Journal articles: 'Viral Drug Resistance'

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Richman, Douglas D. "Viral drug resistance." Current Opinion in Infectious Diseases 3, no. 6 (December 1990): 819–23. http://dx.doi.org/10.1097/00001432-199012000-00014.

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McKeegan, Kenneth S., M. Ines Borges-Walmsley, and Adrian R. Walmsley. "Microbial and viral drug resistance mechanisms." Trends in Microbiology 10, no. 10 (October 2002): s8—s14. http://dx.doi.org/10.1016/s0966-842x(02)02429-0.

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de Koning, Harry P. "Drug resistance in protozoan parasites." Emerging Topics in Life Sciences 1, no. 6 (December 22, 2017): 627–32. http://dx.doi.org/10.1042/etls20170113.

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As with all other anti-infectives (antibiotics, anti-viral drugs, and anthelminthics), the limited arsenal of anti-protozoal drugs is being depleted by a combination of two factors: increasing drug resistance and the failure to replace old and often shamefully inadequate drugs, including those compromised by (cross)-resistance, through the development of new anti-parasitics. Both factors are equally to blame: a leaking bathtub may have plenty of water if the tap is left open; if not, it will soon be empty. Here, I will reflect on the factors that contribute to the drug resistance emergency that is unfolding around us, specifically resistance in protozoan parasites.

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Endy, Drew, and John Yin. "Toward Antiviral Strategies That Resist Viral Escape." Antimicrobial Agents and Chemotherapy 44, no. 4 (April 1, 2000): 1097–99. http://dx.doi.org/10.1128/aac.44.4.1097-1099.2000.

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ABSTRACT We studied the effect on viral growth of drugs targeting different virus functions using a computer simulation for the intracellular growth of bacteriophage T7. We found that drugs targeting components of negative-feedback loops gain effectiveness against mutant viruses that attenuate the drug-target interaction. The greater inhibition of such mutants than of the wild type suggests a drug design strategy that would hinder the development of drug resistance.

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Kurt Yilmaz, Nese, Ronald Swanstrom, and Celia A. Schiffer. "Improving Viral Protease Inhibitors to Counter Drug Resistance." Trends in Microbiology 24, no. 7 (July 2016): 547–57. http://dx.doi.org/10.1016/j.tim.2016.03.010.

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Menendez-Arias, Luis, and Jose Este. "HIV-Resistance to Viral Entry Inhibitors." Current Pharmaceutical Design 10, no. 15 (June 1, 2004): 1845–60. http://dx.doi.org/10.2174/1381612043384574.

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Schiffer, Celia. "Combatting Drug Resistance: Lessons from the viral proteases of HIV and HCV." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C116. http://dx.doi.org/10.1107/s2053273314098830.

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Drug resistance negatively impacts the lives of millions of patients and costs our society billions of dollars by limiting the longevity of many of our most potent drugs. Drug resistance can be caused by a change in the balance of molecular recognition events that selectively weakens inhibitor binding but maintains the biological function of the target. To reduce the likelihood of drug resistance, a detailed understanding of the target's function is necessary. Both structure at atomic resolution and evolutionarily constraints on its variation is required. "Resilient" targets are less susceptible to drug resistance due to their key location in a particular pathway. This rationale was derived through crystallographic studies elucidating substrate recognition and drug resistance in HIV-1 protease and Hepatitis C (HCV) NS3/4A protease. Both are key therapeutic targets and are potentially "resilient" targets where resistant mutations occur outside of the substrate binding site. To reduce the probability of drug resistance inhibitors should be designed to fit within what we define as the "substrate envelope". These principals are likely more generally applicable to other quickly evolving diseases where drug resistance is quickly evolving. http://www.umassmed.edu/schifferlab/index.aspx

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Raugi, Dana N., Robert S. Nixon, Sally Leong, Khadim Faye, Jean Phillipe Diatta, Fatima Sall, Robert A. Smith, et al. "HIV-2 Drug Resistance Genotyping from Dried Blood Spots." Journal of Clinical Microbiology 59, no. 1 (October 14, 2020): e02303-20. http://dx.doi.org/10.1128/jcm.02303-20.

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ABSTRACTThe treatment of HIV-2 in resource-limited settings (RLS) is complicated by the limited availability of HIV-2-active antiretroviral drugs and inadequate access to HIV-2 viral load and drug resistance testing. Dried blood spots (DBS)-based drug resistance testing, widely studied for HIV-1, has not been reported for HIV-2 and could present an opportunity to improve care for HIV-2-infected individuals. We selected 150 DBS specimens from ongoing studies of antiretroviral therapy (ART) for HIV-2 infection in Senegal and subjected them to genotypic drug resistance testing. Total nucleic acid was extracted from DBS, reverse transcribed, PCR amplified, and analyzed by population-based Sanger sequencing, and major drug resistance-associated mutations (RAM) were identified. Parallel samples from plasma and peripheral blood mononuclear cells (PBMC) were also genotyped. We obtained 58 protease/reverse transcriptase genotypes. Plasma viral load was significantly correlated with genotyping success (P < 0.001); DBS samples with corresponding plasma viral load >250 copies/ml had a success rate of 86.8%. In paired DBS-plasma genotypes, 83.8% of RAM found in plasma were also found in DBS, and replicate DBS genotyping revealed that a single test detected 86.7% of known RAM. These findings demonstrate that DBS-based genotypic drug resistance testing for HIV-2 is feasible and can be deployed in RLS with limited infrastructure.

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Beljanski, Vladimir, Cindy Chiang, and John Hiscott. "The intersection between viral oncolysis, drug resistance, and autophagy." Biological Chemistry 396, no. 12 (December 1, 2015): 1269–80. http://dx.doi.org/10.1515/hsz-2015-0147.

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Abstract Resistance to both cytotoxic and targeted therapies is a major problem facing cancer treatment. The mechanisms of resistance to unrelated drugs share many common features, including up-regulation of detoxifying pathways, activation of pro-survival mechanisms, and ineffective induction of cell death. Oncolytic viruses (OVs) are promising biotherapeutics for cancer treatment that specifically replicate in and lyse cancer cells. In addition to direct viral lysis, the anti-tumor effects of OVs are mediated via innate and adaptive immune responses, and several adaptation mechanisms such as autophagy appear to contribute to their anti-tumor properties. Autophagy is a versatile pathway that plays a key role in cancer survival during stressful conditions such as starvation or cytotoxic drug challenges. Autophagy also plays a role in mediating innate and adaptive immune responses by contributing to antigen presentation and cytokine secretion. This role of autophagy in regulation of immune responses can be utilized to design therapeutic combinations using approaches that either stimulate or block autophagy to potentiate therapeutic efficacy of OVs. Additional studies are needed to determine optimal multimodal combination approaches that will facilitate future successful clinical implementation of OV-based therapies.

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Neagu, Iulia A., Jason Olejarz, Mark Freeman, Daniel I. S. Rosenbloom, Martin A. Nowak, and Alison L. Hill. "Life cycle synchronization is a viral drug resistance mechanism." PLOS Computational Biology 14, no. 2 (February 15, 2018): e1005947. http://dx.doi.org/10.1371/journal.pcbi.1005947.

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López, Pablo, Grissell Tirado, Andrea Arias, Raphael Sánchez, Elliott R. Rodríguez-López, and Vanessa Rivera-Amill. "Short Communication: Integrase Strand Transfer Inhibitors Drug Resistance Mutations in Puerto Rico HIV-Positive Individuals." International Journal of Environmental Research and Public Health 18, no. 5 (March 8, 2021): 2719. http://dx.doi.org/10.3390/ijerph18052719.

