Viral interleukin-6: Molecular biology and pathogenesis

Human herpesvirus 8 (HHV-8, also called Kaposi's sarcoma-associated herpesvirus) was discovered in 1994, but interleukin-6 (IL-6) had been implicated in Kaposi's sarcoma and HHV-8-associated multicentric Castleman's disease (MCD) several years prior to this date. The predicted role of IL-6 in KS and MCD pathogenesis was based on its known pro-angiogenic and B-cell mitogenic properties. Thus, when viral IL-6 (vIL-6) was identified in HHV-8, the first reported viral interleukin-6 homologue, this was immediately recognized as a potential contributor to HHV-8-associated pathogenesis. Indeed, the pro-angiogenic, proliferative, and signaling properties of vIL-6 reflected those of its human counterpart. It is now known that there are significant differences in the precise mechanisms of signaling complex formation and in signal transduction induced by the human and viral IL-6 proteins and also that vIL-6 is able to signal intracellularly, which is likely to be highly relevant to its functions in virus biology and viral pathogenesis. The unique properties of vIL-6 suggest that it may be possible to target the viral cytokine specifically with inhibitory agents, but they also highlight special challenges with respect to appropriate targeting of inhibitory agents to the sites of vIL-6 activity. This review discusses the molecular biology of vIL-6, the means by which it may contribute to virus biology and viral pathogenesis, and possible methods of inhibiting the activity of the viral cytokine.