scholarly journals Reviewing HIV-1 Gag Mutations in Protease Inhibitors Resistance: Insights for Possible Novel Gag Inhibitor Designs

2019 ◽  
Author(s):  
Chinh Tran-To Su ◽  
Darius Wen-Shuo Koh ◽  
Samuel Ken-En Gan
Keyword(s):  
Drug Resistance ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Drug Target ◽  
Treatment Strategies ◽  
Hiv Treatment ◽  
Gag Polyprotein ◽  
Hiv 1 ◽  
New Strategies

HIV treatment strategies against viral enzymes are continuously hampered by viral drug resistance. Recent findings show that viral substrate Gag contributes to HIV-1 Protease Inhibitor (PI) resistance, leading to demands for new strategies in HIV treatment where Gag is recognized as a drug target. To successfully target Gag, there is a need of in-depth understanding of the Gag polyprotein and the effects of Gag mutations. Here, we propose new strategies in designing novel Gag inhibitors against existing and novel emerging Gag mutations via a structural understanding of the Gag-Protease relationship in PI resistance. In this review, we discuss the role of both novel and previously reported mutations, revealing insights to how they aid in PI resistance, and how new Gag inhibitors can be designed.

scholarly journals Transient HIV-1 Gag–protease interactions revealed by paramagnetic NMR suggest origins of compensatory drug resistance mutations

2016 ◽  
Vol 113 (44) ◽  
pp. 12456-12461 ◽  
Author(s):  
Lalit Deshmukh ◽  
John M. Louis ◽  
Rodolfo Ghirlando ◽  
G. Marius Clore
Keyword(s):  
Drug Resistance ◽  
Protease Inhibitors ◽  
Specific Antigen ◽  
Paramagnetic Nmr ◽  
Cleavage Sites ◽  
Resistance Mutations ◽  
Gag Polyprotein ◽  
Intrinsically Disordered ◽  
Drug Resistance Mutations ◽  
Hiv 1

Cleavage of the group-specific antigen (Gag) polyprotein by HIV-1 protease represents the critical first step in the conversion of immature noninfectious viral particles to mature infectious virions. Selective pressure exerted by HIV-1 protease inhibitors, a mainstay of current anti–HIV-1 therapies, results in the accumulation of drug resistance mutations in both protease and Gag. Surprisingly, a large number of these mutations (known as secondary or compensatory mutations) occur outside the active site of protease or the cleavage sites of Gag (located within intrinsically disordered linkers connecting the globular domains of Gag to one another), suggesting that transient encounter complexes involving the globular domains of Gag may play a role in guiding and facilitating access of the protease to the Gag cleavage sites. Here, using large fragments of Gag, as well as catalytically inactive and active variants of protease, we probe the nature of such rare encounter complexes using intermolecular paramagnetic relaxation enhancement, a highly sensitive technique for detecting sparsely populated states. We show that Gag-protease encounter complexes are primarily mediated by interactions between protease and the globular domains of Gag and that the sites of transient interactions are correlated with surface exposed regions that exhibit a high propensity to mutate in the presence of HIV-1 protease inhibitors.

scholarly journals Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain

2015 ◽  
Vol 90 (2) ◽  
pp. 768-779 ◽  
Author(s):  
Angelica N. Martins ◽  
Abdul A. Waheed ◽  
Sherimay D. Ablan ◽  
Wei Huang ◽  
Alicia Newton ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Biochemical Analysis ◽  
Replication Capacity ◽  
Resistance Mutations ◽  
Cellular Machinery ◽  
Ptap Motif ◽  
Hiv 1

