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[PMID]:29480838
[Au] Autor:Cheng Y; Nickman NA; Jamjian C; Stevens V; Zhang Y; Sauer B; LaFleur J
[Ad] Endereço:Biomedical Informatics Center, George Washington University, Washington, DC.
[Ti] Título:Predicting poor adherence to antiretroviral therapy among treatment-naïve veterans infected with human immunodeficiency virus.
[So] Source:Medicine (Baltimore);97(2):e9495, 2018 Jan.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous studies suggested that human immunodeficiency virus (HIV) infected patients at risk of poor adherence were not distinguishable only based on the baseline characteristics. This study is to identify patient characteristics that would be consistently associated with poor adherence across regimens and to understand the associations between initial and long-term adherence. HIV treatment-naïve patients initiated on protease inhibitors, nonnucleoside reverse transcriptase inhibitors, or integrase strand transfer inhibitors were identified from the Veteran Health Administration system. Initial adherence measured as initial coverage ratio (ICR) and long-term adherence measured as thereafter 1-year proportion days covered (PDC) of base agent and complete regimen were estimated for each patient. The patients most likely to exhibit poor adherence were African-American, with lower socioeconomic status, and healthier. The initial coverage ratio of base agent and complete regimen were highly correlated, but the correlations between ICR and thereafter 1-year PDC were low. However, including initial adherence as a predictor in predictive model would substantially increase predictive accuracy of future adherence.
[Mh] Termos MeSH primário: Infecções por HIV/tratamento farmacológico
Inibidores de Integrase de HIV/uso terapêutico
Adesão à Medicação
Inibidores de Proteases/uso terapêutico
Inibidores da Transcriptase Reversa/uso terapêutico
[Mh] Termos MeSH secundário: Análise de Variância
Feminino
Infecções por HIV/diagnóstico
Infecções por HIV/epidemiologia
Integrase de HIV
Nível de Saúde
Seres Humanos
Modelos Logísticos
Masculino
Meia-Idade
Prognóstico
Estudos Retrospectivos
Fatores de Risco
Fatores Socioeconômicos
Estados Unidos
United States Department of Veterans Affairs
Veteranos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Integrase Inhibitors); 0 (Protease Inhibitors); 0 (Reverse Transcriptase Inhibitors); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180227
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009495


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[PMID]:29199485
[Au] Autor:de Miguel R; Montejano R; Stella-Ascariz N; Arribas JR
[Ad] Endereço:a HIV Unit, Internal Medicine Service , Hospital Universitario La Paz-IdiPAZ , Madrid , Spain.
[Ti] Título:A safety evaluation of raltegravir for the treatment of HIV.
[So] Source:Expert Opin Drug Saf;17(2):217-223, 2018 Feb.
[Is] ISSN:1744-764X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Raltegravir (RAL) was the first commercialized agent from a new drug class with an innovative target, the integrase. Since its introduction in clinical practice RAL has become widely used for the treatment of HIV-1 infected patients. A decade after its approval, this article reviews key evidence from RAL with a special interest on safety outcomes. Areas covered: Pharmacologic, safety and efficacy data of RAL from clinical trials and post-commercialization published reports are hereby summarized after a literature review including PubMed search, relating proceedings and abstracts from relevant international HIV conferences, assessment reports from European and United States regulatory agencies and treatment guidelines (World Health Organization, United States Department of Health and Human Services and European AIDS Clinical Society), up to October 2017. Most frequent search terms were 'raltegravir', 'safety', 'adverse events', 'efficacy' and 'integrase-inhibitors'. Expert opinion: Despite the arrival of new integrase strand transfer inhibitors (INSTIs) with advantages in terms of dosing convenience (elvitegravir, ELV) and higher genetic barrier (dolutegravir, DTG), RAL has stood the test of time and its overall favourable safety profile, without significant appearance of unexpected adverse events, vouch for its relevance in the antiretroviral armamentarium.
[Mh] Termos MeSH primário: Infecções por HIV/tratamento farmacológico
Inibidores de Integrase de HIV/administração & dosagem
Raltegravir Potássico/administração & dosagem
[Mh] Termos MeSH secundário: Integrase de HIV/efeitos dos fármacos
Inibidores de Integrase de HIV/efeitos adversos
Seres Humanos
Raltegravir Potássico/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (HIV Integrase Inhibitors); 43Y000U234 (Raltegravir Potassium); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1080/14740338.2018.1411903


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[PMID]:28741965
[Au] Autor:Pialoux G; Marcelin AG; Cawston H; Guilmet C; Finkielsztejn L; Laurisse A; Aubin C
[Ad] Endereço:a Service des Maladies Infectieuses et Tropicales , AP-HP Hôpital Tenon , PARIS , France.