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The HIV-1 integrase viral protein is responsible for incorporating the viral DNA into the genomic DNA. The inhibition of viral integration into host cell DNA is part of recent therapeutic procedures. Combination therapy with protease and reverse transcriptase inhibitors has demonstrated good synergistic results in reducing viral replication. The purpose of this study is to assess the occurrence of integrase drug resistance mutations from the period comprising 2013 through 2018 in Puerto Rico (PR). We analyzed 131 nucleotide sequences available in our HIV genotyping database, and we performed drug resistance mutation analyses using the Stanford HIV Drug Resistance Database. Twenty-one sequences (16.03%) harbored major or resistance-associated mutations. We identified the Q148HKR, G140S, Y143R, N155H, S147G, and E138EA major drug resistance mutations and the D232DN, T97TA, E157Q, G163GART accessory mutations. We detected high-level drug resistance to Elvitegravir and Raltegravir (76.19% and 85.71%). Moreover, we identified sequences harboring drug resistance mutations that could provide resistance to Dolutegravir. The transmission of strains with integrase antiretroviral resistance has been previously documented in treatment naïve patients. Given the increase of patients treated with integrase inhibitors, surveillance of drug resistance mutations is an essential aspect of PR’s clinical management of HIV infection.

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Milani, Alireza, Parya Basimi, Elnaz Agi, and Azam Bolhassani. "Pharmaceutical Approaches for Treatment of Hepatitis C virus." Current Pharmaceutical Design 26, no. 34 (October 13, 2020): 4304–14. http://dx.doi.org/10.2174/1381612826666200509233215.

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Many studies have been performed to develop an antiviral therapy against the hepatitis C virus (HCV) infections. The usual treatment for HCV infection is a combination of PEGylated interferon and ribavirin which offer restricted efficiency and major side effects. Thus, recent development in molecular biology of HCV and its life cycle led to the design of many drugs that target viral proteins and host factors required for viral replication. These drugs were named as direct-acting antivirals (DAAs) that were specifically designed for inhibition of viral life cycle, promising tolerability, short duration of treatment, higher barrier to resistance, and fewer drug interactions. The use of DAAs for the treatment of HCV infection resulted in high virological cure rates in patients. However, the use of combined DAA regimens may present drug interactions especially in patients under treatment for other co-morbidities. On the other hand, drug resistance against virus infection determines the success of long-term therapy. High genetic diversity among HCV virions due to error-prone polymerase activity led to the reduced susceptibility to DAA-therapy. Therefore, preclinical and clinical analysis of HCV resistance to novel drugs is needed. In this review, we describe pharmaceutical approaches for HCV treatment, structural and functional properties of DAAs, the principles of HCV drug-drug interaction, and finally HCV resistance to DAAs.

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13

Kuiken, Carla. "Designing a low-cost drug resistance database for viral hepatitis." Antiviral Therapy 15, no. 3 Part B (2010): 517–20. http://dx.doi.org/10.3851/imp1554.

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Andreatta, Kristen N., Derrick D. Goodman, Michael D. Miller, and Kirsten L. White. "Reduced Viral Fitness and Lack of Cross-Class Resistance with Integrase Strand Transfer Inhibitor and Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations." Antimicrobial Agents and Chemotherapy 59, no. 6 (March 30, 2015): 3441–49. http://dx.doi.org/10.1128/aac.00040-15.

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ABSTRACTThe most common pattern of emergent resistance in the phase III clinical trials of coformulated elvitegravir (EVG)-cobicistat (COBI)-emtricitabine (FTC)-tenofovir disoproxil fumarate (TDF) was the EVG resistance substitution E92Q in integrase (IN) with the FTC resistance substitution M184V in reverse transcriptase (RT), with or without the tenofovir (TFV) resistance substitution K65R. In this study, the effect of these IN and RT substitutions alone and in combination in the same genome on susceptibility to antiretroviral inhibitors and viral replication fitness was characterized. Single resistance substitutions (E92Q in IN [IN-E92Q], M184V in RT [RT-M184V], and K65R in RT [RT-K65R]) specifically affected susceptibility to the corresponding inhibitor classes, with no cross-class resistance observed. The IN-E92Q mutant displayed reduced susceptibility to EVG (50-fold), which was not impacted by the addition of RT-M184V or RT-K65R/M184V. Viruses containing RT-M184V had high-level resistance to FTC (>1,000-fold) that was not affected by the addition of IN-E92Q or RT-K65R. During pairwise growth competitions, each substitution contributed to decreased viral fitness, with the RT-K65R/M184V + IN-E92Q triple mutant being the least fit in the absence of drug. In the presence of drug concentrations approaching physiologic levels, however, drug resistance offset the replication defects, resulting in single mutants outcompeting the wild type with one drug present, and double and triple mutants outcompeting single mutants with two drugs present. Taken together, these results suggest that the reduced replication fitness and phenotypic resistance associated with RT and IN resistance substitutions are independent and additive. In the presence of multiple drugs, viral growth is favored for viruses with multiple substitutions, despite the presence of fitness defects.

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Buskin, SE, S. Zhang, and CS Thibault. "Prevalence of and Viral Outcomes Associated with Primary HIV-1 Drug Resistance." Open AIDS Journal 6, no. 1 (September 7, 2012): 181–87. http://dx.doi.org/10.2174/1874613601206010181.

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Primary, or transmitted, HIV antiretroviral resistance is an ongoing concern despite continuing development of new antiretroviral therapies. We examined HIV surveillance data, including both patient demographic characteristics and laboratory data, combined with HIV genotypic test results to evaluate the comprehensiveness of drug resistance surveillance, prevalence of primary drug resistance, and impact, if any, of primary resistance on population-based virological outcomes. The King County, WA Variant, Atypical, and Resistant HIV Surveillance (VARHS) system increased coverage of eligible genotypic testing – within three months of an HIV diagnosis among antiretroviral naïve individuals -- from – 15% in 2003 to 69% in 2010. VARHS under-represented females, Blacks, Native Americans, and injection drug users. Primary drug resistance was more common among males, individuals aged 20 – 29 years, men who had sex with men, and individuals with an initial CD4+ lymphocyte count of 200 cells/µL and higher. High level resistance to two or three antiretroviral classes declined over time. Over 90% of sequences were HIV-1 subtype B. The proportion of individuals with a most recent viral load (closest to April 2011) that was undetectable (<50 copies/mL) was not statistically significantly associated with primary drug resistance. This was true for both number and type of antiretroviral drug class; although small numbers of specimens with drug resistance may have limited our statistical power. In summary, although we found disparities in testing coverage and prevalence of drug resistance, we were unable to detect a significantly deleterious impact of primary drug resistance based on a most recent viral load.

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Lurain, Nell S., and Sunwen Chou. "Antiviral Drug Resistance of Human Cytomegalovirus." Clinical Microbiology Reviews 23, no. 4 (October 2010): 689–712. http://dx.doi.org/10.1128/cmr.00009-10.

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SUMMARY The study of human cytomegalovirus (HCMV) antiviral drug resistance has enhanced knowledge of the virological targets and the mechanisms of antiviral activity. The currently approved drugs, ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV), target the viral DNA polymerase. GCV anabolism also requires phosphorylation by the virus-encoded UL97 kinase. GCV resistance mutations have been identified in both genes, while FOS and CDV mutations occur only in the DNA polymerase gene. Confirmation of resistance mutations requires phenotypic analysis; however, phenotypic assays are too time-consuming for diagnostic purposes. Genotypic assays based on sequencing provide more rapid results but are dependent on prior validation by phenotypic methods. Reports from many laboratories have produced an evolving list of confirmed resistance mutations, although differences in interpretation have led to some confusion. Recombinant phenotyping methods performed in a few research laboratories have resolved some of the conflicting results. Treatment options for drug-resistant HCMV infections are complex and have not been subjected to controlled clinical trials, although consensus guidelines have been proposed. This review summarizes the virological and clinical data pertaining to HCMV antiviral drug resistance.

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Pauly, Matthew D., and Adam S. Lauring. "Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs." Journal of Virology 89, no. 7 (January 14, 2015): 3584–97. http://dx.doi.org/10.1128/jvi.03483-14.