ABSTRACTHIV-1 uses cellular machinery to bud from infected cells. This cellular machinery is comprised of several multiprotein complexes known as endosomal sorting complexes required for transport (ESCRTs). A conserved late domain motif, Pro-Thr-Ala-Pro (PTAP), located in the p6 region of Gag (p6Gag), plays a central role in ESCRT recruitment to the site of virus budding. Previous studies have demonstrated that PTAP duplications are selected in HIV-1-infected patients during antiretroviral therapy; however, the consequences of these duplications for HIV-1 biology and drug resistance are unclear. To address these questions, we constructed viruses carrying a patient-derived PTAP duplication with and without drug resistance mutations in the viral protease. We evaluated the effect of the PTAP duplication on viral release efficiency, viral infectivity, replication capacity, drug susceptibility, and Gag processing. In the presence of protease inhibitors, we observed that the PTAP duplication in p6Gagsignificantly increased the infectivity and replication capacity of the virus compared to those of viruses bearing only resistance mutations in protease. Our biochemical analysis showed that the PTAP duplication, in combination with mutations in protease, enhances processing between the nucleocapsid and p6 domains of Gag, resulting in more complete Gag cleavage in the presence of protease inhibitors. These results demonstrate that duplication of the PTAP motif in p6Gagconfers a selective advantage in viral replication by increasing Gag processing efficiency in the context of protease inhibitor treatment, thereby enhancing the drug resistance of the virus. These findings highlight the interconnected role of PTAP duplications and protease mutations in the development of resistance to antiretroviral therapy.IMPORTANCEResistance to current drug therapy limits treatment options in many HIV-1-infected patients. Duplications in a Pro-Thr-Ala-Pro (PTAP) motif in the p6 domain of Gag are frequently observed in viruses derived from patients on protease inhibitor (PI) therapy. However, the reason that these duplications arise and their consequences for virus replication remain to be established. In this study, we examined the effect of PTAP duplication on PI resistance in the context of wild-type protease or protease bearing PI resistance mutations. We observe that PTAP duplication markedly enhances resistance to a panel of PIs. Biochemical analysis reveals that the PTAP duplication reverses a Gag processing defect imposed by the PI resistance mutations in the context of PI treatment. The results provide a long-sought explanation for why PTAP duplications arise in PI-treated patients.

scholarly journals Simian-Tropic HIV as a Model To Study Drug Resistance against Integrase Inhibitors

2015 ◽  
Vol 59 (4) ◽  
pp. 1942-1949 ◽  
Author(s):  
Melissa Wares ◽  
Said Hassounah ◽  
Thibault Mesplède ◽  
Paul A. Sandstrom ◽  
Mark A. Wainberg
Keyword(s):  
Drug Resistance ◽  
Nonhuman Primate ◽  
Hiv Treatment ◽  
Replication Capacity ◽  
Primate Model ◽  
Primary Resistance ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Hiv 1

ABSTRACTDrug resistance represents a key aspect of human immunodeficiency virus (HIV) treatment failure. It is important to develop nonhuman primate models for studying issues of drug resistance and the persistence and transmission of drug-resistant viruses. However, relatively little work has been conducted using either simian immunodeficiency virus (SIV) or SIV/HIV recombinant viruses for studying resistance against integrase strand transfer inhibitors (INSTIs). Here, we used a T-cell-tropic SIV/HIV recombinant virus in which the capsid andvifregions of HIV-1 were replaced with their SIV counterparts (simian-tropic HIV-1 [stHIV-1](SCA,SVIF)) to study the impact of a number of drug resistance substitutions in the integrase coding region at positions E92Q, G118R, E138K, Y143R, S153Y, N155H, and R263K on drug resistance, viral infectivity, and viral replication capacity. Our results show that each of these substitutions exerted effects that were similar to their effects in HIV-1. Substitutions associated with primary resistance against dolutegravir were more detrimental to stHIV-1(SCA,SVIF)infectiousness than were resistance substitutions associated with raltegravir and elvitegravir, consistent with data that have been reported for HIV-1. These findings support the role of stHIV-1(SCA,SVIF)as a useful model with which to evaluate the role of INSTI resistance substitutions on viral persistence, transmissibility, and pathogenesis in a nonhuman primate model.

scholarly journals The role of polymorphisms at position 89 in the HIV-1 protease gene in the development of drug resistance to HIV-1 protease inhibitors

