The new lymphotropic herpesviruses (HHV-6, HHV-7, HHV-8) and hepatitis C virus (HCV) in human lymphoproliferative diseases: An overview

Considerable evidence has been accumulating in favor of a possible involvement of viral agents in the pathogenesis of human lymphomas. The most recent proposal for a lymphoma classification, the Revised European-American Classification, emphasized for the first time the pathogenetic importance of two viruses, namely Epstein-Barr virus (EBV) and human T lymphotropic virus I (HTLV-I) in the development of certain lymphoid neoplasias. However, in the last ten years new viral agents possibly related to lymphoproliferative activity have been discovered: three herpesviruses [human herpesvirus-6 (HHV-6), -7 (HHV-7) and -8 (HHV-8)] and a flavivirus, HCV. HHV-6 was isolated from the peripheral blood of patients with lymphomas and a possible role for this beta-herpesvirus in Hodgkin's disease and in angioimmunoblastic lymphadenopathy (AILD) has emerged from serological and molecular studies. HHV-7, a beta-herpesvirus genetically close to HHV-6, has not yet been found in a human disease but it utilizes CD4 as a receptor on the lymphocyte surface. Only partial HHV-8 genomic sequences have been identified so far, suggesting a genetic homology with members of the gamma-herpesvirus family, including EBV. HHV-8 sequences have been identified for the first time in all forms of Kaposi's sarcoma as well as in a variety of lymphoid disorders, including body-cavity-based non Hodgkin's lymphomas, Castleman's disease, AILD and a type of HIV-negative reactive lymphadenopathy with peculiar histologic features. Finally, after its identification as the major cause of post-transfusion and sporadic non-A, non-B hepatitis, HCV has revealed a lymphotropism both in vitro and in vivo. A strong association between HCV infection and a benign lymphoproliferative disease, essential mixed cryoglobulinemia type II, has clearly emerged both from serological and molecular studies. A possible role for this viral infection in B-cell non Hodgkin's lymphomas not associated with cryoglobulinemia has also been proposed recently. The present work offers an overview of the huge amount of experimental and clinical observations supporting the possible involvement of these new lymphotropic viruses in human lymphoproliferative diseases.