A Single Amino Acid Substitution at HIV-1 Protease Termini Dimer Interface Significantly Reduces Viral Particles Processing Efficiency
Japanese journal of infectious diseases (Print)
The dimeric form of HIV-1 protease (PR) is required for full proteolytic activity. The stability of the dimer primarily depends on the termini interface, with N-terminal residues 1-4 of one monomer encountering C-terminal residues 96-99 of another. We made an alanine substitution for valine 3(V3) or leucine 97(L97) at the termini dimer interface, and tested the proteolytic activity in each. The results showed that an alanine substitution for L97 (PRL97A) completely inhibited the proteolytic
... the proteolytic activity of protease. However, an alanine substitution for V3 (PRV3A) partially impaired proteolytic activity. We then introduced two forced-dimerization systems involving NC replacement or addition of 1-2 leucine zippers to determine whether proteolytic activity of dimer-defective PRs could be restored. We found that two forced-dimerization systems compensated for the defect in PRV3A but not PRL97A. This implies that PRV3A and PRL97A potentially impair PR via different mechanisms or different extent of defect in PR activity. These novel findings will likely serve as a foundation for developing new PR inhibitors for treating drug-resistant HIV-1 infections in the future.