Chronic Fatigue Syndrome — Could a "Stealth Virus" Be Lurking?
Abstract & Commentary
By John F. Joseph, MD, FACP, FIDSA, FSHEA, Associate Chief of Staff for Education, Ralph H. Johnson Veterans Administration Medical Center; Professor of Medicine, Medical University of South Carolina, Charleston, is Associate Editor for Infectious Disease Alert.
Dr. John is a consultant for Cubist, Genzyme, and bioMerieux, and is on the speaker's bureau for Cubist, GSK, Merck, Bayer, and Wyeth.
Source: Lombardi VC et al. Science. 8 October 2009 (10.1126/science.1179052).
It has been known for years that patients with chronic fatigue syndrome (CFS) have a defect in a major antiviral pathway, the 2-5A/RNase L pathway. The RNaseL produces non-specific viral cleavage and, thus, protects us from many viral infections (innate immunity). Defects in this pathway not only lead to susceptibility to viral infections but may also increase our susceptibility to tumor development. The RNaseL gene, called Human Prostate Cancer 1 (HPC1), has a variant R462Q related to a potential etiologic agent of prostate cancer, a novel human retrovirus, xenotropic murine leukemia virus (MuLV), named XMRV.
So, it was by a bit of serendipity that a group of workers headed by several from the Whittemore Peterson Institute in Reno, Nevada, asked if XMRV could be associated with CFS. What led to any rationale connection between prostate cancer and CFS is not clear, but the question led to a series of experiments that culminated in a very recent publication showing an association between the presence of this retrovirus in the peripheral blood mononuclear cells (PBMCs) of patients with CFS.
We are dealing here with intricate science that surely took these 13 scientists and a host of technicians years to produce. Yet the paper contains astounding findings that I'll try to summarize succinctly, for besides the eight primary article pages from Science Express, there are 18 additional pages of "supporting" materials that also contain fascinating data.
Here is what the paper reports. In 101 banked samples of PBMCs, 67% (68) were positive for a XMRV gag sequence. Next, seven of 11 PBMC CFS samples held at the Cleveland Clinic were shown to have XMRV gag plus env. Only 3.7% of PBMC DNA from healthy controls had XMRV gag when tested by PCR. Amazingly, those gag and env sequences were nearly identical to those from XMRV from prostate cancer-associated strains (PLoS Pathol. 2006;2:211). Full-length SMRV from two patients differed from prostate cancer strain VP62 by only six nucleotides, showing again a > 99% identity between the CFS and prostate cancer XMRV.
A phylogenetic comparison of six isolates from CFS/Prostate cancer showed them to be significantly different from other murine leukemic viruses. In all, 50 other isolates of MLV were used to make the neighbor-joining trees. The suspected closest relatives were other xenotropic murine viruses (Xmv 15-19 and Xmv 10, 13, 16) and polytropic (Pmv) plus modified polytropic (Mmpv) viruses, which were in fact very removed genetically from XMRV.
Next, it was shown that several antibodies with "novel viral specificities" all reacted with VP62 XMRV proteins when grown in several cell lines, including a line called LNCaP of prostate cells that are known to permit infection with MXRV. Flow cytometry of activated lymphocytes also showed that 19 of 30 PBMC CFS samples reacted with antibodies to MLV P30 Gag and other MLV proteins whereas PBMCs from normal patients were negative, for an odds ratio of 54.1. (confidence intervals of 23.8-122). So, there is a non-random association of CFS PBMCs with XMRV. Both activated T and B cells from CFS were infected with XMRV.
The next experiment was quite ingenious. PBMCs from CFS patients were co-cultured with LNCaP cells, the ones defective in RNaseL pathways. The LNCaP cells became infected, as shown by presence of XMRV gag and env proteins and by the presence of whole virus, as seen by electron microscope both at the time of infection and upon release. The electron micrographs are quite stunning. The same type of infectivity was also seen when only plasma from CFS patients was applied to LNCaP cells. Thus, cell-associated and cell-free virus seems to be infectious, at least to some cell lines. Finally, it was shown that 50% of plasma samples from patients with CFS have a humoral response to XMRV, demonstrated by presence in flow cytometry assays of antibodies to a viral env closely related to XMRV env.
Commentary
It was courageous of Science to publish this paper because there are obvious epidemiologic data missing from the report. Still, patients with CFS can clearly see from this article the sophistication and dedication of scientists studying CFS, giving them hope that there will be some etiologies discovered in the near future. Indeed, when Robert Suhadolnik and colleagues at Temple University School of Medicine described the defects in RNaseL in the mid 1990s, the newer methods in retrovirology were just emerging so, in a sense, these new studies had to await the sophistication that has come with laboratory advances in the HIV/AIDS era. Good science (methodology) begets better science.
Esteemed Professors John M. Coffin and Jonathan P. Stoye of Tufts University wrote an accompanying editorial in the issue of Science Express. They emphasize that the gammaretroviruses of mice, including endogenous MLVs, have given us much understanding of cancer pathogenesis; no such association has been made in humans until XMRV was discovered in prostate cancer tissue only three years ago.
This work will have its critics. One concern is laboratory contamination with MLV. It is very unlikely that laboratory contamination freed the XMRV into human cell lines. CFS PBMCs and prostate cancer patients come from very disparate backgrounds. Indeed, the patients at the Whittemore Peterson Institute also come from diverse geographies and, except for their common diagnosis of CFS, have little in common. That fact makes it even more remarkable that out of nearly 8000 nucleotides in XMRV-a retrovirus — only about 30 show variation. That lack of genetic variation for XMRV lies in great contrast to the huge variation we are used to seeing in HIV, suggesting that XMRV has recently descended from a common ancestor.
Drs. Coffin and Stoye in their editorial also focus on the 3.7% of XMRV positivity in normal PBMCs and non-cancerous prostate tissue. If this rate were to hold up in studies from other geographic regions of the world, that would suggest that at least 10 million people worldwide harbor the virus and perhaps are more susceptible to a wide variety of full expression of the retroviral infection.
As one of a group of physicians who has recognized and managed patients with CFS for many years, my bias is to believe the validity of these current data. Yet, many theories about the cause of CFS have come and gone. CFS patients are always looking for new hope. Indeed, an article in the New York Times of October 13 by Denise Grady speaks to thousands of patients already clamoring to be tested for the new virus. Of note also is that the Whittemore Peterson Institute was founded by parents of a young woman with CFS, so the data from Whittemore need to be verified in additional cohorts of CFS patients. Nevertheless, the passion of physicians like Dan Peterson himself, and others in that kindred, has driven the science of CFS. Steadfast organizations like our national CFS foundation, CFIDS (www.cfids.org), and many state CFS organizations continue to sponsor patients and programs that demand a balanced scientific playing field which in part has led to the quality of work demonstrated in the paper by Lombardi et al.
It has been known for years that patients with chronic fatigue syndrome (CFS) have a defect in a major antiviral pathway, the 2-5A/RNase L pathway. The RNaseL produces non-specific viral cleavage and, thus, protects us from many viral infections (innate immunity).You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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