Retroviruses have long been associated with both hematological malignancies and neurological disorders in humans. Infection with the retrovirus HTLV-1 can lead either to the development of adult T cell leukemia (ATL) or HTLV-1 associated myelopathy. Infection with HIV is associated with the development of Non- Hodgkin's lymphoma (NHL) and the development of dementia in addition to its immunosuppressive effects. In preliminary testing we have found significantly elevated rates of both IgG and IgM antibody reactivity to the gag region of the human endogenous retrovirus Herv-K/HML-2 in plasma samples from individuals with amyotrophic lateral sclerosis (ALS). We have also found IgG reactivity to the Herv-K gag protein in some individuals with lymphoma. Thus we hypothesize that Herv-K may have a role as a cofactor in the development of both ALS and lymphoma. This is supported by an elevated prevalence of lymphoproliferative disorders in individuals with ALS. We hypothesize that expression of Herv-K/HML-2 endogenous retrovirus in macrophages and/or microglial cells drives a local inflammatory process that leads to the generation of an immune response, and ultimately to either neuronal death (in ALS) or tumorgenesis (in lymphoma). If this hypothesis is correct, we would predict that elevated rates of immunoreactivity to Herv-K should be observed in some types of lymphoma. Therefore we propose to determine the frequency of antibody reactivity to HERV-K/HML-2 and plasma Herv-K viremia in a large cohort of individuals with Non- Hodgkin's lymphoma. In addition to potentially confirming a link between ALS and lymphoma, this study will identify epidemiological factors associated with Herv-K/HML-2 re-activation and/or transmission. If successful, this Phase I STTR study can provide the basis for the development of new assays for the classification of lymphoma and ALS. Additionally this study can open up new avenues of investigation into the etiology, pathogenesis and, ultimately, the treatment of both lymphoma and ALS.