[Ti] Título:Cost-effectiveness of dolutegravir/abacavir/lamivudine in HIV-1 treatment-Naive (TN) patients in France.
[So] Source:Expert Rev Pharmacoecon Outcomes Res;18(1):83-91, 2018 Feb.
[Is] ISSN:1744-8379
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: To evaluate the cost-effectiveness of an integrase inhibitor (INI), dolutegravir (DTG), in combination with abacavir (ABC)/lamivudine (3TC) in France, in treatment-naive (TN) HIV adult patients. METHODS: The ARAMIS microsimulation Markov model, evaluates costs and effects of DTG vs. first-line ARVs options including INIs (raltegravir, elvitegravir/c), protease inhibitors (PIs) (darunavir/r, atazanavir/r, lopinavir/r), non-nucleoside reverse transcriptase inhibitors (efavirenz and rilpivirine). Efficacy and safety data were derived from phase III studies and network meta-analysis. Treatment algorithms were based on French guidelines and experts opinion. Costs included routine HIV and opportunistic infection care, and death. RESULTS: The model showed the fixed-dose combination DTG/ABC/3TC was more effective than all other recommended regimens: patients stayed longer on first-line, and lived longer and healthier. With the exception of EFV, DTG/ABC/3TC was more efficacious and less costly compared to all strategies. The cost per QALY gained (ICER) for DTG compared to EFV was €6,939. DTG/ABC/3TC was more efficacious and less costly compared to INIs and PIs in all deterministic sensitivity analyses. CONCLUSION: DTG/ABC/3TC was cost-effective in the management of HIV TN patients in France. These results are mainly explained by its lower price compared to other INIs and PIs, DTG's superior efficacy and high barrier to resistance.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/administração & dosagem
Didesoxinucleosídeos/administração & dosagem
Infecções por HIV/tratamento farmacológico
Compostos Heterocíclicos com 3 Anéis/administração & dosagem
Lamivudina/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Algoritmos
Fármacos Anti-HIV/efeitos adversos
Fármacos Anti-HIV/economia
Análise Custo-Benefício
Didesoxinucleosídeos/efeitos adversos
Didesoxinucleosídeos/economia
Combinação de Medicamentos
França
Infecções por HIV/economia
Inibidores de Integrase de HIV/administração & dosagem
Inibidores de Integrase de HIV/efeitos adversos
Inibidores de Integrase de HIV/economia
HIV-1
Compostos Heterocíclicos com 3 Anéis/efeitos adversos
Compostos Heterocíclicos com 3 Anéis/economia
Seres Humanos
Lamivudina/efeitos adversos
Lamivudina/economia
Cadeias de Markov
Guias de Prática Clínica como Assunto
Anos de Vida Ajustados por Qualidade de Vida
Resultado do Tratamento
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Dideoxynucleosides); 0 (Drug Combinations); 0 (HIV Integrase Inhibitors); 0 (Heterocyclic Compounds, 3-Ring); 0 (abacavir, lamivudine drug combination); 2T8Q726O95 (Lamivudine); DKO1W9H7M1 (dolutegravir)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171227
[Lr] Data última revisão:
171227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1080/14737167.2017.1359542


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[PMID]:28956664
[Au] Autor:Han Y; Mesplède T; Wainberg MA
[Ad] Endereço:a McGill University AIDS Centre, Lady Davis Institute for Medical Research , Jewish General Hospital , Montreal , QC , Canada.
[Ti] Título:Investigational HIV integrase inhibitors in phase I and phase II clinical trials.
[So] Source:Expert Opin Investig Drugs;26(11):1207-1213, 2017 Nov.