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ABSTRACTLethal mutagenesis is a broad-spectrum antiviral strategy that exploits the high mutation rate and low mutational tolerance of many RNA viruses. This approach uses mutagenic drugs to increase viral mutation rates and burden viral populations with mutations that reduce the number of infectious progeny. We investigated the effectiveness of lethal mutagenesis as a strategy against influenza virus using three nucleoside analogs, ribavirin, 5-azacytidine, and 5-fluorouracil. All three drugs were active against a panel of seasonal H3N2 and laboratory-adapted H1N1 strains. We found that each drug increased the frequency of mutations in influenza virus populations and decreased the virus' specific infectivity, indicating a mutagenic mode of action. We were able to drive viral populations to extinction by passaging influenza virus in the presence of each drug, indicating that complete lethal mutagenesis of influenza virus populations can be achieved when a sufficient mutational burden is applied. Population-wide resistance to these mutagenic agents did not arise after serial passage of influenza virus populations in sublethal concentrations of drug. Sequencing of these drug-passaged viral populations revealed genome-wide accumulation of mutations at low frequency. The replicative capacity of drug-passaged populations was reduced at higher multiplicities of infection, suggesting the presence of defective interfering particles and a possible barrier to the evolution of resistance. Together, our data suggest that lethal mutagenesis may be a particularly effective therapeutic approach with a high genetic barrier to resistance for influenza virus.IMPORTANCEInfluenza virus is an RNA virus that causes significant morbidity and mortality during annual epidemics. Novel therapies for RNA viruses are needed due to the ease with which these viruses evolve resistance to existing therapeutics. Lethal mutagenesis is a broad-spectrum strategy that exploits the high mutation rate and the low mutational tolerance of most RNA viruses. It is thought to possess a higher barrier to resistance than conventional antiviral strategies. We investigated the effectiveness of lethal mutagenesis against influenza virus using three different drugs. We showed that influenza virus was sensitive to lethal mutagenesis by demonstrating that all three drugs induced mutations and led to an increase in the generation of defective viral particles. We also found that it may be difficult for resistance to these drugs to arise at a population-wide level. Our data suggest that lethal mutagenesis may be an attractive anti-influenza strategy that warrants further investigation.

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Resa-Infante, Patricia, Duncan Paterson, Jaume Bonet, Anna Otte, Baldo Oliva, Ervin Fodor, and Gülsah Gabriel. "Targeting Importin-α7 as a Therapeutic Approach against Pandemic Influenza Viruses." Journal of Virology 89, no. 17 (June 17, 2015): 9010–20. http://dx.doi.org/10.1128/jvi.00583-15.

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ABSTRACTViral drug resistance is believed to be less likely to occur if compounds are directed against cellular rather than viral proteins. In this study, we analyzed the feasibility of a crucial viral replication factor, namely, importin-α7, as a cellular drug target to combat pandemic influenza viruses. Surprisingly, only five viral lung-to-lung passages were required to achieve 100% lethality in importin-α7−/−mice that otherwise are resistant. Viral escape from importin-α7 requirement was mediated by five mutations in the viral ribonucleoprotein complex and the surface glycoproteins. Moreover, the importin-α7−/−mouse-adapted strain became even more virulent for wild-type mice than the parental strain. These studies show that targeting host proteins may still result in viral escape by alternative pathways, eventually giving rise to even more virulent virus strains. Thus, therapeutic intervention strategies should consider a multitarget approach to reduce viral drug resistance.IMPORTANCEHere, we investigated the long-standing hypothesis based onin vitrostudies that viral drug resistance occurrence is less likely if compounds are directed against cellular rather than viral proteins. Here, we challenged this hypothesis by analyzing, in anin vivoanimal model, the feasibility of targeting the cellular factor importin-α7, which is crucial for human influenza virus replication and pathogenesis, as an efficient antiviral strategy against pandemic influenza viruses. In summary, our studies suggest that resistance against cellular factors is possiblein vivo, and the emergence of even more virulent viral escape variants calls for particular caution. Thus, therapeutic intervention strategies should consider a multitarget approach using compounds against viral as well as cellular factors to reduce the risk of viral drug resistance and potentially increased virulence.

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Su, Chinh Tran-To, Darius Wen-Shuo Koh, and Samuel Ken-En Gan. "Reviewing HIV-1 Gag Mutations in Protease Inhibitors Resistance: Insights for Possible Novel Gag Inhibitor Designs." Molecules 24, no. 18 (September 6, 2019): 3243. http://dx.doi.org/10.3390/molecules24183243.

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HIV protease inhibitors against the viral protease are often hampered by drug resistance mutations in protease and in the viral substrate Gag. To overcome this drug resistance and inhibit viral maturation, targeting Gag alongside protease rather than targeting protease alone may be more efficient. In order to successfully inhibit Gag, understanding of its drug resistance mutations and the elicited structural changes on protease binding needs to be investigated. While mutations on Gag have already been mapped to protease inhibitor resistance, there remain many mutations, particularly the non-cleavage mutations, that are not characterized. Through structural studies to unravel how Gag mutations contributes to protease drug resistance synergistically, it is thus possible to glean insights to design novel Gag inhibitors. In this review, we discuss the structural role of both novel and previously reported Gag mutations in PI resistance, and how new Gag inhibitors can be designed.

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Siljic, Marina, Dubravka Salemovic, Dj Jevtovic, Ivana Pesic-Pavlovic, Sonja Zerjav, Valentina Nikolic, and Maja Stanojevic. "HIV-1 resistance profile in plasma and peripheral blood lymphocytes in a group of naive patients." Archives of Biological Sciences 64, no. 4 (2012): 1261–70. http://dx.doi.org/10.2298/abs1204261s.

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Transmitted HIV-1 drug resistance (TDR) is a persisting problem, even though the prevalence of primary resistance may remain stable or start to decline. Proviral DNA detectable in peripheral blood mononuclear cells (PBMCs) is a reservoir of drug resistant viral variants and could be an alternative marker to viral RNA for the detection of drug resistance mutations. The aim of this study was to compare the HIV-1 resistance profile between plasma viral RNA and proviral DNA in a group of untreated patients. Thirty-one HIV-1 seropositive patients without prior ARV treatment were included in the study. The presence of non-polymorphic drug resistance mutations was identified in 10 cases in proviral DNA and in 11 cases in plasma according to different scoring systems. Our results show a similar resistance profile between plasma RNA and proviral DNA, but with some discordances present. The sequencing of proviral DNA could provide useful additional information with regard to primary resistance.

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Cadosch, Dominique, Sebastian Bonhoeffer, and Roger Kouyos. "Assessing the impact of adherence to anti-retroviral therapy on treatment failure and resistance evolution in HIV." Journal of The Royal Society Interface 9, no. 74 (March 14, 2012): 2309–20. http://dx.doi.org/10.1098/rsif.2012.0127.

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The adherence of patients to therapy is a crucial factor for successful HIV anti-retroviral therapy. Imperfect adherence may lead to treatment failure, which can cause the emergence of resistance within viral populations. We have developed a stochastic model that incorporates compartments of latently infected cells and virus genotypes with different susceptibilities to three simultaneously used drugs. With this model, we study the impact of several key parameters on the probability of treatment failure, i.e. insufficient viral suppression, and the emergence of resistance. Specifically, we consider the impact of drug dosage, drug half-lives, fitness costs for resistance, different basic reproductive numbers of the virus and the influence of pre-existing mutations under various levels of adherence. Furthermore, we also investigate the influence of different temporal distributions of non-adherent days (drug holidays) during a treatment. Factors that promote resistance evolution include a high reproductive number, extended drug holidays and poor adherence. Pre-existing mutations only have a substantial effect if they confer resistance against more than one drug. Overall, our study highlights the importance of the interactions between imperfect adherence, pharmacodynamics, pharmacokinetics and latently infected cells for our understanding of drug resistance and therapy failure in HIV anti-retroviral therapy.

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Maldonado, José, and Louis Mansky. "The HIV-1 Reverse Transcriptase A62V Mutation Influences Replication Fidelity and Viral Fitness in the Context of Multi-Drug-Resistant Mutations." Viruses 10, no. 7 (July 19, 2018): 376. http://dx.doi.org/10.3390/v10070376.

