Noncytolytic control of viral infections by the innate and adaptive immuneresponse

This review describes the contribution of noncytolytic mechanisms to the co ntrol of viral infections with a particular emphasis on the role of cytokin es in these processes. It has long been known that most cell types in the b ody respond to an incoming viral infection by rapidly secreting antiviral c ytokines such as interferon alpha/beta (IFN-alpha/beta). After binding to s pecific receptors on the surface of infected cells, IFN-alpha/beta has the potential to trigger the activation of multiple noncytolytic intracellular antiviral pathways that can target many steps in the viral life cycle, ther eby limiting the amplification and spread of the virus and attenuating the infection. Clearance of established viral infections, however, requires add itional functions of the immune response. The accepted dogma is that comple te clearance of intracellular viruses by the immune response depends on the destruction of infected cells by the effector cells of the innate and adap tive immune system [natural killer (NK) cells and cytotoxic T cells (CTLs)] . This notion, however, has been recently challenged by experimental eviden ce showing that much of the antiviral potential of these cells reflects the ir ability to produce antiviral cytokines such as IFN-gamma and tumor necro sis factor (TNF)-alpha at the site of the infection. Indeed, these cytokine s can purge viruses from infected cells noncytopathically as long as the ce ll is able to activate antiviral mechanisms and the virus is sensitive to t hem. Importantly, the same cytokines also control viral infections indirect ly, by modulating the induction, amplification, recruitment, and effector f unctions of the immune response and by upregulating antigen processing and display of viral epitopes at the surface of infected cells. In keeping with these concepts, it is not surprising that a number of viruses encode prote ins that have the potential to inhibit the antiviral activity of cytokines.