[Is] ISSN:1744-7658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: To date, three HIV integrase strand transfer inhibitors (INSTIs), i.e. raltegravir, elvitegravir and dolutegravir, have been approved for clinical use. Recent research has focused on new integrase inhibitors including those targeting non-catalytic sites of HIV integrase. Areas covered: This paper reviews two investigational INSTIs in phase I and II clinical trials, bictegravir (BIC) and cabotegravir (CAB), as well as an investigational noncatalytic integrase inhibitor (NCINI) termed BI 224436. Expert opinion: Data from phase I and II clinical trials demonstrate that CAB has good efficacy and is well-tolerated. CAB is promising because it can be formulated both orally and as a long-acting (LA) injectable for treatment and prevention of HIV infection. Since LA-CAB formulation offers the possibility of favourable dosing, it may help individuals who struggle with adherence issues. BIC also represents a promising safe, effective and well-tolerated drug that can be administered as a single once-daily regimen in coformulation with emtricitabine and tenofovir alafenamide (FTC/TAF). Ongoing phase III trials should clarify optimal doses and reveal the potential clinical advantages of these new drugs and formulations over other current regimens. Exploration of novel HIV integrase inhibitors acting through mechanisms different from those of INSTIs is still needed.
[Mh] Termos MeSH primário: Drogas em Investigação/administração & dosagem
Infecções por HIV/tratamento farmacológico
Inibidores de Integrase de HIV/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Ensaios Clínicos Fase I como Assunto
Ensaios Clínicos Fase II como Assunto
Drogas em Investigação/efeitos adversos
Drogas em Investigação/farmacologia
Infecções por HIV/enzimologia
Inibidores de Integrase de HIV/efeitos adversos
Inibidores de Integrase de HIV/farmacologia
Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem
Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia
Seres Humanos
Adesão à Medicação
Piridonas/administração & dosagem
Piridonas/efeitos adversos
Piridonas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Drugs, Investigational); 0 (GSK1265744); 0 (HIV Integrase Inhibitors); 0 (Heterocyclic Compounds, 4 or More Rings); 0 (Pyridones); 0 (bictegravir)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170929
[St] Status:MEDLINE
[do] DOI:10.1080/13543784.2017.1378643


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[PMID]:28835492
[Au] Autor:Anstett K; Brenner B; Mesplède T; Wainberg MA
[Ad] Endereço:Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montreal, Canada.
[Ti] Título:HIV-1 Resistance to Dolutegravir Is Affected by Cellular Histone Acetyltransferase Activity.
[So] Source:J Virol;91(21), 2017 Nov 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Integrase strand transfer inhibitors (INSTIs) are the newest class of antiretrovirals to be approved for the treatment of HIV infection. Canonical resistance to these competitive inhibitors develops through substitutions in the integrase active site that disrupt drug-protein interactions. However, resistance against the newest integrase inhibitor, dolutegravir (DTG), is associated with an R263K substitution at the C terminus of integrase that causes resistance through an unknown mechanism. The integrase C-terminal domain is involved in many processes over the course of infection and is posttranslationally modified via acetylation of three lysine residues that are important for enzyme activity, integrase multimerization, and protein-protein interactions. Here we report that regulation of the acetylation of integrase is integral to the replication of HIV in the presence of DTG and that the R263K mutation specifically disrupts this regulation, likely due to enhancement of interactions with the histone deacetylase I complex, as suggested by coimmunoprecipitation assays. Although no detectable differences in the levels of cell-free acetylation of the wild-type (WT) and mutated R263K enzymes were observed, the inhibition of cellular histone acetyltransferase enzymes sensitized the NL4.3 virus to DTG, while NL4.3 was almost completely unaffected. When levels of endogenous acetylation were manipulated in virus-producing cells, inhibitors of acetylation enhanced the replication of NL4.3 , whereas inhibition of deacetylation greatly diminished the replication of NL4.3 Taken together, these results point to a pivotal role of acetylation in the resistance mechanism of HIV to some second-generation integrase strand transfer inhibitors, such as DTG. This is, to our knowledge, the first report of the influence of posttranslational modifications on HIV drug resistance. Both viral replication and resistance to second-generation integrase strand transfer inhibitors of both WT and INSTI-resistant HIV strains were differentially affected by acetylation, likely as a result of altered interactions between integrase and the cellular deacetylation machinery. Many "shock and kill" strategies to eradicate HIV manipulate endogenous levels of acetylation in order to reactivate latent HIV. However, our results suggest that some drug-resistant viruses may differentially respond to such stimulation, which may complicate the attainment of this goal. Our future work will further illuminate the mechanisms involved.