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Emergence of human immunodeficiency virus type 1 (HIV-1) drug resistance arises from mutation fixation in the viral genome during antiretroviral therapy. Primary mutations directly confer antiviral drug resistance, while secondary mutations arise that do not confer drug resistance. The A62V amino acid substitution in HIV-1 reverse transcriptase (RT) was observed to be associated with multi-drug resistance, but is not known to be a resistance-conferring mutation. In particular, A62V was observed in various multi-dideoxynucleoside resistant (MDR) mutation complexes, including the Q151M complex (i.e., A62V, V75I, F77L, F116Y, and Q151M), and the T69SSS insertion complex, which has a serine–serine insertion between amino acid positions 69 and 70 (i.e., M41L, A62V, T69SSS, K70R, and T215Y). However, what selective advantage is conferred to the virus remains unresolved. In this study, we hypothesized that A62V could influence replication fidelity and viral fitness with viruses harboring the Q151M and T69SSS MDR mutation complexes. A single-cycle replication assay and a dual-competition fitness assay were used to assess viral mutant frequency and viral fitness, respectively. A62V was found to increase the observed lower mutant frequency identified with each of the viruses harboring the MDR mutation complexes in the single-cycle assay. Furthermore, A62V was observed to improve viral fitness of replication-competent MDR viruses. Taken together, these observations indicate an adaptive role of A62V in virus replication fidelity and viral fitness, which would likely enhance virus persistence during drug-selective pressure.

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Hachem, Ahmad A., Essa H. Hariri, Anthony Mansour, and Jacques Mokhbat. "Human Immunodeficiency Virus type 1 Drug Resistance Mutations in Patients Failing Antiretroviral Therapy in Lebanon from 2009 to 2013." International Journal of Clinical Research 1, no. 1 (January 27, 2021): 113–23. http://dx.doi.org/10.38179/ijcr.v1i1.20.

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Background: Antiretroviral drug resistance remains a significant problem in the clinical management of patients infected with the Human Immunodeficiency Virus type-1. Aim: This study investigates and reports data on the molecular characterization of HIV-1 isolates from patients who are in a state of therapy failure. Methods: This is a retrospective study conducted on 65 patients in therapy failure. Inclusion criteria included patients diagnosed as being in therapy failure between the years 2009 and 2013. We defined ART failure as either a failure to achieve viral suppression or a failure to detect viral loads below 500 copies/mL after virological suppression in at least two plasma samples. We used the published WHO list for surveillance of transmitted resistance and the Stanford HIV Drug Resistance Database to identify drug resistance mutations. Results: 65% of the participants had at least one drug resistance mutation (DRM). 12% of the population sampled had resistance to only one ART class, 32% presented with resistance to two classes of antiretroviral drugs, and 20% had resistance to all three classes of drugs. The prevalence of nucleoside transcriptase inhibitor (NRTI) mutations was 55%, the most common DRM being M184V. The prevalence of non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations was 58%, with the most common mutation being the K103N mutation. The prevalence of protease inhibitors drug resistance mutations was 23%, with mutations V82A and I47V being present in 10% of the study population. Conclusion: Our study is the first molecular characterization of DRM emergence in HIV-1 strains from patients failing antiretroviral therapy in Lebanon. Continuous monitoring of resistance patterns for HIV in the country is necessary to tackle the emergent drug resistance.

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Williams, Kadie-Ann, and Pleuni Pennings. "Drug Resistance Evolution in HIV in the Late 1990s: Hard Sweeps, Soft Sweeps, Clonal Interference and the Accumulation of Drug Resistance Mutations." G3: Genes|Genomes|Genetics 10, no. 4 (February 19, 2020): 1213–23. http://dx.doi.org/10.1534/g3.119.400772.

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The evolution of drug resistance in pathogens such as HIV is an important and widely known example in the field of evolutionary medicine. Here, we focus on a unique data set from the late 1990s with multiple viral sequences from multiple time points in 118 patients. We study patterns of evolutionary dynamics in the viral populations in these patients who were treated with Reverse Transcriptase Inhibitors and Protease Inhibitors in the late 1990s. Specifically, we aim to visualize and analyze examples of population genetic processes such as selective sweeps and clonal interference. The figures and descriptions in this paper can be used in evolution and population genetics classes. We show and analyze a wide variety of patterns, specifically: soft sweeps, hard sweeps, softening sweeps and hardening sweeps, simultaneous sweeps, accumulation of mutations and clonal interference.

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Trompet, Erika, Arturo Temblador, Sarah Gillemot, Dimitrios Topalis, Robert Snoeck, and Graciela Andrei. "An MHV-68 Mutator Phenotype Mutant Virus, Confirmed by CRISPR/Cas9-Mediated Gene Editing of the Viral DNA Polymerase Gene, Shows Reduced Viral Fitness." Viruses 13, no. 6 (May 26, 2021): 985. http://dx.doi.org/10.3390/v13060985.

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Drug resistance studies on human γ-herpesviruses are hampered by the absence of an in vitro system that allows efficient lytic viral replication. Therefore, we employed murine γ-herpesvirus-68 (MHV-68) that efficiently replicates in vitro as a model to study the antiviral resistance of γ-herpesviruses. In this study, we investigated the mechanism of resistance to nucleoside (ganciclovir (GCV)), nucleotide (cidofovir (CDV), HPMP-5azaC, HPMPO-DAPy) and pyrophosphate (foscarnet (PFA)) analogues and the impact of these drug resistance mutations on viral fitness. Viral fitness was determined by dual infection competition assays, where MHV-68 drug-resistant viral clones competed with the wild-type virus in the absence and presence of antivirals. Using next-generation sequencing, the composition of the viral populations was determined at the time of infection and after 5 days of growth. Antiviral drug resistance selection resulted in clones harboring mutations in the viral DNA polymerase (DP), denoted Y383SGCV, Q827RHPMP-5azaC, G302WPFA, K442TPFA, G302W+K442TPFA, C297WHPMPO-DAPy and C981YCDV. Without antiviral pressure, viral clones Q827RHPMP-5azaC, G302WPFA, K442TPFA and G302W+K442TPFA grew equal to the wild-type virus. However, in the presence of antivirals, these mutants had a growth advantage over the wild-type virus that was moderately to very strongly correlated with antiviral resistance. The Y383SGCV mutant was more fit than the wild-type virus with and without antivirals, except in the presence of brivudin. The C297W and C981Y changes were associated with a mutator phenotype and had a severely impaired viral fitness in the absence and presence of antivirals. The mutator phenotype caused by C297W in MHV-68 DP was validated by using a CRISPR/Cas9 genome editing approach.

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Valantin, Marc-Antoine, Lise Durand, Marc Wirden, Lambert Assoumou, Fabienne Caby, Cathia Soulié, Thi Thu-Thuy Nguyen, et al. "Antiretroviral drug reduction in highly experienced HIV-infected patients receiving a multidrug regimen: the ECOVIR study." Journal of Antimicrobial Chemotherapy 74, no. 9 (July 4, 2019): 2716–22. http://dx.doi.org/10.1093/jac/dkz255.

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Abstract Objectives In a context of life-long therapy, we asked whether it could be possible to reduce the number of antiretroviral drugs without jeopardizing viral suppression. Methods ECOVIR was a prospective study aiming to assess whether in patients on combination ART with ≥4 antiretrovirals for ≥24 weeks and virally suppressed for ≥48 weeks, a drug-reduced (DR) regimen could be proposed. The intervention consisted of discontinuing genotypically less susceptible drugs to reach a DR regimen with ≤3 antiretrovirals. The primary endpoint was the proportion of patients maintaining viral suppression at week (W) 24. Results From 89 eligible individuals for the study, a DR regimen was proposed in 86 (97%) patients, of whom 71 were switched to a DR regimen. Baseline characteristics [median (IQR)] were: age 58 (53–65) years, duration of treatment 24 (21–26) years and viral suppression 8 (6–11) years. The cumulative resistance profile showed full resistance to lamivudine/emtricitabine (91%), abacavir (74%), efavirenz/nevirapine (70%), rilpivirine (56%), darunavir (q24h/q12h) (42%/29%), lopinavir (69%), atazanavir (71%) and raltegravir (24%). The final DR regimen consisted of a two-drug or three-drug regimen in 54 patients (76%) and in 17 patients (24%), respectively. The success rate of a DR regimen at W24 was 93.9% (95% CI 84.4–97.6, Kaplan–Meier estimate). Four patients experienced virological failure (at W4, W8 and W12), all with plasma viral load (pVL) <600 copies/mL and no emergence of resistance mutations. The DR strategy allowed a monthly cost saving of 36%. Conclusions In experienced patients with high-level resistance, individualized strategies based on expert advice can offer DR regimen options with fewer drug–drug interactions and a significant economic impact while ensuring virological success.

