Concluding Remarks

Publication Details

This chapter has presented the basic mechanisms regulating retroviral gene transcription and RNA processing and has illustrated these mechanisms with detailed discussions of regulatory events associated with specific retroviruses. As seen from these examples, retroviral gene expression is completely dependent on the mechanisms responsible for regulating host cellular gene expression. This intimate interaction with the host-cell machinery has a number of important consequences for retroviral infection. Cell-type-specific differences in host-cell regulatory machinery can dramatically alter retroviral replication in infected cells. These effects can have dramatic consequences for pathogenesis of retrovirus-induced disease. For example, subtle changes in the repertoire of cellular transcription factors that bind to the LTR can alter the kinds of diseases induced by MLVs. Furthermore, the essential role that host regulatory pathways have in controlling retroviral gene expression presents serious obstacles to the development of antiretroviral agents designed to block retroviral transcription or RNA processing. Even in the cases of complex retroviruses, which encode their own trans-acting regulatory proteins, these viral regulators exert their function through interactions with cellular proteins that control normal gene expression. Thus, attempts to block virally encoded trans-activators will need to be directed specifically against the viral proteins without blocking normal cellular activities. In this regard, the rapidly progressing structural analyses of retroviral regulatory proteins and their nucleic acid targets, such as the interactions of Rev with RRE and of Tat with TAR, are critically important. These studies may suggest approaches for the development of agents that specifically disrupt the retroviral components of these regulatory events, without inhibiting normal cellular gene expression. The critical dependence of retroviral gene expression on host regulatory pathways has also provided a revealing window for the elucidation of basic principles in eukaryotic gene regulation. The initial understanding of the properties of enhancers emerged, in part, from work on retroviral transcription, and studies of HIV Rev function have shed new light on the importance of regulatory pathways controlling export of RNA from the nucleus. The study of retroviral gene expression has been a topic of intense investigation during the last decade and will continue to be so in the foreseeable future. With the increasing incorporation of structural biological approaches to these problems, profound new insights into retroviral and cellular gene regulation will undoubtedly be gained.