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C-Terminal HIV-1 Transframe P6* Tetrapeptide Blocks Enhanced Gag Cleavage Incurred by Leucine Zipper Replacement of a Deleted P6* Domain

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Journal J Virol
Date 2017 Mar 3
PMID 28250114
Citations 12
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Abstract

HIV-1 protease (PR) functions as a homodimer mediating virus maturation following virus budding. Gag-Pol dimerization is believed to trigger embedded PR activation by promoting PR dimer formation. Early PR activation can lead to markedly reduced virus yields due to premature Gag cleavage. The p6* peptide, located between Gag and PR, is believed to ensure virus production by preventing early PR maturation. Studies aimed at finding supporting evidence for this proposal are limited due to a reading frame overlap between p6* and the p6gag budding domain. To determine if p6* affects virus production via the modulation of PR activation, we engineered multiple constructs derived from Dp6*PR (an assembly- and processing-competent construct with Pol fused at the inactivated PR C terminus). The data indicated that a p6* deletion adjacent to active PR significantly impaired virus processing. We also observed that the insertion of a leucine zipper (LZ) dimerization motif in the deleted region eliminated virus production in a PR activity-dependent manner, suggesting that the LZ insertion triggered premature PR activation by facilitating PR dimer formation. As few as four C-terminal p6* residues remaining at the p6*/PR junction were sufficient to restore virus yields, with a Gag processing profile similar to that of the wild type. Our study provides supporting evidence in a virus assembly context that the C-terminal p6* tetrapeptide plays a role in preventing premature PR maturation. Supporting evidence for the assumption that p6* retards PR maturation in the context of virus assembly is lacking. We found that replacing p6* with a leucine zipper peptide abolished virus assembly due to the significant enhancement of Gag cleavage. However, as few as four C-terminal p6* residues remaining in the deleted region were sufficient for significant PR release, as well as for counteracting leucine zipper-incurred premature Gag cleavage. Our data provide evidence that (i) p6* ensures virus assembly by preventing early PR activation and (ii) four C-terminal p6* residues are critical for modulating PR activation. Current PR inhibitor development efforts are aimed largely at mature PR, but there is a tendency for HIV-1 variants that are resistant to multiple protease inhibitors to emerge. Our data support the idea of modulating PR activation by targeting PR precursors as an alternative approach to controlling HIV-1/AIDS.

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References
1.
Lee S, Potempa M, Swanstrom R . The choreography of HIV-1 proteolytic processing and virion assembly. J Biol Chem. 2012; 287(49):40867-74. PMC: 3510790. DOI: 10.1074/jbc.R112.399444. View

2.
Mildner A, Rothrock D, Leone J, Bannow C, Lull J, Reardon I . The HIV-1 protease as enzyme and substrate: mutagenesis of autolysis sites and generation of a stable mutant with retained kinetic properties. Biochemistry. 1994; 33(32):9405-13. DOI: 10.1021/bi00198a005. View

3.
Tang C, Louis J, Aniana A, Suh J, Clore G . Visualizing transient events in amino-terminal autoprocessing of HIV-1 protease. Nature. 2008; 455(7213):693-6. PMC: 2798589. DOI: 10.1038/nature07342. View

4.
Louis J, Clore G, Gronenborn A . Autoprocessing of HIV-1 protease is tightly coupled to protein folding. Nat Struct Biol. 1999; 6(9):868-75. DOI: 10.1038/12327. View

5.
HILL M, Hooker C, Harrich D, Crowe S, Mak J . Gag-Pol supplied in trans is efficiently packaged and supports viral function in human immunodeficiency virus type 1. J Virol. 2001; 75(15):6835-40. PMC: 114410. DOI: 10.1128/JVI.75.15.6835-6840.2001. View