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Althaus, Christian L., and Sebastian Bonhoeffer. "Stochastic Interplay between Mutation and Recombination during the Acquisition of Drug Resistance Mutations in Human Immunodeficiency Virus Type 1." Journal of Virology 79, no. 21 (November 1, 2005): 13572–78. http://dx.doi.org/10.1128/jvi.79.21.13572-13578.2005.

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ABSTRACT The emergence of drug resistance mutations in human immunodeficiency virus (HIV) has been a major setback in the treatment of infected patients. Besides the high mutation rate, recombination has been conjectured to have an important impact on the emergence of drug resistance. Population genetic theory suggests that in populations limited in size recombination may facilitate the acquisition of beneficial mutations. The viral population in an infected patient may indeed represent such a population limited in size, since current estimates of the effective population size range from 500 to 105. To address the effects of limited population size, we therefore expand a previously described deterministic population genetic model of HIV replication by incorporating the stochastic processes that occur in finite populations of infected cells. Using parameter estimates from the literature, we simulate the evolution of drug-resistant viral strains. The simulations show that recombination has only a minor effect on the rate of acquisition of drug resistance mutations in populations with effective population sizes as small as 1,000, since in these populations, viral strains typically fix beneficial mutations sequentially. However, for intermediate effective population sizes (104 to 105), recombination can accelerate the evolution of drug resistance by up to 25%. Furthermore, a reduction in population size caused by drug therapy can be overcome by a higher viral mutation rate, leading to a faster evolution of drug resistance.

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Nikolic, Valentina, D. Salemovic, Dj Jevtovic, I. Pesic-Pavlovic, S. Zerjav, J. Ranin, M. Siljic, and M. Stanojevic. "Primary HIV-1 resistance: Persistence of transmitted drug resistance mutations." Archives of Biological Sciences 64, no. 4 (2012): 1301–9. http://dx.doi.org/10.2298/abs1204301n.

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Transmitted drug resistance (TDR) is one of the consequences of the high variability of HIV-1. The widespread use of antiretroviral therapy for the treatment of HIV-1 infection results in a large circulating pool of resistant virus variants. It is known that TDR mutations can persist for extended periods and may pose an important problem to the overall success of antiretroviral therapy. Factors that determine the duration of continuous persistence of resistance-associated mutations are the number and type of these mutations and their impact on viral fitness. Here we describe the follow-up of a case study of prolonged persistence of resistance-associated mutations, namely RT mutations Q151M, K65KR and Y181C conferring an intermediate-to-high level resistance to multiple NRTIs and NNRTIs that lasted for seven years. The infection was caused by subtype G virus.

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Kageyama, Seiji, Alfredo Amolong Hinay, Elizabeth Freda Omengan Telan, Genesis May Jopson Samonte, Prisca Susan Agustin Leano, Akeno Tsuneki-Tokunaga, and Kyosuke Kanai. "Intrinsic Replication Competences of HIV Strains After Zidovudine/Lamivudine/Nevirapine Treatment in the Philippines." Journal of the International Association of Providers of AIDS Care (JIAPAC) 18 (January 1, 2019): 232595821985657. http://dx.doi.org/10.1177/2325958219856579.

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Although drug-resistant HIV variants are considered to be less fit than drug-susceptible viruses, replication competence of these variants harbored by patients has not yet been elucidated in detail. We herein assessed the replication competence of strains obtained from individuals receiving antiretroviral therapy. Among 11 306 participants in a drug resistance surveillance in the Philippines, 2629 plasma samples were obtained from individuals after a 12-month treatment with zidovudine (ZDV)/lamivudine (3TC)/nevirapine (NVP). The replication competence of HIV isolates was then assessed by reinoculation into seronegative peripheral blood mononuclear cells in the absence of drugs in vitro. The drug resistance rate was estimated to be 9.2%. Drug-resistant strains were still a minority of closely related strains in a phylogenetic cluster. Among the available 295 samples, 37 HIV strains were successfully isolated. Progeny viruses were produced at a wide range (5.1 × 106 to 3.4 × 109 copies/mL) in primary culture of peripheral blood mononuclear cells. The viral yields were higher than the corresponding plasma viral load (1300 to 3.4 × 106 copies/mL) but correlated with those ( r = 0.4). These results suggest that strains with higher intrinsic replication competence are one of the primary targets of newly selected drugs at the increasing phase of the plasma viral load during antiretroviral therapy.

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Chou, Sunwen, Nell S. Lurain, Kenneth D. Thompson, Richard C. Miner, and W. Lawrence Drew. "Viral DNA Polymerase Mutations Associated with Drug Resistance in Human Cytomegalovirus." Journal of Infectious Diseases 188, no. 1 (July 2003): 32–39. http://dx.doi.org/10.1086/375743.

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BONHOEFFER, SEBASTIAN. "Models of Viral Kinetics and Drug Resistance in HIV-1 Infection." AIDS Patient Care and STDs 12, no. 10 (October 1998): 769–74. http://dx.doi.org/10.1089/apc.1998.12.769.

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Ramadhani, Habib O., Charles Muiruri, Venance P. Maro, Balthazar Nyombi, Michael Omondi, Julian B. Mushi, Eileen S. Lirhunde, and John A. Bartlett. "Patient-Initiated Repackaging of Antiretroviral Therapy, Viral Suppression and Drug Resistance." AIDS and Behavior 22, no. 5 (February 9, 2017): 1671–78. http://dx.doi.org/10.1007/s10461-017-1721-x.

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Zala, C., D. Rouleau, and B. Conway. "Is There Anything Left to Learn? A Report on the Fifth Interanational Workshop on HIV Drug Resistance." Canadian Journal of Infectious Diseases 9, no. 3 (1998): 172–76. http://dx.doi.org/10.1155/1998/347961.

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Although insight into the viral dynamics of human immunodeficiency virus (HIV) infection has increased dramatically over the past year, there remains much to learn in the field of antiretroviral drug resistance. Transmission of isolates with primary drug resistance is increasingly recognized. With respect to reverse transcriptase inhibitors, it appears that the use of drugs in combination may forestall the development of resistance once therapy has been initiated. Further, certain findings, particularly with respect to zidovudine and lamivudine, suggest that emergence of resistance to one agent may lead to increased susceptibility to another. These data may allow evaluation of innovative treatment strategies to avoid the development of multidrug resistance, which has now been reported in a number of settings. Protease inhibitors (PIs) are, on an individual basis, the most potent antiretroviral compounds available today. A number of studies have shown that resistance to these agents develops after the accumulation of several mutations in the protease gene of HIV. As with reverse transcriptase inhibitors, the use of PIs in the context of regimens designed to suppress viral replication as much as possible appears to forestall, perhaps indefinitely, the development of drug resistance. Although different patterns of resistance mutations have been described for the different PIs available, the issue of cross-resistance remains unresolved. For the time being, it may be best to consider all PIs as a single agent that must always be used in a regimen designed to maximally suppress viral load. In conclusion, research in the field of antiretroviral drug resistance has never been more active and productive. It is hoped that such research will lead to the development of an integrated model of the clinical and laboratory management of HIV-infected individuals.

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Hurt, Aeron C. "Antiviral drug resistance in seasonal and pandemic influenza." Microbiology Australia 32, no. 1 (2011): 26. http://dx.doi.org/10.1071/ma11026.

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Two classes of anti-influenza drugs are currently available for the treatment or prophylaxis of influenza. These are the adamantanes (amantadine and rimantadine), which block the activity of the M2 ion channel of influenza A viruses (but not influenza B viruses), and the neuraminidase inhibitors (NAIs), which act by binding to the enzymatic site of the influenza neuraminidase (NA) thereby preventing progeny virions from being released from the host cell during viral replication. Antiviral resistance can occur in influenza viruses and render the drug ineffective for the treatment of patients. Virtually all influenza A viruses currently circulating in the human population are resistant to the adamantanes, while in comparison these viruses remain susceptible to the NAIs. In particular, very low NAI resistance has been observed in pandemic A(H1N1) 2009 viruses, even though unprecedented amounts of these drugs were used.

