No Evidence for Persistence of Multidrug-Resistant Viral Strains After a 7-Month Treatment Interruption in an HIV-1–Infected Individual

Walter, Hauke; Löw, P.; Harrer, Thomas; Schmitt, Matthias; Schwingel, Eva; Tschochner, M.; Helm, Martin; Korn, Klaus; Überla, Klaus; Schmidt, Bárbara

doi:10.1097/00126334-200210010-00003

Cited by 13 publications

(9 citation statements)

References 38 publications

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“…Additional studies are also necessary to assess the real utility of treatment interruption in patients infected with drugresistant viruses. This subject is obviously now quite controversial, and this important point must be better defined in the future [19,20].…”

mentioning

confidence: 99%

Q151M‐Mediated Multinucleoside Resistance: Prevalence, Risk Factors, and Response to Salvage Therapy

Zaccarelli¹,

Perno²,

Forbici³

et al. 2004

CLIN INFECT DIS

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Among 470 patients with acquired immune deficiency syndrome and/or human immunodeficiency virus infection (HIV/AIDS) who underwent genotype resistance testing (GRT) after the failure of therapy, 17 (3.6%) harbored the Q151M mutation. The Q151M mutation was associated with younger age, lower CD4(+) lymphocyte count, higher HIV RNA level, and treatment with >2 pre-GRT regimens. By contrast, the Q151M mutation was inversely associated with lamivudine administration. A full reversion of the Q151M mutation was observed in 5 of 5 patients who underwent treatment interruption after GRT. The reversion was followed by a response to salvage therapy in 4 (80%) of 5 patients.

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confidence: 99%

Q151M‐Mediated Multinucleoside Resistance: Prevalence, Risk Factors, and Response to Salvage Therapy

Zaccarelli¹,

Perno²,

Forbici³

et al. 2004

CLIN INFECT DIS

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“…The intention here is to remind that resistance-associated mutations can reverse to wild type, especially if the mutations lead to a disadvantage in viral replication [24] . Whereas the reappearance of wild-type mutations in cases of therapy interruption has been extensively reported [25,26] , the disappearance of resensitizing drug resistance mutations mediating higher susceptibility to a current regimen is not well described. The advantage of specific drug combinations, particularly one drug being resensitized by a mutation causing resistance to a certain second drug and this second drug only being administered to keep the selective pressure on this mutation, remains unclear.…”

Section: Discussionmentioning

confidence: 99%

HIV-GRADE: A Publicly Available, Rules-Based Drug Resistance Interpretation Algorithm Integrating Bioinformatic Knowledge

Obermeier¹,

Pironti

Berg³

et al. 2012

Intervirology

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tion system (geno2pheno [resistance] ). HIV-GRADE presents the option of seeing the rules and results of other drug resistance algorithms for a given sequence simultaneously. Methods: The HIV-GRADE rules-based interpretation system was developed by the members of the HIV-GRADE registered society. For continuous updates, this expert committee meets twice a year to analyze data from various sources. Besides data from clinical studies and the centers involved, published correlations for mutations with drug resistance and genotype-phenotype correlation data information from the bioinformatic models of geno2pheno are used to generate the rules for the HIV-GRADE interpretation system. A freely available online tool was developed on the basis of the Stanford HIVdb rules interpretation tool using the algorithm specification interface. Clinical validation of the interpretation system was performed on the data of treatment episodes consisting of sequence information, antiretroviral treatment and viral load, before and 3 months after treatment change. Data were analyzed using multiple linear regression. Results: As the developed online tool allows easy Key Words HIV-GRADE ؒ Genotypic drug resistance ؒ Clinical validation Abstract Background: Genotypic drug resistance testing provides essential information for guiding treatment in HIV-infected patients. It may either be used for identifying patients with transmitted drug resistance or to clarify reasons for treatment failure and to check for remaining treatment options. While different approaches for the interpretation of HIV sequence information are already available, no other available rules-based systems specifically have looked into the effects of combinations of drugs. HIV-GRADE (Genotypischer Resistenz Algorithmus Deutschland) was planned as a countrywide approach to establish standardized drug resistance interpretation in Germany and also to introduce rules for estimating the influence of mutations on drug combinations. The rules for HIV-GRADE are taken from the literature, clinical follow-up data and from a bioinformatics-driven interpreta- comparison of different drug resistance interpretation systems, coefficients of determination (R 2 ) were compared for the freely available rules-based systems. HIV-GRADE (R 2 = 0.40), Stanford HIVdb (R 2 = 0.40), REGA algorithm (R 2 = 0.36) and ANRS (R 2 = 0.35) had a very similar performance using this multiple linear regression model. Conclusion: The performance of HIV-GRADE is comparable to alternative rulesbased interpretation systems. While there is still room for improvement, HIV-GRADE has been made publicly available to allow access to our approach regarding the interpretation of resistance against single drugs and drug combinations.

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“…Virus was pelleted through 20% ( w / v ) sucrose (20,000× g , 4 °C, 90 min). Alternatively, CEMx174 cells were infected with cell culture supernatant containing HIV-1 4lig7 [ 50 , 51 ]. After syncytium formation, supernatant was harvested and passed through a 0.45 μm pore-size filter.…”

Section: Methodsmentioning

confidence: 99%

Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes

Setz

Friedrich

Rauch

et al. 2017

Viruses

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In recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)—the proteasome holoenzymes and a number of ubiquitin ligases—play a crucial role, not only in virus replication but also in the regulation of the immunogenicity of human immunodeficiency virus type 1 (HIV-1). However, the role in HIV-1 replication of the third major component, the deubiquitinating enzymes (DUBs), has remained largely unknown. In this study, we show that the DUB-inhibitors (DIs) P22077 and PR-619, specific for the DUBs USP7 and USP47, impair Gag processing and thereby reduce the infectivity of released virions without affecting viral protease activity. Furthermore, the replication capacity of X4- and R5-tropic HIV-1NL4-3 in human lymphatic tissue is decreased upon treatment with these inhibitors without affecting cell viability. Most strikingly, combinatory treatment with DIs and proteasome inhibitors synergistically blocks virus replication at concentrations where mono-treatment was ineffective, indicating that DIs can boost the therapeutic effect of proteasome inhibitors. In addition, P22077 and PR-619 increase the polyubiquitination of Gag and thus its entry into the UPS and the major histocompatibility complex (MHC)-I pathway. In summary, our data point towards a model in which specific inhibitors of DUBs not only interfere with virus spread but also increase the immune recognition of HIV-1 expressing cells.

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No Evidence for Persistence of Multidrug-Resistant Viral Strains After a 7-Month Treatment Interruption in an HIV-1–Infected Individual

Cited by 13 publications

References 38 publications

Q151M‐Mediated Multinucleoside Resistance: Prevalence, Risk Factors, and Response to Salvage Therapy

Q151M‐Mediated Multinucleoside Resistance: Prevalence, Risk Factors, and Response to Salvage Therapy

HIV-GRADE: A Publicly Available, Rules-Based Drug Resistance Interpretation Algorithm Integrating Bioinformatic Knowledge

Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes

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