Structural Characterization of B and non-B Subtypes of HIV-Protease: Insights into the Natural Susceptibility to Drug Resistance Development

Sanches, Mário; Krauchenco, Sandra; Martins, N.H.; Gustchina, Alla; Wlodawer, Alexander; Polikarpov, Igor

doi:10.1016/j.jmb.2007.03.049

Cited by 40 publications

(60 citation statements)

References 40 publications

(41 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…17 In fact, residues 33-44 vary in sequence and conformation among different groups and subtypes of PR 1 although little effect on inhibition has been reported. [29][30][31] Structurally, PR 1M resembles PR 1 more than PR 2 . However, PR 1M and PR 2 share very similar side chain conformations for Ile32, Val47, and Ile82 reflecting the importance of local effects for recognition.…”

Section: Discussionmentioning

confidence: 99%

Critical differences in HIV‐1 and HIV‐2 protease specificity for clinical inhibitors

Tie¹,

Wang²,

Boross³

et al. 2012

Protein Science

View full text Add to dashboard Cite

Clinical inhibitor amprenavir (APV) is less effective on HIV-2 protease (PR 2 ) than on HIV-1 protease (PR 1 ). We solved the crystal structure of PR 2 with APV at 1.5 Å resolution to identify structural changes associated with the lowered inhibition. Furthermore, we analyzed the PR 1 mutant (PR 1M ) with substitutions V32I, I47V, and V82I that mimic the inhibitor binding site of PR 2 . PR 1M more closely resembled PR 2 than PR 1 in catalytic efficiency on four substrate peptides and inhibition by APV, whereas few differences were seen for two other substrates and inhibition by saquinavir (SQV) and darunavir (DRV). High resolution crystal structures of PR 1M with APV, DRV, and SQV were compared with available PR 1 and PR 2 complexes. Val/Ile32 and Ile/Val47 showed compensating interactions with SQV in PR 1M and PR 1 , however, Ile82 interacted with a second SQV bound in an extension of the active site cavity of PR 1M . Residues 32 and 82 maintained similar interactions with DRV and APV in all the enzymes, whereas Val47 and Ile47 had opposing effects in the two subunits. Significantly diminished interactions were seen for the aniline of APV bound in PR 1M and PR 2 relative to the strong hydrogen bonds observed in PR 1 , consistent with 15-and 19-fold weaker inhibition, respectively. Overall, PR 1M partially replicates the specificity of PR 2 and gives insight into drug resistant mutations at residues 32, 47, and 82. Moreover, this analysis provides a structural explanation for the weaker antiviral effects of APV on HIV-2.

show abstract

Section: Discussionmentioning

confidence: 99%

Critical differences in HIV‐1 and HIV‐2 protease specificity for clinical inhibitors

Tie¹,

Wang²,

Boross³

et al. 2012

Protein Science

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Hiv-1 Protease Variants Have Different Saltmentioning

confidence: 99%

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

Huang

Britto

Kear-Scott

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: HIV-1 protease is an essential enzyme for HIV maturation. Results: Select and naturally occurring polymorphisms alter the conformational sampling and backbone dynamics of HIV-1 protease. Conclusion: These mutations lead to an alternative flap ensemble that we suspect is a curled flap orientation. Significance: The mechanism of distal mutations on drug resistance is unclear, but altered dynamics and conformational equilibria likely play key roles.

show abstract

“…[15][16][17] The impact of these genetic differences on the clinical response to antiretroviral therapy has yet to be fully assessed. [18][19][20][21][22][23][24] Nigeria is the most populous country in sub-Saharan Africa with a recent national census indicating a population exceeding 140 million. As in neighboring West African countries, HIV is thought to have entered the country in the mid-1980s.…”

Section: Introductionmentioning

confidence: 99%

Impact of HIV Type 1 Subtype on Drug Resistance Mutations in Nigerian Patients Failing First-Line Therapy

Chaplin

Eisen

Idoko

et al. 2011

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

A diverse array of non-subtype B HIV-1 viruses circulates in Africa and dominates the global pandemic. It is important to understand how drug resistance mutations in non-B subtypes may develop differently from the patterns described in subtype B. HIV-1 reverse transcriptase and protease sequences from 338 patients with treatment failure to first-line ART regimens were evaluated. Multivariate logistic regression was used to examine the effect of subtype on each mutation controlling for regimen, time on therapy, and total mutations. The distribution of HIV-1 subtypes included CRF02_AG (45.0%), G (37.9%), CRF06_cpx (4.4%), A (3.6%), and other subtypes or recombinant sequences (9.2%). The most common NRTI mutations were M184V (89.1%) and thymidine analog mutations (TAMs). The most common NNRTI mutations were Y181C (49.7%), K103N (36.4%), G190A (26.3%), and A98G (19.5%). Multivariate analysis showed that CRF02_AG was less likely to have the M41L mutation compared to other subtypes [adjusted odds ratio (AOR) ¼ 0.35; p ¼ 0.022]. Subtype A patients showed a 42.5-fold increased risk (AOR ¼ 42.5, p ¼ 0.001) for the L210W mutation. Among NNRTI mutations, subtype G patients had an increased risk for A98G (AOR ¼ 2.40, p ¼ 0.036) and V106I (AOR ¼ 6.15, p ¼ 0.010), whereas subtype CRF02_AG patients had an increased risk for V90I (AOR ¼ 3.16; p ¼ 0.003) and a decreased risk for A98G (AOR ¼ 0.48, p ¼ 0.019). Five RT mutations were found to vary significantly between different non-B West African subtypes. Further study to understand the clinical impact of subtype-specific diversity on drug resistance will be critically important to the continued success of ART scale-up in resource-limited settings.

show abstract

Structural Characterization of B and non-B Subtypes of HIV-Protease: Insights into the Natural Susceptibility to Drug Resistance Development

Cited by 40 publications

References 40 publications

Critical differences in HIV‐1 and HIV‐2 protease specificity for clinical inhibitors

Critical differences in HIV‐1 and HIV‐2 protease specificity for clinical inhibitors

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

Impact of HIV Type 1 Subtype on Drug Resistance Mutations in Nigerian Patients Failing First-Line Therapy

Contact Info

Product

Resources

About