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Simon, Viviana, Neal Padte, Deya Murray, Jeroen Vanderhoeven, Terri Wrin, Neil Parkin, Michele Di Mascio, and Martin Markowitz. "Infectivity and Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1 Variants Isolated during Primary Infection." Journal of Virology 77, no. 14 (July 15, 2003): 7736–45. http://dx.doi.org/10.1128/jvi.77.14.7736-7745.2003.

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ABSTRACT It is believed that replication capacity is an important determinant of human immunodeficiency virus type 1 (HIV-1) pathogenicity and transmissibility. To explore this, we conducted a comprehensive analysis of the replication properties of nine drug-resistant and nine drug-susceptible viral isolates derived from patients with primary HIV-1 infection. Viral isolates were tested for single-cycle infectivity in the GHOST cell line. The infectivity of isolates carrying resistance-associated mutations was significantly higher than that of drug-susceptible isolates. Additionally, the growth kinetics of these isolates were determined in CD4+ T lymphocytes. Drug-resistant isolates replicated as well as drug-susceptible viruses. Insertion of the resistance-conferring regions into an NL4-3-based molecular background resulted in chimeras that displayed a modest but significant reduction in replication capacity compared to the drug-susceptible chimeric viruses. Of note, two multidrug-resistant isolates and one protease inhibitor-resistant isolate displayed higher rates of infectivity and growth kinetics than the other drug-resistant or drug-susceptible isolates. These distinct replicative features, however, were not seen in the corresponding chimeras, indicating that changes within the C-terminal region of Gag as well as within the protease and reverse transcriptase genes contribute to but are not sufficient for the level of compensatory adaptation observed. These findings suggest that some drug-resistant viruses isolated during primary infection possess unique adaptive changes that allow for both high viral replication capacity and resistance to one or more classes of antiretroviral drugs. Further studies are needed to elucidate the precise regions that are essential for these characteristics.

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Bimber, Benjamin N., Dawn M. Dudley, Michael Lauck, Ericka A. Becker, Emily N. Chin, Simon M. Lank, Haiying L. Grunenwald, et al. "Whole-Genome Characterization of Human and Simian Immunodeficiency Virus Intrahost Diversity by Ultradeep Pyrosequencing." Journal of Virology 84, no. 22 (September 15, 2010): 12087–92. http://dx.doi.org/10.1128/jvi.01378-10.

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ABSTRACT Rapid evolution and high intrahost sequence diversity are hallmarks of human and simian immunodeficiency virus (HIV/SIV) infection. Minor viral variants have important implications for drug resistance, receptor tropism, and immune evasion. Here, we used ultradeep pyrosequencing to sequence complete HIV/SIV genomes, detecting variants present at a frequency as low as 1%. This approach provides a more complete characterization of the viral population than is possible with conventional methods, revealing low-level drug resistance and detecting previously hidden changes in the viral population. While this work applies pyrosequencing to immunodeficiency viruses, this approach could be applied to virtually any viral pathogen.

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van de Vijver, David A. M. C., Shreoshee Mukherjee, and Jeroen J. A. van Kampen. "Antiretroviral Drug Treatment of Individuals that Used Preexposure Prophylaxis (PrEP) Before Diagnosis." Current Treatment Options in Infectious Diseases 13, no. 3 (March 8, 2021): 141–52. http://dx.doi.org/10.1007/s40506-021-00246-9.

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Abstract Purpose of review The antiretroviral drugs, tenofovir and emtricitabine used as preexposure prophylaxis (PrEP), are also used in treatment of HIV. Drug resistance due to PrEP can therefore jeopardize future treatment options. This review discusses treatment of individuals that used PrEP in whom viral mutations against tenofovir (K65R) or emtricitabine (M184I/V) are found. Recent findings Although no studies systematically investigated the optimal treatment of individuals who used PrEP before diagnosis, there is anecdotal evidence that HIV including the K65R and/or M184I/V can be successfully treated using recommended first-line regimens. Summary Drug resistance can be ascribed to use of PrEP while having an unrecognized acute HIV infection, partial adherence to PrEP, and transmission of HIV resistant to PrEP drugs. First-line antiretroviral drug treatment in individuals who used PrEP before diagnosis must be optimized based on genotypic resistance test results. Individuals in whom M184I/V and/or K65R is detected can be treated with dolutegravir-based, bictegravir-based, or darunavir-based regimens plus tenofovir plus lamivudine or emtricitabine. Dual therapy using dolutegravir plus lamivudine is not recommended for induction therapy in individuals with viral mutations against the drugs used as PrEP. There is an urgent need to confirm the anecdotal evidence for successful treatment using first-line regimens.

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Wares, Melissa, Said Hassounah, Thibault Mesplède, Paul A. Sandstrom, and Mark A. Wainberg. "Simian-Tropic HIV as a Model To Study Drug Resistance against Integrase Inhibitors." Antimicrobial Agents and Chemotherapy 59, no. 4 (January 12, 2015): 1942–49. http://dx.doi.org/10.1128/aac.04829-14.

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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.

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Kierczak, Marcin, Michał Dramiński, Jacek Koronacki, and Jan Komorowski. "Computational Analysis of Molecular Interaction Networks Underlying Change of HIV-1 Resistance to Selected Reverse Transcriptase Inhibitors." Bioinformatics and Biology Insights 4 (January 2010): BBI.S6247. http://dx.doi.org/10.4137/bbi.s6247.

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Motivation Despite more than two decades of research, HIV resistance to drugs remains a serious obstacle in developing efficient AIDS treatments. Several computational methods have been developed to predict resistance level from the sequence of viral proteins such as reverse transcriptase (RT) or protease. These methods, while powerful and accurate, give very little insight into the molecular interactions that underly acquisition of drug resistance/hypersusceptibility. Here, we attempt at filling this gap by using our Monte Carlo feature selection and interdependency discovery method (MCFS-ID) to elucidate molecular interaction networks that characterize viral strains with altered drug resistance levels. Results We analyzed a number of HIV-1 RT sequences annotated with drug resistance level using the MCFS-ID method. This let us expound interdependency networks that characterize change of drug resistance to six selected RT inhibitors: Abacavir, Lamivudine, Stavudine, Zidovudine, Tenofovir and Nevirapine. The networks consider interdependencies at the level of physicochemical properties of mutating amino acids, eg,: polarity. We mapped each network on the 3D structure of RT in attempt to understand the molecular meaning of interacting pairs. The discovered interactions describe several known drug resistance mechanisms and, importantly, some previously unidentified ones. Our approach can be easily applied to a whole range of problems from the domain of protein engineering. Availability A portable Java implementation of our MCFS-ID method is freely available for academic users and can be obtained at: http://www.ipipan.eu/staff/m.draminski/software.htm .

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Roosenhoff, Rueshandra, Vaughan Reed, Andy Kenwright, Martin Schutten, Charles A. Boucher, Arnold Monto, Barry Clinch, et al. "Viral Kinetics and Resistance Development in Children Treated with Neuraminidase Inhibitors: The Influenza Resistance Information Study (IRIS)." Clinical Infectious Diseases 71, no. 5 (September 27, 2019): 1186–94. http://dx.doi.org/10.1093/cid/ciz939.

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Abstract Background We studied the effect of age, baseline viral load, vaccination status, antiviral therapy, and emergence of drug resistance on viral shedding in children infected with influenza A or B virus. Methods Samples from children (aged ≤13 years) enrolled during the 7 years of the prospective Influenza Resistance Information Study were analyzed using polymerase chain reaction to determine the influenza virus (sub-)type, viral load, and resistance mutations. Disease severity was assessed; clinical symptoms were recorded. The association of age with viral load and viral clearance was examined by determining the area under the curve for viral RNA shedding using logistic regression and Kaplan-Meier analyses. Results A total of 2131 children infected with influenza (683, A/H1N1pdm09; 825, A/H3N2; 623, influenza B) were investigated. Age did not affect the mean baseline viral load. Children aged 1−5 years had prolonged viral RNA shedding (±1–2 days) compared with older children and up to 1.2-fold higher total viral burden. Besides, in older age (odds ratio [OR], 1.08; confidence interval [CI], 1.05–1.12), prior vaccination status (OR, 1.72; CI, 1.22–2.43) and antiviral treatment (OR, 1.74; CI, 1.43–2.12) increased the rate of viral clearance. Resistance mutations were detected in 49 children infected with influenza A virus (34, A/H1N1pdm09; 15, A/H3N2) treated with oseltamivir, most of whom were aged <5 years (n = 39). Conclusions Children aged 1−5 years had a higher total viral burden with prolonged virus shedding and had an increased risk of acquiring resistance mutations following antiviral treatment. Clinical Trials Registration NCT00884117.

