. Coffin thought of three main possibilities;
- the patients happened to live in areas where outbreaks of this virus had occurred
- they had an immune system defect that left them particularly vulnerable to the virus
- the virus actually infects everybody but is just easier to find (is more active) in people chronic fatigue syndrome (the opportunistic virus theory).
Those ‘Unhealthy?’ Healthy Controls - the Feds are many times more concerned about the 4% of the health controls that tested positive for XMRV than the 67% of the sick ME/CFS patients who did. If these healthy controls were close contacts of the XMRV positive patients we would expect that number to go down - but they weren’t- they were taken from the broad population. Expect that 4% figure to stay strong - and research money to keep pouring into this virus no matter what happens with chronic fatigue syndrome
Some Answers - There are alot of questions but one important one - how widespread is this virus in ME/CFS and what types of patients carry it? - should be answered soon. Dr. Bateman and Dr. Klimas and others have their blood samples lined up and ready to be tested. Dr. Bateman stated she’ll be sharing her results as they come out.
“There have to be co-factors” Dr. Peterson
No Simple Answers - Even after we learn just how widespread this virus is the situation will remain complex. Since we know that many people can carry this virus and still remain healthy its clear that the virus is going to need at least one ‘partner’ to work with in order to wreak its damage. What that other essential element is is, of course, unclear. The virus’s cortisol receptors indicate that it reacts in some way to cortisol. High cortisol levels could concievably trigger its activation but ME/CFS patients, at least in the later stages of their disease, are known to have low cortisol levels. (Could the opposite be true? Could high cortisol levels send it into hibernation and low cortisol levels leave it in an activated state?).
The Money - We’ve seen that the traditional sources of ME/CFS research in the federal government, the ORWH and the CDC’s CFS program have been left by the wayside. The research money for this virus is coming from other sources. The retrovirologists want in. When something this potentially big comes on the scene they find ways; they shift funds around at their labs, they drop projects…they basically do what they have to do to get their foot in the door. The CDC’s HIV team started their XMRV project the day after the Science paper came out. The WPI, the CFIDS Association, basically anyone with blood samples is getting with requests - some of them from world renowned resesarchers. (The CFIDS Association requires their investigators to bank samples for future study)
“There are pockets of money at the NIH that can be tapped” Dr. John Coffin
The researchers will pretty quickly have to tap traditional funding sources, though, which historically has been a problem. Every ‘CFS’ grant to my knowledge automatically goes to the CFS grant review board - often a death trap for ME/CFS grants. These review panels typically have been top loaded with pain (and dental!) researchers and rarely have reviewers with immune expertise. The expertise of the review panel is supposed to match the types of grants before them. Will they this time? Only time will tell.
Doing It Right - Interestingly everyone - the NCI, the CDC, the Blood researchers, are developing their own tests. Dr. Miller explained that you can set up a PCR test for a virus almost overnight. PCR tests simply screen for select bits of DNA in a virus. The problem comes when the different labs choose slightly different sections of DNA to test or prepare the ‘reagents’ the virus comes in differently. (One reagent can be far better at uncovering the virus than another.) The Dr. Coffin stated that agreeing on the right test - a validated, standardized assay - for XMRV was the critical issue facing the field. He hopes that will be done in six months.
The Other Stuff - Its going to take years and years to figure out how this virus - if it is proved to be a or even the major factor in ME/CFS - creates its effects. Meanwhile research into its downstream effects of it - the low blood volume, the gastrointestinal problems, the immune, HPA axis and autonomic nervous system problems etc. - will remain vital. People with AIDS don’t die of HIV - they die of opportunistic infections that show up in HIV’s wake and thirty years later researchers are still trying to figure out how to deal with the ‘downstream’ effects of having a retroviral infection. If XMRV turns out to be ‘it’ the same will most likely be true for ME/CFS.
Wanda Jones - Wanda Jones is proving her worth in different ways every meeting; there was the first webcast, then the upgraded webcast, the increased organization, the more expansive website. Dr. Coffin was her ‘catch’. She called him the day before and got him in there. She’s stuck her neck out on this meeting (3 cameras this time and we took up the Lobby of the building - those are government resources she’s using!) and it paid off - hence her big smile when she announced almost 900 hits the first day of the videocast and the room was full. Congratulations to everybody who came out or clicked in and good for the CAA as well for targeting her at the Office of Women’s Health (OWH) and pushing for her to come on board.
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