[Mh] Termos MeSH primário: Farmacorresistência Viral
Infecções por HIV/tratamento farmacológico
Integrase de HIV/química
HIV-1/efeitos dos fármacos
Compostos Heterocíclicos com 3 Anéis/farmacologia
Histona Acetiltransferases/metabolismo
Replicação Viral/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acetilação
Células Cultivadas
Infecções por HIV/virologia
Inibidores de Integrase de HIV/farmacologia
HIV-1/enzimologia
Histona Acetiltransferases/genética
Seres Humanos
Mutação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Integrase Inhibitors); 0 (Heterocyclic Compounds, 3-Ring); DKO1W9H7M1 (dolutegravir); EC 2.3.1.48 (Histone Acetyltransferases); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170825
[St] Status:MEDLINE


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[PMID]:28737946
[Au] Autor:Zhao XZ; Smith SJ; Maskell DP; Métifiot M; Pye VE; Fesen K; Marchand C; Pommier Y; Cherepanov P; Hughes SH; Burke TR
[Ti] Título:Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors.
[So] Source:J Med Chem;60(17):7315-7332, 2017 Sep 14.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Integrase mutations can reduce the effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previously described.
[Mh] Termos MeSH primário: Inibidores de Integrase de HIV/química
Inibidores de Integrase de HIV/farmacologia
Integrase de HIV/metabolismo
HIV-1/efeitos dos fármacos
Naftiridinas/química
Naftiridinas/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular
Cristalografia por Raios X
Farmacorresistência Viral
Infecções por HIV/tratamento farmacológico
Infecções por HIV/virologia
Integrase de HIV/química
Integrase de HIV/genética
HIV-1/enzimologia
HIV-1/genética
HIV-1/fisiologia
Seres Humanos
Modelos Moleculares
Mutação
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Integrase Inhibitors); 0 (Naphthyridines); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170725
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00596


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[PMID]:28628528
[Au] Autor:Davy-Mendez T; Eron JJ; Zakharova O; Wohl DA; Napravnik S
[Ad] Endereço:Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
[Ti] Título:Increased Persistence of Initial Treatment for HIV Infection With Modern Antiretroviral Therapy.
[So] Source:J Acquir Immune Defic Syndr;76(2):111-115, 2017 Oct 01.
[Is] ISSN:1944-7884
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Initiating antiretroviral therapy (ART) early improves clinical outcomes and prevents transmission. Guidelines for first-line therapy have changed with the availability of newer ART agents. In this study, we compared persistence and virologic responses with initial ART according to the class of anchor agent used. SETTING: An observational clinical cohort study in the Southeastern United States. METHODS: All HIV-infected patients participating in the UNC Center for AIDS Research Clinical Cohort (UCHCC) and initiating ART between 1996 and 2014 were included. Separate time-to-event analyses with regimen discontinuation and virologic failure as outcomes were used, including Kaplan-Meier survival curves and adjusted Cox proportional hazards models. RESULTS: One thousand six hundred twenty-four patients were included (median age of 37 years at baseline, 28% women, 60% African American, and 28% white). Eleven percent initiated integrase strand transfer inhibitor (INSTI), 33% non-nucleoside reverse transcriptase inhibitor (NNRTI), 20% boosted protease inhibitor, 27% other, and 9% NRTI only regimens. Compared with NNRTI-containing regimens, INSTI-containing regimens had an adjusted hazard ratio of 0.49 (95% confidence interval, 0.35 to 0.69) for discontinuation and 0.70 (95% confidence interval, 0.46 to 1.06) for virologic failure. All other regimen types were associated with increased rates of discontinuation and failure compared with NNRTI. CONCLUSIONS: Initiating ART with an INSTI-containing regimen was associated with lower rates of regimen discontinuation and virologic failure.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/uso terapêutico
Terapia Antirretroviral de Alta Atividade/métodos
Infecções por HIV/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Estudos de Coortes
Feminino
Inibidores de Integrase de HIV/uso terapêutico
Seres Humanos
Estimativa de Kaplan-Meier
Masculino
Meia-Idade
Inibidores de Proteases/uso terapêutico
Inibidores da Transcriptase Reversa/uso terapêutico
Estados Unidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (HIV Integrase Inhibitors); 0 (Protease Inhibitors); 0 (Reverse Transcriptase Inhibitors)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM; X
[Da] Data de entrada para processamento:170620
[St] Status:MEDLINE
[do] DOI:10.1097/QAI.0000000000001481


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[PMID]:28615207
[Au] Autor:Madison MK; Lawson DQ; Elliott J; Ozantürk AN; Koneru PC; Townsend D; Errando M; Kvaratskhelia M; Kutluay SB
[Ad] Endereço:Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, USA.
[Ti] Título:Allosteric HIV-1 Integrase Inhibitors Lead to Premature Degradation of the Viral RNA Genome and Integrase in Target Cells.