2012 ◽  
Vol 67 (4) ◽  
pp. 988-994 ◽  
Author(s):  
J. L. Martinez-Cajas ◽  
M. A. Wainberg ◽  
M. Oliveira ◽  
E. L. Asahchop ◽  
F. Doualla-Bell ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Protease Inhibitors ◽  
Protease Gene ◽  
Hiv 1

scholarly journals Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility

2012 ◽  
Vol 56 (5) ◽  
pp. 2719-2725 ◽  
Author(s):  
André F. A. Santos ◽  
Denis M. Tebit ◽  
Matthew S. Lalonde ◽  
Ana B. Abecasis ◽  
Annette Ratcliff ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Outcome ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Antiretroviral Drugs ◽  
Response To Treatment ◽  
Resistance Mutations ◽  
Subtype B ◽  
Direct Head ◽  
Hiv 1

ABSTRACTHypersusceptibility (HS) to inhibition by different antiretroviral drugs (ARVs) among diverse HIV-infected individuals may be a misnomer because clinical response to treatment is evaluated in relation to subtype B infections while drug susceptibility of the infecting virus, regardless of subtype, is compared to a subtype B HIV-1 laboratory strain (NL4-3 or IIIB). Mounting evidence suggests that HS to different ARVs may result in better treatment outcome just as drug resistance leads to treatment failure. We have identified key amino acid polymorphisms in the protease coding region of a non-B HIV-1 subtype linked to protease inhibitor HS, namely, 17E and 64M in CRF02_AG. These HS-linked polymorphisms were introduced in the BD6-15 CRF02_AG molecular clone and tested for inhibition using a panel of protease inhibitors. In general, suspected HS-linked polymorphisms did increase susceptibility to specific protease inhibitors such as amprenavir and atazanavir, but the combination of the 17E/64M polymorphisms showed greater HS. These two mutations were found at low frequencies but linked in a sequence database of over 700 protease sequences of CRF02_AG. In direct head-to-head virus competitions, CRF02_AG harboring the 17E/64M polymorphisms also had higher replicative fitness than did the 17E or the 64M polymorphism in the CFR02_AG clone. These findings suggest that subtype-specific, linked polymorphisms can result in hypersusceptibility to ARVs. Considering the potential benefit of HS to treatment outcome, screening for potential HS-linked polymorphisms as well as preexisting drug resistance mutations in treatment-naïve patients may guide the choice of ARVs for the best treatment outcome.

scholarly journals Mutation Patterns and Structural Correlates in Human Immunodeficiency Virus Type 1 Protease following Different Protease Inhibitor Treatments

2003 ◽  
Vol 77 (8) ◽  
pp. 4836-4847 ◽  
Author(s):  
Thomas D. Wu ◽  
Celia A. Schiffer ◽  
Matthew J. Gonzales ◽  
Jonathan Taylor ◽  
Rami Kantor ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Although many human immunodeficiency virus type 1 (HIV-1)-infected persons are treated with multiple protease inhibitors in combination or in succession, mutation patterns of protease isolates from these persons have not been characterized. We collected and analyzed 2,244 subtype B HIV-1 isolates from 1,919 persons with different protease inhibitor experiences: 1,004 isolates from untreated persons, 637 isolates from persons who received one protease inhibitor, and 603 isolates from persons receiving two or more protease inhibitors. The median number of protease mutations per isolate increased from 4 in untreated persons to 12 in persons who had received four or more protease inhibitors. Mutations at 45 of the 99 amino acid positions in the protease—including 22 not previously associated with drug resistance—were significantly associated with protease inhibitor treatment. Mutations at 17 of the remaining 99 positions were polymorphic but not associated with drug treatment. Pairs and clusters of correlated (covarying) mutations were significantly more likely to occur in treated than in untreated persons: 115 versus 23 pairs and 30 versus 2 clusters, respectively. Of the 115 statistically significant pairs of covarying residues in the treated isolates, 59 were within 8 Å of each other—many more than would be expected by chance. In summary, nearly one-half of HIV-1 protease positions are under selective drug pressure, including many residues not previously associated with drug resistance. Structural factors appear to be responsible for the high frequency of covariation among many of the protease residues. The presence of mutational clusters provides insight into the complex mutational patterns required for HIV-1 protease inhibitor resistance.

scholarly journals Drug Resistance in Osteosarcoma: Emerging Biomarkers, Therapeutic Targets and Treatment Strategies

