Karolinska Institute, Stockholm, Sweden
September 5, 1999
At the VIIth International Myeloma Workshop in Stockholm, the IMF initiated, for the first time, a focused workshop on the role of viruses in multiple myeloma. This special virus symposium, hosted by Prof. Haakan Mellestdt and co-chaired by Prof. Brian Durie and Dr. James Berenson at the Karolinska Institute, brought together investigators studying viruses which may contribute to the pathogenesis of multiple myeloma. The participants in the symposium included Dr. Robert Kyle, Dr. Robert Vescio, Dr. Kenneth Anderson, Dr. Howard Urnovitz, Dr. Shou-Jiang Gao, and Dr. John Lednicky of the U.S., Prof. Luc Montagnier of France, Prof. Peter Biberfeld of Sweden, and Dr. Frank Neipel of Germany.
The meeting convened with mutual introductions around the table. One exciting aspect was that several investigators had not met directly and therefore were initiating interaction and collaboration for the first time. There was particular excitement to have Prof. Luc Montangier from the Pasteur Institute of Paris present. The involvement of the world renowned co-discoverer of the HIV virus is clearly a strong advantage for the myeloma community overall. In addition, the several groups working on HHV-8 Kaposis Sarcoma virus were represented, including Dr. James Berenson from UCLA, Dr. Kenneth Anderson from the Dana Farber Cancer Center, as well as the group from Germany, plus Dr. Shou-Jiang Gao from the University of Health Sciences Center in San Antonio, Texas. In addition, investigators prominent in the field of SV40 virus infections were represented including Dr. John Lednicky from the Division of Molecular Virology, Baylor College of Medicine in Houston, Texas, and Dr. Howard Urnovitz from Calyptebiomedical in Berkeley, California.
After the introductions, Prof. Brian Durie presented an overview of the field discussing the potential role of a variety of viruses toward the pathogenesis of multiple myeloma. He briefly addressed the mechanisms whereby viruses can interact with plasma cells and interfere with plasma cell growth, differentiation and cell survival. Viruses can have an impact on plasma cell and myeloma cell growth by a variety of mechanisms both direct and indirect. Viruses, including HIV, hepatitis, EBV, and several herpes viruses such as HHV-8 have been implicated in the triggering of myeloma as well as related B-cell malignancies. The increased risk of multiple myeloma in patients with HIV infection is well established. A recent large analysis showed an odds ratio of 4.5 to 1 in patients with AIDS in terms of increased likelihood of developing myeloma during the course of their disease.
The potential role of SV40 (simian virus number 40) infection was then summarized by Dr. John Lednicky and Dr. Howard Urnovitz. SV40 is a known cancer causing virus first discovered in polio vaccine lots prepared from monkey (simian) kidney cells in the 1950s and 1960s. The rationale for exploring the molecular genetics of SV40 was discussed. RNA containing SV40 T-antigen binding sites is expressed in the blood of patients with active multiple myeloma. This has raised the possibility that latent SV40 may become involved in the pathogenesis of multiple myeloma during the active phase of the
Dr. Lednicky summarized the various mechanisms which are important in the pathogenesis in several types of cancer related to SV40 infection. Increasing evidence supports the notion that SV40 can participate in the pathogenesis of a whole range of human cancers particularly soft tissue tumors and brain tumors in children, but also a variety of cancers in adults including mesotheliomas and, most recently, B-cell malignancies such as multiple myeloma. The very recent observation that active SV40 infections can occur in young children indicate that SV40 has entered the human population and is occurring in individuals who were not directly vaccinated with the polio vaccine which was contaminated with SV40.
Following this presentation and discussion, Prof. Montangier showed electron microscope pictures of RNA complexes prepared from the plasma of patients with active multiple myeloma. Of historical interest, these pictures were taken using the same electron microscope which was used in the initial discovery of the AIDS virus. Careful evaluation of the plasma RNA from myeloma patients did not reveal any encapsulated virus particles. However, free floating RNA particles were noted which had a configuration that resembled CMV (cytomegalovirus) particles. Different terminology has been used to describe such RNA in the plasma. Since the RNA observed is palindronic (able to fold upon itself) and can bind to RNA binding proteins it may be a stabilized complex or RNA-protein-lipid material. However, separate literature has documented that such particles may have infectious properties and can be described as virusoids or viroids. Such material has been widely reported in plants. In separate studies with myeloma patients Prof. Durie, in collaboration with Dr. John Martin, has cultured "stealth virus" (mutated form of CMV) from the blood of myeloma patients which can produce a cytopathic effect in vitro. "Stealth virus" culture results have been positive in patients with active myeloma and revealed RNA fragments which match the RNA identified in separate studies using PCR technology. Furthermore, detailed electron microscope studies are underway to clarify the nature and properties of the RNA noted in the blood of myeloma patients.
After a break, the various groups working on HHV-8 sequentially presented their results. Some of this information had been presented at the earlier VIIth International Workshop formal meetings, however had not been discussed in the context of other viruses. The various mechanisms potentially involved in HHV-8 triggering of myeloma cell growth were summarized in detail by Dr. Anderson. The group from Germany highlighted the fact that they are consistently unable to detect an antibody response to HHV-8 in the patients with active myeloma. Potential reasons for this were addressed by Dr. Gao. His studies have revealed that an aberrant form of HHV-8 subtype C3 may be present in multiple myeloma patients as well as patients with other kinds of disease. The possibility that the mutated forms of HHV-8 may be unable to elicit an antibody response was discussed at some length. Further molecular analyses of HHV-8 from patients with multiple myeloma will be crucial in assessing the impact of molecular hedrogeneity on antibody generation.
The workshop finished with some overview summaries and comments. The various participants were able to continue the discussions through the evening at the dinner hosted to celebrate this very successful first virus workshop in multiple myeloma.