Induction of HHV-8 lytic cycle replication by inflammatory cytokines produced by HIV-1-infected T cells

Human herpesvirus 8 (HHV-8) is a gamma 2-herpesvirus consistently identifie d in Kaposi's sarcoma (KS), primary effusion lymphoma, and multicentric Cas tleman's disease. Although HHV-8 infection appears to be necessary, it may not be sufficient for development of KS without the involvement of other co factors, One potentially important cofactor is HIV-1, HIV-1-infected cells produce HIV-1-related proteins and cytokines, both of which have been shown to promote growth of KS cells in vitro. Though HIV-1 Is not absolutely nec essary for KS development, KS is the most frequent neoplasm in AIDS patient s, and AIDS-KS is recognized as a particularly aggressive form of the disea se. To determine whether HIV-1 could participate in the pathogenesis of KS by modulating HHV-8 replication (rather than by inducing immunodeficiency), HIV-1-infected T cells were cocultured with the HHV-8-infected cell line, BCBL-1. The results demonstrate soluble factors produced by or in response to HIV-1-infected T cells induced HHV-8 replication, as determined by produ ction of lytic phase mRNA transcripts, viral proteins, and detection of pro geny virions. By focusing on cytokines produced in the coculture system, se veral cytokines known to be important in growth and proliferation of KS cel ls in vitro, particularly Oncostatin M, hepatocyte growth factor/scatter fa ctor, and interferon-gamma, were found to induce HHV-8 lytic replication wh en added individually to BCBL-1 cells. These results suggest specific cytok ines can play an important role in the initiation and progression of KS thr ough reactivation of HHV-8. Thus, HIV-1 may participate more directly than previously recognized in KS by promoting HHV-8 replication and, hence, incr easing local HHV-8 viral load.