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2878
Author(s):  
Claudia Maria Hattinger ◽  
Maria Pia Patrizio ◽  
Leonardo Fantoni ◽  
Chiara Casotti ◽  
Chiara Riganti ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Therapeutic Targets ◽  
Treatment Strategies ◽  
Cure Rate ◽  
Acquired Drug Resistance ◽  
Unselected Patient ◽  
Dismal Prognosis ◽  
Non Coding Rnas ◽  
High Grade Osteosarcoma

High-grade osteosarcoma (HGOS), the most common primary malignant tumor of bone, is a highly aggressive neoplasm with a cure rate of approximately 40–50% in unselected patient populations. The major clinical problems opposing the cure of HGOS are the presence of inherent or acquired drug resistance and the development of metastasis. Since the drugs used in first-line chemotherapy protocols for HGOS and clinical outcome have not significantly evolved in the past three decades, there is an urgent need for new therapeutic biomarkers and targeted treatment strategies, which may increase the currently available spectrum of cure modalities. Unresponsive or chemoresistant (refractory) HGOS patients usually encounter a dismal prognosis, mostly because therapeutic options and drugs effective for rescue treatments are scarce. Tailored treatments for different subgroups of HGOS patients stratified according to drug resistance-related biomarkers thus appear as an option that may improve this situation. This review explores drug resistance-related biomarkers, therapeutic targets and new candidate treatment strategies, which have emerged in HGOS. In addition to consolidated biomarkers, specific attention has been paid to the role of non-coding RNAs, tumor-derived extracellular vesicles, and cancer stem cells as contributors to drug resistance in HGOS, in order to highlight new candidate markers and therapeutic targets. The possible use of new non-conventional drugs to overcome the main mechanisms of drug resistance in HGOS are finally discussed.

scholarly journals Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance

2013 ◽  
Vol 20 (9) ◽  
pp. 1116-1124 ◽  
Author(s):  
Madhavi N.L. Nalam ◽  
Akbar Ali ◽  
G.S. Kiran Kumar Reddy ◽  
Hong Cao ◽  
Saima G. Anjum ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Protease Inhibitors ◽  
Hiv 1 ◽  
Substrate Envelope

scholarly journals Analysis of Low-Frequency Mutations Associated with Drug Resistance to Raltegravir before Antiretroviral Treatment

2010 ◽  
Vol 55 (3) ◽  
pp. 1114-1119 ◽  
Author(s):  
Jia Liu ◽  
Michael D. Miller ◽  
Robert M. Danovich ◽  
Nathan Vandergrift ◽  
Fangping Cai ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Failure ◽  
Low Frequency ◽  
Hiv Treatment ◽  
Viral Population ◽  
Virologic Suppression ◽  
Resistance Mutations ◽  
The Difference ◽  
Allele Specific Sequencing ◽  
Hiv 1

ABSTRACTRaltegravir is highly efficacious in the treatment of HIV-1 infection. The prevalence and impact on virologic outcome of low-frequency resistant mutations among HIV-1-infected patients not previously treated with raltegravir have not been fully established. Samples from HIV treatment-experienced patients entering a clinical trial of raltegravir treatment were analyzed using a parallel allele-specific sequencing (PASS) assay that assessed six primary and six secondary integrase mutations. Patients who achieved and sustained virologic suppression (success patients,n= 36) and those who experienced virologic rebound (failure patients,n= 35) were compared. Patients who experienced treatment failure had twice as many raltegravir-associated resistance mutations prior to initiating treatment as those who achieved sustained virologic success, but the difference was not statistically significant. The frequency of nearly all detected resistance mutations was less than 1% of viral population, and the frequencies of mutations between the success and failure groups were similar. Expansion of pre-existing mutations (one primary and five secondary) was observed in 16 treatment failure patients in whom minority resistant mutations were detected at baseline, suggesting that they might play a role in the development of drug resistance. Two or more mutations were found in 13 patients (18.3%), but multiple mutations were not present in any single viral genome by linkage analysis. Our study demonstrates that low-frequency primary RAL-resistant mutations were uncommon, while minority secondary RAL-resistant mutations were more frequently detected in patients naïve to raltegravir. Additional studies in larger populations are warranted to fully understand the clinical implications of these mutations.

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