Abstract
Despite the major role of Gag in establishing resistance of HIV-1 to protease inhibitors (PIs), very limited data are available on the total contribution of Gag residues to resistance to PIs. To identify in detail Gag residues and structural interfaces associated with the development of HIV-1 resistance to PIs, we traced viral evolution under the pressure of PIs using Gag-protease single genome sequencing and coevolution analysis of protein sequences in 4 patients treated with PIs over a 9-year period. We identified a total of 38 Gag residues correlated with the protease, 32 of which were outside Gag cleavage sites. These residues were distributed in 23 Gag-protease groups of coevolution, with the viral matrix and the capsid represented in 87% and 52% of the groups. In addition, we uncovered the distribution of Gag correlated residues in specific protein surfaces of the inner face of the viral matrix and at the Cyclophilin A binding loop of the capsid. In summary, our findings suggest a tight interdependency between Gag structural proteins and the protease during the development of resistance of HIV-1 to PIs.
Highlights
The introduction of protease inhibitors (PIs) as part of the highly active antiretroviral therapy (HAART) have led to a dramatic reduction in morbidity and mortality rates in HIV-1–infected patients[1]
Sequence analysis confirmed the stepwise accumulation of Gag cleavage site mutations (CSM) at the following positions: V128I at p17/p24; S373P, I376V at p2/NC; and A431V NC/p1, K436R NC/ p1 and P453A at p1/p6
Of these Gag CSM, A431V was previously associated with drug resistance mutations at positions M46I/L and V82A/T in the protease, K436R was associated with the mutation V82A, and P453A was associated with the drug resistance mutations I84V and L90M in the protease[4]
Summary
The introduction of protease inhibitors (PIs) as part of the highly active antiretroviral therapy (HAART) have led to a dramatic reduction in morbidity and mortality rates in HIV-1–infected patients[1]. Central residues of the Gag matrix (R76K, Y79F, and T81A) have been directly associated with reduced susceptibility to PIs and increased viral replicative capacity[10, 11] These “alternative” PI resistance pathways have been shown to include mutations in the cytoplasmic tail of gp[41] that can alter interactions between gp[41] and Gag, affecting viral entry[12, 13]. The previous studies evidence the importance of HIV-1 Gag in the mechanisms of susceptibility to PIs and support the association of Gag and protease as a functional unit These studies demonstrate that, despite many years since the introduction of PIs, the determinants of virological failure have not been fully characterized. 3-dimensional information on coevolving sites in the matrix and the capsid shed light on the structural and functional constraints governing Gag coevolution under pressure from PIs
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
