Effects of reduced gag cleavage efficiency on HIV-1 Gag-Pol package

Abstract

Background HIV-1 pol, which encodes enzymes required for virus replication, is initially translated as a Gag-Pol fusion protein. Gag-Pol is incorporated into virions via interactions with Gag precursor Pr55gag. Protease (PR) embedded in Gag-Pol mediates the proteolytic processing of both Pr55gag and Gag-Pol during or soon after virus particle release from cells. Since efficient Gag-Pol viral incorporation depends on interaction with Pr55gag via its N-terminal Gag domain, the prevention of premature Gag cleavage may alleviate Gag-Pol packaging deficiencies associated with cleavage enhancement from PR. Results We engineered PR cleavage-blocking Gag mutations with the potential to significantly reduce Gag processing efficiency. Such mutations may mitigate the negative effects of enhanced PR activation on virus assembly and Gag-Pol packaging due to an RT dimerization enhancer or leucine zipper dimerization motif. When co-expressed with Pr55gag, we noted that enhanced PR activation resulted in reduced Gag-Pol cis or trans incorporation into Pr55gag particles, regardless of whether or not Gag cleavage sites within Gag-Pol were blocked. Conclusions Our data suggest that the amount of HIV-1 Gag-Pol or Pol viral incorporation is largely dependent on virus particle production, and that cleavage blocking in the Gag-Pol N-terminal Gag domain does not exert significant impacts on Pol packaging.

The HIV-1 Gag Protein Displays Extensive Functional and Structural Roles in Virus Replication and Infectivity

“…In the human immunodeficiency virus type 1 (HIV-1), the autocatalytic cleavage of the aspartyl protease enzyme from Gag–Pol (PR160) prompts the cleavage of both Gag-Pol and Gag (PR55) at predefined sites in the polyprotein [ 1 ]. Group specific antigen, commonly referred to as Gag, is the HIV-1 polyprotein associated with viral structure and infectivity [ 2 ].…”

Combined Pharmacophore Modeling, 3D-QSAR, Molecular Docking and Molecular Dynamics Study on Indolyl-aryl-sulfone Derivatives as New HIV1 Inhibitors

“…Since efficient viral incorporation of Gag-Pol depends on interaction with Pr55gag through its N-terminal Gag domain, prevention of premature Gag cleavage may attenuate Gag-Pol packaging deficiencies associated with enhancement of the PR cleavage. 8 The vital role of HIV protease in viral maturation makes it a popular drug design target; there are 10 FDA-approved HIV protease inhibitors, namely: Saquinavir, Indinavir, Ritonavir, Nelfinavir, Amprenavir, Fosamprenavir, Lopinavir, Atazanavir, Tipranavir, and Darunavir. The FDA-approved HIV protease inhibitors have structural similarities and a similar binding pattern, which might explain some of the protease inhibitor-related adverse effects such as dyslipidaemia, hyperglycaemia, and body-fat distribution.…”