Dr Frank Ruscetti on XMRV

XMRV symposium, June 9, 2011, Leuven, Belgium (part 1)

Dr Frank Ruscetti was introduced as the father of retroviruses and kicked off the symposium about XMRV.

Today we have three known retroviruses and XMRV turns out to be 'atrocious'. It appears to be involved in prostate cancer by men, the second most common cancer in men. He asked with a smile if we knew what the first was? ... Marriage.

How did they make the link between prostate cancer and XMRV?
Research in the area of genetic susceptibility to prostate cancer has revealed two potential genes but he essentially spoke about RNaseL:

RNase L turns out to be a candidate prostate cancer gene on chromosome 1q24-25 (HPC1)

=> XMRV is a human retrovirus and is similar to HIV and HTLV-1. It was first identified by Dr. Robert Silverman, in prostate cancer tissue of men with a specific genetic defect in their antiviral defense pathway. (http://www.wpinstitute.com/)

What is the link with ME/CFS?

RNase L is one promising marker that is consistent with an activated immune system in CFS.

The first studies of RNase L in individuals with CFS were initiated because the clinical symptoms associated with CFS could often be explained by a persistent viral infection or immune suppression, particularly in those patients who experience acute onset. Viral infection of cells results in the production and secretion of cytokines, including the interferons. Interferons control the way cells respond to a virus through a group of inter-related enzymes that comprise an antiviral defense pathway. This pathway is known as the 2',5'-oligoadenylate synthetase/RNase L pathway.

Antiviral pathway abnormalities

The status of the RNase L pathway is measured in humans by sampling peripheral blood mononuclear cells (lymphocytes). RNase L is the key enzyme of the antiviral pathway, and it is designed to degrade viral RNA. While RNase L is found in nearly all mammalian cells, it has to be "turned on" by a small molecule, 2-5A.

Binding of 2-5A to RNase L changes the enzyme from its inactive (latent) state to its active state.

Source: http://www.cfids.org/archives/2000rr/2000-rr1-article01.asp


Is prostate cancer an infectious disease?

Variants in:
- RNase L
- MSR1 (variants of the macrophage scavenger receptor 1 (MSR1) gene)
- and TLR4 (toll-like receptor 4 is a key innate immunity receptor that initiates an inflammatory response primarily against gram-negative bacteria)

associated with risk
- for infections in mammals
- prostate cancer in humans

  

XMRV is related to MLV


In mice, MLV and related viruses cause:
- immune defiency
- neurodegenerative diseases
- cancer

 
 
 
 
 
 
 
 
 
His conclusion:
 
XMRV must be heterogenous.
 
Definition: heterogenous [ˌhɛtəˈrɒdʒɪnəs]

adj
(Life Sciences & Allied Applications / Biology) Biology Med not originating within the body; of foreign origin


He emphasized that XMRV was detected in stroma (human fluid) not tumor cells. Men who stimulated their prostate contained more viral antibodies to ENV (envelop or the cover of the virus) and infectious XMRV in their bodily fluids than men who didn't.
It seems important not to stress the tissue where XMRV is hiding?

http://www.nature.com/nrurol/journal/v7/n7/fig_tab/nrurol.2010.77_T2.html

Conclusion: This is impossible to be explained by contamination.

Image: http://vipdx.com/faqs/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739868/
XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors

He explained how he found antibodies with the help of his wife Dr Sandra Ruscetti, Head of the Retroviral Pathogenesis Section, Laboratory of Cancer Prevention. She never throws anything away, that's the reason why he's still married to her ...


Why does he think the negative studies are negative? 

• XMRV is not truly associated with human disease;
• The technique: everything is in the details;
• unrecognized sequence details
• geographical distribution (cfr HTLV)
• Primates don't necessarily develop human diseases (cfr HIV)

HTLV is asymptomatic in majority of individuals.

• 5-8% lifetime risk
• evidence for geographical distribution like Japan
• adult T-cell leukemia
• clonal malignancy of CD and T cells
• long latency
• immune deficiency
• TAX and HBZ needed for transformation
• inflammatory syndromes

How is XMRV identified?

1. antibody detection
2. PCR for viral genes
3. FISH (Fluorescence in situ hybridization)
4. integration into human tissue

Dr Ruscetti mentioned an interesting quote from Dr Judy Mikovits: "In chronic diseases viruses seldom come alone, and in ME/CFS many viruses may be implicated."

He referred to the article "War and Peace between microbes" if you like more information about it.

Summary

HIV-1 disrupts the homeostatic equilibrium between the host and coinfecting microbes, facilitating reactivation of persistent viruses and invasion by new viruses. These viruses usually accelerate HIV disease but occasionally create conditions detrimental for HIV-1. Understanding these phenomena may lead to anti-HIV-1 strategies that specifically target interactions between HIV-1 and coinfecting viruses.

http://www.cell.com/cell-host-microbe/abstract/S1931-3128(09)00354-0
 
 
Where are we now? Is there contamination?
 
http://www.retrovirology.com/content/7/1/112
 
The question remains:
 
1. the virus has spread through several labs as a cell lab contaminant
or
2. people are contaminated with a virus that originated from cancer research
or
... there is no contamination.