REGULATION OF APOPTOSIS BY VIRAL GENE-PRODUCTS

Apoptosis is the process whereby individual cells of multicellular org anisms undergo systematic self-destruction in response to a wide varie ty of stimuli. Apoptosis is a genetically controlled preprogrammed eve nt which eliminates cells during development when they have become red undant or which functions as an emergency response after radiation dam age, viral infection, or aberrant growth induced by the activation of oncogenes. In the case of virus-infected cells, the induction of early cell death would severely limit virus production and reduce or elimin ate spread of progeny virus in the host. Thus, most animal viruses hav e evolved strategies to evade or delay early apoptosis to allow produc tion of high yields of progeny virus. Over the past few years both the biochemical basis of apoptosis and its regulation by viral products h ave become clearer. For example, part of the apoptotic program include s the induction of cellular endonucleases which could target replicati ng viral DNA and prevent virus production at a very early stage. Thus, the problem facing the virus is to replicate and package large number s of progeny genomes safely within newly synthesized viral capsids. Ma ny viruses have evolved genes encoding proteins which effectively supp ress or delay apoptosis long enough for the production of sufficient q uantities of progeny. In addition, a growing number of viruses are now known to induce apoptosis actively at late stages of infection. This process may represent a final and important step in the spread of prog eny to neighboring cells while also evading host immune inflammatory r esponses and protecting progeny virus from host enzymes and antibodies . Such virally induced apoptosis may also contribute to some clinical manifestations and cytotoxicity associated with several human diseases of viral origin. The purpose of this review is to summarize recent in formation on the induction and suppression of apoptosis by viral produ cts as well as to propose how this knowledge may provide insights into basic cell biology and offer the potential of new therapeutic applica tions. A recent comprehensive review by Shen and Shenk (75) also deals with some aspects of the subjects covered below.