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Koizumi, Yoshiki, Hirofumi Ohashi, Syo Nakajima, Yasuhito Tanaka, Takaji Wakita, Alan S. Perelson, Shingo Iwami, and Koichi Watashi. "Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection." Proceedings of the National Academy of Sciences 114, no. 8 (February 7, 2017): 1922–27. http://dx.doi.org/10.1073/pnas.1610197114.

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With the introduction of direct-acting antivirals (DAAs), treatment against hepatitis C virus (HCV) has significantly improved. To manage and control this worldwide infectious disease better, the “best” multidrug treatment is demanded based on scientific evidence. However, there is no method available that systematically quantifies and compares the antiviral efficacy and drug-resistance profiles of drug combinations. Based on experimental anti-HCV profiles in a cell culture system, we quantified the instantaneous inhibitory potential (IIP), which is the logarithm of the reduction in viral replication events, for both single drugs and multiple-drug combinations. From the calculated IIP of 15 anti-HCV drugs from different classes [telaprevir, danoprevir, asunaprevir, simeprevir, sofosbuvir (SOF), VX-222, dasabuvir, nesbuvir, tegobuvir, daclatasvir, ledipasvir, IFN-α, IFN-λ1, cyclosporin A, and SCY-635], we found that the nucleoside polymerase inhibitor SOF had one of the largest potentials to inhibit viral replication events. We also compared intrinsic antiviral activities of a panel of drug combinations. Our quantification analysis clearly indicated an advantage of triple-DAA treatments over double-DAA treatments, with triple-DAA treatments showing enhanced antiviral activity and a significantly lower probability for drug resistance to emerge at clinically relevant drug concentrations. Our framework provides quantitative information to consider in designing multidrug strategies before costly clinical trials.

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Chou, Sunwen, Ronald J. Ercolani, Malaya K. Sahoo, Martina I. Lefterova, Lynne M. Strasfeld, and Benjamin A. Pinsky. "Improved Detection of Emerging Drug-Resistant Mutant Cytomegalovirus Subpopulations by Deep Sequencing." Antimicrobial Agents and Chemotherapy 58, no. 8 (June 2, 2014): 4697–702. http://dx.doi.org/10.1128/aac.03214-14.

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ABSTRACTIn immunosuppressed hosts, the development of multidrug resistance complicates the treatment of cytomegalovirus (CMV) infection. Improved genotypic detection of impending drug resistance may follow from recent technical advances. A severely T-cell-depleted patient with chronic lymphocytic leukemia developed CMV pneumonia and high plasma viral loads that were poorly responsive to antiviral therapy. Serial plasma specimens were analyzed for mutant viral populations by conventional and high-throughput deep-sequencing methods. Uncharacterized mutations were phenotyped for drug resistance using recombinant viruses. Conventional genotyping detected viruses with the UL97 kinase substitution C607Y after ganciclovir treatment, a transient subpopulation of UL54 polymerase L773V mutants first detected 8 weeks after foscarnet was started, and a subpopulation of a mutant with deletion of UL54 codons 981 and 982 2 months after the addition of cidofovir. Deep sequencing of the same serial specimens revealed the same UL54 mutants sooner, along with a more complex evolution of known and newly recognized mutant subpopulations missed by conventional sequencing. The UL54 exonuclease substitutions D413N, K513R, and C539G were newly shown to confer ganciclovir-cidofovir resistance, while L773V was shown to confer foscarnet resistance and add to the ganciclovir resistance conferred by UL97 C607Y. Increased sequencing depth provided a more timely and detailed diagnosis of mutant viral subpopulations that evolved with changing anti-CMV therapy.

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Zhang, Jiantao, Kasey Vernon, Qi Li, Zsigmond Benko, Anthony Amoroso, Mohamed Nasr, and Richard Y. Zhao. "Single-Agent and Fixed-Dose Combination HIV-1 Protease Inhibitor Drugs in Fission Yeast (Schizosaccharomyces pombe)." Pathogens 10, no. 7 (June 24, 2021): 804. http://dx.doi.org/10.3390/pathogens10070804.

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Successful combination antiretroviral therapies (cART) eliminate active replicating HIV-1, slow down disease progression, and prolong lives. However, cART effectiveness could be compromised by the emergence of viral multidrug resistance, suggesting the need for new drug discoveries. The objective of this study was to further demonstrate the utility of the fission yeast cell-based systems that we developed previously for the discovery and testing of HIV protease (PR) inhibitors (PIs) against wild-type or multi-PI drug resistant M11PR that we isolated from an infected individual. All thirteen FDA-approved single-agent and fixed-dose combination HIV PI drugs were tested. The effect of these drugs on HIV PR activities was tested in pure compounds or formulation drugs. All FDA-approved PI drugs, except for a prodrug FPV, were able to suppress the wild-type PR-induced cellular and enzymatic activities. Relative drug potencies measured by EC50 in fission yeast were discussed in comparison with those measured in human cells. In contrast, none of the FDA-approved drugs suppressed the multi-PI drug resistant M11PR activities. Results of this study show that fission yeast is a reliable cell-based system for the discovery and testing of HIV PIs and further demonstrate the need for new PI drugs against viral multi-PI resistance.

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Andreatta, Kristen N., Michael D. Miller, and Kirsten L. White. "Drug Susceptibility and Viral Fitness of HIV-1 with Integrase Strand Transfer Inhibitor Resistance Substitution Q148R or N155H in Combination with Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Resistance Substitutions." Antimicrobial Agents and Chemotherapy 60, no. 2 (November 16, 2015): 757–65. http://dx.doi.org/10.1128/aac.02096-15.

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ABSTRACTIn clinical trials of coformulated elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF), emergent drug resistance predominantly involved the FTC resistance substitution M184V/I in reverse transcriptase (RT), with or without the tenofovir (TFV) resistance substitution K65R, accompanied by a primary EVG resistance substitution (E92Q, N155H, or Q148R) in integrase (IN). We previously reported that the RT-K65R, RT-M184V, and IN-E92Q substitutions lacked cross-class phenotypic resistance and replicative fitness compensation. As a follow-up, thein vitrocharacteristics of mutant HIV-1 containing RT-K65R and/or RT-M184V with IN-Q148R or IN-N155H were also evaluated, alone and in combination, for potential interactions. Single mutants displayed reduced susceptibility to their corresponding inhibitor classes, with no cross-class resistance. Viruses with IN-Q148R or IN-N155H exhibited reduced susceptibility to EVG (137- and 40-fold, respectively) that was not affected by the addition of RT-M184V or RT-K65R/M184V. All viruses containing RT-M184V were resistant to FTC (>1,000-fold). Mutants with RT-K65R had reduced susceptibility to TFV (3.3- to 3.6-fold). Without drugs present, the viral fitness of RT and/or IN mutants was diminished relative to that of the wild type in the following genotypic order: wild type > RT-M184V ≥ IN-N155H ≈ IN-Q148R ≥ RT-M184V + IN-N155H ≥ RT-M184V + IN-Q148R ≥ RT-K65R/M184V + IN-Q148R ≈ RT-K65R/M184V + IN-N155H. In the presence of drug concentrations approaching physiologic levels, drug resistance counteracted replication defects, allowing single mutants to outcompete the wild type with one drug present and double mutants to outcompete single mutants with two drugs present. These results suggest that during antiretroviral treatment with multiple drugs, the development of viruses with combinations of resistance substitutions may be favored despite diminished viral fitness.

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Hiscox, Julian A., Saye H. Khoo, James P. Stewart, and Andrew Owen. "Shutting the gate before the horse has bolted: is it time for a conversation about SARS-CoV-2 and antiviral drug resistance?" Journal of Antimicrobial Chemotherapy 76, no. 9 (June 18, 2021): 2230–33. http://dx.doi.org/10.1093/jac/dkab189.

