WOLVERHAMPTON, UK – Human endogenous retroviruses (HERVs), the genetic dregs of past infections, infest about 8% of the human genome and are expressed at low levels in the blood of even healthy subjects. These "fossil viruses,"  which are transmitted vertically through the germline, are generally noninfectious but occasionally produce proviruses, which are sprinkled throughout the DNA of human cells.

HERV-K10 is expressed at high levels in RA patients, and is expressed more in synovial fluid from affected joints than in peripheral blood.
A few types of HERVs retain the ability to produce viral products and to form viral particles, and these HERV-K viruses are suspected of triggering or contributing to autoimmune disease and/or cancer in the genetically susceptible. A British research group led by Peter N. Nelson, MD, of the University of Wolverhampton, UK, has identified an HERV that is expressed at high levels in RA patients and is expressed more in synovial fluid from affected joints than in peripheral blood. Dr. Nelson reports in Annals of the Rheumatic Diseases that messenger RNA (mRNA) for the HERV-K10 gag gene is found at significantly higher levels in the peripheral blood monocytes (PBMCs) of rheumatoid arthritis (RA) patients than in osteoarthritis (OA) patients (P = .01) or in healthy controls (P = .02).1

"For some years we and other groups looked at retroviruses akin to HIV or HTLV, but found nothing," Dr. Nelson told CIAOMed. "However, HIV patients do show RA tendencies, so the story shifted to HERVs. Our data show that HERV-K10 is expressed in patients at the site of disease and in the periphery." Dr. Nelson recently presented new data that highlight a serological response to HERV-K10 in patients with RA and show that systemic lupus erythematosus (SLE) patients also have high levels of HERV-K10 expression compared to controls.2

"It's an interesting story, since the HERV virus has some homology to host proteins like collagen and immunoglobulin—sites where rheumatoid factors bind," Dr. Nelson said. "It could be that if the virus is activated, then the immune response goes into action. Because the virus shares some homology with host proteins/tissues, there is some collateral damage; ie, destruction in the joint. This becomes a cycle with an inflammatory response occurring that is not regulated, and over time joint damage/deformity occurs."

Dr. Nelson's group developed a novel multiplex reverse transcription polymerase chain reaction (RT-PCR) to measure HERV-K10 mRNA expression and used it to compare viral gag gene expression levels in 40 patients with RA, 10 patients with OA, and 27 healthy subjects.

The authors describe HERVs as "footprints of previous retroviral infection ... transmitted vertically through the germline and thus inherited by successive generations in a Mendelian manner." HERVs are under active study by cancer researchers and are suspected of influencing autoimmunity through either molecular mimicry, superantigen motifs that bypass the normal major histocompatibility complex (MHC) brake on T-cell stimulation, expression of aberrant antigens, or teaming up with an exogenous virus to produce neoantigens.

Earlier, Dr. Nelson and colleagues had found antiretroviral antibodies in patients with RA, lupus, and polymyositis, and retroviral antigens in 45% of synovial sections from RA patients, but had found no exogenous retroviruses, which sparked their search for endogenous viruses.

"Our data confirm earlier work, which showed that normal, healthy donors have a baseline level of HERV expression in the peripheral blood," Dr. Nelson said. "Consequently, it is possible that differential expression of HERVs may be critical in disease states."

This raises the question of whether the HERV overexpression triggers RA, is triggered by RA, or is the result of a common underlying pathology. James J. Goedert, MD, of the Viral Epidemiology Branch of the US National Cancer Institute in Rockville, Maryland, has long been on the track of HERV-K10 in cancer and discussed these endogenous retroviruses with CIAOMed.

"HERVs are a large part of the human genome, [constituting] perhaps as much as 8%, and were acquired [over] thousands of years. They don't have identified functions and appear to be the remnants of human retroviral infections," Dr. Goedert said. "In highly activated situations such as RA or cancer, some of these genetic remnants are turned on. That presents the ultimate 'chicken and egg' question: Given that viral genes abound among the 30,000 genes in the human genome, what starts the process of HERV expression? It might be an environmental trigger such as [exposure to] a chemical, a bacterial infection such as strep, or the flu. And once turned on, these viral genes might be contributing their own bit to the disease process."


Reference

  1. Ejtehadi HD, Freimanis GL, Ali HA, et al. The potential role of human endogenous retrovirus K10 in the pathogenesis of rheumatoid arthritis: a preliminary study. Ann Rheum Dis. 2006;65:612-616.
  2. Nelson PN, Shaw M, Roden D, et al. Human endogenous retrovirus HERV-K10 implicated in rheumatoid arthritis and system lupus erythematosus: potential pathological triggers. Presented at: The 3rd Congress of the Czech Society of Pathologists; May 4-6, 2005; Olmuc, Czech Republic.