Recent results have shown that integrase binds genomic RNA in virions, and that mutational or pharmacological disruption of integrase-RNA binding yields eccentric virion particles with ribonucleoprotein complexes situated outside of the capsid shell. However, the underlying mechanisms of integrase in these non-catalytic-related viral replication steps have remained elusive. Co-packaged with viral RNA and reverse transcriptase into capsid-encased viral cores, human immunodeficiency virus 1 (HIV-1) integrase has long been implicated in reverse transcription and virion maturation. Integrase is the retroviral protein responsible for integrating reverse transcripts into cellular genomes. These results suggest that the effects of a lack of IN sequences on particle formation require the synthesis of a Gag-Pol precursor which contains RT sequences and are due to inappropriate PR activity. Finally particle formation was restored in the presence of A77003, a specific inhibitor of human immunodeficiency virus type 1 PR. Particle formation was similarly restored by a second site mutation in the viral protease (PR) gene which prevented proteolytic processing of the Gag polyprotein. Particle production by IN mutants was restored to wild-type levels when a second premature termination codon was introduced at the 5' end of the RT-coding sequence. By contrast, a mutant which lacked both IN and reverse transcriptase (RT) formed particles with normal efficiency. Marked effects on particle production were seen when premature termination codons were introduced into the integrase (IN)-coding region. However, in this report we demonstrate that the synthesis of a truncated Gag-Pol precursor due to a premature termination codon in pol can reduce the ability of a full-length provirus to direct the formation of viral particles. The Gag-Pol polyprotein of human immunodeficiency virus type 1 is not required for efficient viral particle assembly or release.
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