The pathogenic human retrovirus Human Immunodeficiency Virus 1 (HIV-1) gives rise to a long-lasting disease course which is marked by a number of distinct phases. In particular, these include an initial asymptomatic period that may last for several years but that eventually leads, in most cases, to progressively more severe immune dysfunction. The observed interaction between this human retroviral pathogen and the infected host shares some similarities with the chronic disease states induced by related animal retroviruses of the lentivirus sub-group. It is presumably no coincidence that HIV-1 also shares with these animal lentiviruses an unexpectedly complex genetic make-up. Thus, HIV-1 has been shown to encode a number of apparently non-structural proteins of which at least two termed tat and rev (formerly art/trs) have been shown to be essential for viral replication in vitro. This grant proposal addresses itself to the mechanism of action of the second of these two proteins, rev. In particular, we will attempt to define functional domains within the rev protein by a comprehensive mutational analysis approach. We will define sequences within the HIV-1 genome which are required in cis for phenotypic response to the rev gene product. We will then use this information to define and characterize proteins that are involved in mediating functional recognition of this sequence. Finally, we will attempt to completely dissect the effect of rev on viral mRNA transport and stability and on the differential processing of viral transcripts. This comprehensive approach to the understanding of rev function should lead to significant insights into the regulation of HIV-1 gene expression. Such an understanding is potentially key to the relational design of agents intended to intervene in the pathogenic course of human HIV-1 infection.
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