The Contribution of Naturally Occurring Polymorphisms in Altering the Biochemical and Structural Characteristics of HIV-1 Subtype C Protease

Abstract

Fourteen subtype B and C protease variants have been engineered in an effort to study whether the preexistent baseline polymorphisms, by themselves or in combination with drug resistance mutations, differentially alter the biochemical and structural features of the subtype C protease when compared with those of subtype B protease. The kinetic studies performed in this work showed that the preexistent polymorphisms in subtype C protease, by themselves, do not provide for a greater level of resistance. Inhibition analysis with eight clinically used protease inhibitors revealed that the natural polymorphisms found in subtype C protease, in combination with drug resistance mutations, can influence enzymatic catalytic efficiency and inhibitor resistance. Structural analyses of the subtype C protease bound to nelfinavir and indinavir showed that these inhibitors form similar interactions with the residues in the active site of subtype B and C proteases. It also revealed that the naturally occurring polymorphisms could alter the position of the outer loops of the subtype C protease, especially the 60's loop.

Understanding the HIV-1 protease nelfinavir resistance mutation D30N in subtypes B and C through molecular dynamics simulations

“…In our simulations, we noticed that one hydrogen bond between the 25D and the nitrogen N37 of the P2 group was lost in the B-D30N mutant when compared with its respective wild-type PR (Table 3). Our data agree with the results obtained by Coman et al [44]. In that study, the authors found that both B and C D30N mutants had drastically increased K i values compared to their wild-type counterparts, evidencing strong loss of affinity to NFV.…”

The Role of Select Subtype Polymorphisms on HIV-1 Protease Conformational Sampling and Dynamics

“…Bridge Formation Patterns-To provide molecular level structural evidence to support our hypothesis that the population in DEER distance profiles ϳ27 Å is a novel conformer rarely seen in molecular dynamics simulations of subtype B, and to explore how this mutation may structurally influence HIV-1 PR, we scrutinized several x-ray crystal structures, including subtype B (51,66,68), C (69,70), subtype F (66), CRF01_A/E (8), and other mutants with (49,71) and without the E35D mutation. We found, as shown in Fig.…”

Short Communication: Antiretroviral Therapy Resistance Mutations Present in the HIV Type 1 Subtype CpolandenvRegions from Therapy-Naive Patients in Zambia

“…Although borderline and minor mutations alone do not significantly increase the level of resistance, when combined with other mutations, they can increase the resistance to inhibitors by influencing the enzyme's catalytic efficiency. 10 Thus, these mutations should be monitored. This surveillance is also important as a prevalence higher than 15% of ART mutations within a population could have negative implications on treatment efficacy.…”

“…2 Moreover, some of these naturally occurring polymorphisms likely accelerate the emergence of ART resistance. 10 In addition to mutations in the pol gene, drug resistance-associated mutations (DRAMs) have also been recently reported in the V3 region of the env against the CCR5 entry inhibitors maraviroc 11 and vicriviroc. 12 Because drug resistance and resistance-associated mutations may have a profound impact on the clinical management of patients, surveillance of ART resistance in both treated and untreated individuals is essential for the development and implementation of an effective therapy.…”