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Abstract This article provides a brief overview of drug resistance to antiviral therapy as well as known and emergent variability in key SARS-CoV-2 viral sequences. The purpose is to stimulate deliberation about the need to consider drug resistance prior to widespread roll-out of antivirals for SARS-CoV-2. Many existing candidate agents have mechanisms of action involving drug targets likely to be critical for future drug development. Resistance emerged quickly with monotherapies deployed for other pulmonary viruses such as influenza virus, and in HIV mutations in key drug targets compromised efficacy of multiple drugs within a class. The potential for drug resistance in SARS-CoV-2 has not yet been rigorously debated or assessed, and we call for more academic and industry research on this potentially important future threat prior to widespread roll-out of monotherapies for COVID-19 treatment and prevention.

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Latinovic, Olga, Janaki Kuruppu, Charles Davis, Nhut Le, and Alonso Heredia. "Pharmacotherapy of HIV-1 Infection: Focus on CCR5 Antagonist Maraviroc." Clinical Medicine. Therapeutics 1 (January 2009): CMT.S2365. http://dx.doi.org/10.4137/cmt.s2365.

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Sustained inhibition of HIV-1, the goal of antiretroviral therapy, is often impeded by the emergence of viral drug resistance. For patients infected with HIV-1 resistant to conventional drugs from the viral reverse transcriptase and protease inhibitor classes, the recently approved entry and integration inhibitors effectively suppress HIV-1 and offer additional therapeutic options. Entry inhibitors are particularly attractive because, unlike conventional antiretrovirals, they target HIV-1 extracellularly, thereby sparing cells from both viral- and drug-induced toxicities. The fusion inhibitor enfuvirtide and the CCR5 antagonist maraviroc are the first entry inhibitors licensed for patients with drug-resistant HIV-1, with maraviroc restricted to those infected with CCR5-tropic HIV-1 (R5 HIV-1) only. Vicriviroc (another CCR5 antagonist) is in Phase III clinical trials, whereas the CCR5 antibodies PRO 140 and HGS 004 are in early stages of clinical development. Potent antiviral synergy between maraviroc and CCR5 antibodies, coupled with distinct patterns of resistance, suggest their combinations might be particularly effective in patients. In addition, given that oral administration of maraviroc achieves high drug levels in cervicovaginal fluid, combinations of maraviroc and other CCR5 inhibitors could be effective in preventing HIV-1 transmission. Moreover, since CCR5 antagonists prevent rejection of transplanted organs, maraviroc could both suppress HIV-1 and prolong organ survival for the growing number of HIV-1 patients with kidney or liver failure necessitating organ transplantation. Thus, maraviroc offers an important treatment option for patients with drug-resistant R5 HIV-1, who presently account for >50% of drug-resistance cases.

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Chou, Sunwen, Laura C. Van Wechel, Heather M. Lichy, and Gail I. Marousek. "Phenotyping of Cytomegalovirus Drug Resistance Mutations by Using Recombinant Viruses Incorporating a Reporter Gene." Antimicrobial Agents and Chemotherapy 49, no. 7 (July 2005): 2710–15. http://dx.doi.org/10.1128/aac.49.7.2710-2715.2005.

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ABSTRACT A new recombinant phenotyping method was developed for the analysis of drug resistance mutations in human cytomegalovirus (CMV). CMV strain T2211 was derived from strain AD169 by inserting unique restriction sites and a secreted alkaline phosphatase (SEAP) reporter gene for rapid viral quantitation. Specific viral UL97 and pol gene mutations were transferred by recombination into T2211, and their drug resistance phenotypes (for ganciclovir, foscarnet, or cidofovir) were determined by the drug concentrations required to reduce supernatant SEAP activity by 50% (IC50). Changes in the IC50 conferred by the mutations tested (UL97 M460V, C592G, A594V, and L595S and pol del981-2) were similar to those previously reported in marker transfer and conventional plaque reduction assays. The combination of UL97 C592G and pol del981-2 conferred much higher ganciclovir resistance than either mutation alone. The UL97 polymorphism D605E had no measurable effect on ganciclovir susceptibility, alone or in combination with common UL97 resistance mutations. Transfer into strain T2211 facilitates the phenotyping of newly observed mutations, combinations of mutations, and clinical CMV sequences without an accompanying viral isolate.

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Cunha, Rita F., Sandra Simões, Manuela Carvalheiro, José M. Azevedo Pereira, Quirina Costa, and Andreia Ascenso. "Novel Antiretroviral Therapeutic Strategies for HIV." Molecules 26, no. 17 (August 31, 2021): 5305. http://dx.doi.org/10.3390/molecules26175305.

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When the first cases of HIV infection appeared in the 1980s, AIDS was a deadly disease without any therapeutic alternatives. Currently, there is still no cure for most cases mainly due to the multiple tissues that act as a reservoir for this virus besides the high viral mutagenesis that leads to an antiretroviral drug resistance. Throughout the years, multiple drugs with specific mechanisms of action on distinct targets have been approved. In this review, the most recent phase III clinical studies and other research therapies as advanced antiretroviral nanodelivery systems will be here discussed. Although the combined antiretroviral therapy is effective in reducing viral loading to undetectable levels, it also presents some disadvantages, such as usual side effects, high frequency of administration, and the possibility of drug resistance. Therefore, several new drugs, delivery systems, and vaccines have been tested in pre-clinical and clinical trials. Regarding drug delivery, an attempt to change the route of administration of some conventional antiretrovirals has proven to be successful and surpassed some issues related to patient compliance. Nanotechnology has brought a new approach to overcoming certain obstacles of formulation design including drug solubility and biodistribution. Overall, the encapsulation of antiretroviral drugs into nanosystems has shown improved drug release and pharmacokinetic profile.

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Cheng, Guofeng, Katie Chan, Huiling Yang, Amy Corsa, Maria Pokrovskii, Matthew Paulson, Gina Bahador, Weidong Zhong, and William Delaney. "Selection of Clinically Relevant Protease Inhibitor-Resistant Viruses Using the Genotype 2a Hepatitis C Virus Infection System." Antimicrobial Agents and Chemotherapy 55, no. 5 (February 28, 2011): 2197–205. http://dx.doi.org/10.1128/aac.01382-10.

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ABSTRACTTreatment of patients infected with hepatitis C virus (HCV) with direct acting antivirals can lead to the emergence of drug-resistant variants that may pose a long-term threat to viral eradication. HCV replicons have been used to select resistance mutations; however, genotype 2a JFH-1-based viruses provide the opportunity to perform resistance selection in abona fideinfection system. In this study, we used a tissue culture-adapted J6/JFH-1 virus to select resistance to the NS3 protease inhibitors BILN-2061 and VX-950. Lunet-CD81 cells were infected with J6/JFH-1 virus and maintained in the presence of inhibitors until high-titer viral supernatant was produced. Viral supernatants were passaged over naive cells at escalating drug concentrations, and the resulting viruses were then characterized. Three NS3 resistance mutations were identified in BILN-2061-resistant viruses: A156G, D168A, and D168V. Interestingly, D168A, D168V, and A156T/V, but not A156G, were selected in parallel using a genotype 2a replicon. For VX-950, the T54A and A156S NS3 resistance mutations were identified in the virus selections, whereas only A156T/V emerged in genotype 2a replicon selections. Of note, VX-950 resistance mutations selected using the 2a virus (T54A and A156S) were also observed during VX-950 clinical studies in genotype 2 patients. We also performed viral fitness evaluations and determined that the mutations selected in the viral system did not confer marked reductions in virus production kinetics or peak titers. Overall, the HCV infection system is an efficient tool for drug resistance selections and has advantages for the rapid identification and characterization of clinically relevant resistance mutations.

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Wainburg, Mark A. "The impact of the M184V substitution on drug resistance and viral fitness." Expert Review of Anti-infective Therapy 2, no. 1 (February 2004): 147–51. http://dx.doi.org/10.1586/14787210.2.1.147.

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Journal articles on the topic 'Viral Drug Resistance'

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