[So] Source:J Virol;91(17), 2017 Sep 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent evidence indicates that inhibition of HIV-1 integrase (IN) binding to the viral RNA genome by allosteric integrase inhibitors (ALLINIs) or through mutations within IN yields aberrant particles in which the viral ribonucleoprotein complexes (vRNPs) are eccentrically localized outside the capsid lattice. These particles are noninfectious and are blocked at an early reverse transcription stage in target cells. However, the basis of this reverse transcription defect is unknown. Here, we show that the viral RNA genome and IN from ALLINI-treated virions are prematurely degraded in target cells, whereas reverse transcriptase remains active and stably associated with the capsid lattice. The aberrantly shaped cores in ALLINI-treated particles can efficiently saturate and be degraded by a restricting TRIM5 protein, indicating that they are still composed of capsid proteins arranged in a hexagonal lattice. Notably, the fates of viral core components follow a similar pattern in cells infected with eccentric particles generated by mutations within IN that inhibit its binding to the viral RNA genome. We propose that IN-RNA interactions allow packaging of both the viral RNA genome and IN within the protective capsid lattice to ensure subsequent reverse transcription and productive infection in target cells. Conversely, disruption of these interactions by ALLINIs or mutations in IN leads to premature degradation of both the viral RNA genome and IN, as well as the spatial separation of reverse transcriptase from the viral genome during early steps of infection. Recent evidence indicates that HIV-1 integrase (IN) plays a key role during particle maturation by binding to the viral RNA genome. Inhibition of IN-RNA interactions yields aberrant particles with the viral ribonucleoprotein complexes (vRNPs) eccentrically localized outside the conical capsid lattice. Although these particles contain all of the components necessary for reverse transcription, they are blocked at an early reverse transcription stage in target cells. To explain the basis of this defect, we tracked the fates of multiple viral components in infected cells. Here, we show that the viral RNA genome and IN in eccentric particles are prematurely degraded, whereas reverse transcriptase remains active and stably associated within the capsid lattice. We propose that IN-RNA interactions ensure the packaging of both vRNPs and IN within the protective capsid cores to facilitate subsequent reverse transcription and productive infection in target cells.
[Mh] Termos MeSH primário: Capsídeo/metabolismo
Proteínas de Transporte/metabolismo
Genoma Viral
Inibidores de Integrase de HIV/farmacologia
Integrase de HIV/metabolismo
Transcriptase Reversa do HIV/metabolismo
[Mh] Termos MeSH secundário: Animais
Células CHO
Cricetulus
Células HEK293
HIV-1/efeitos dos fármacos
HIV-1/genética
Seres Humanos
RNA Viral/genética
Montagem de Vírus/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (HIV Integrase Inhibitors); 0 (RNA, Viral); 0 (TRIM5 protein, human); 0 (p31 integrase protein, Human immunodeficiency virus 1); EC 2.7.7.- (HIV Integrase); EC 2.7.7.49 (HIV Reverse Transcriptase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170903
[Lr] Data última revisão:
170903
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE


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[PMID]:28570368
[Au] Autor:Penazzato M; Palladino C; Sugandhi N; Paediatric ARV Drug Optimization 3 Meeting participants
[Ad] Endereço:aHIV Department, World Health Organization, Geneva, SwitzerlandbResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Lisbon, PortugalcClinton Health Access Initiative, New York, USA.
[Ti] Título:Prioritizing the most needed formulations to accelerate paediatric antiretroviral therapy scale-up.
[So] Source:Curr Opin HIV AIDS;12(4):369-376, 2017 Jul.
[Is] ISSN:1746-6318
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE OF REVIEW: Initiatives are in place to reach super-fast targets by 2018 for paediatric patients living with HIV. However, these efforts are unlikely to be successful until better paediatric antiretrovirals and treatment strategies are available. This commentary reviews the specific features, challenges, and recent developments in paediatric HIV treatment to determine optimal regimen sequencing and use of available drug options. It also outlines a medium and long-term vision for treatment optimization as endorsed by the paediatric antiretroviral drug optimization group. RECENT FINDINGS: Optimizing antiretroviral therapy (ART) is critical in the context of limited treatment options for children. A first-line dolutegravir-based regimen is the long-term goal for paediatric first-line ART across all age groups. Protease inhibitor-based regimens are expected to continue to play a critical role for second and third-line treatment. New efforts are urgently needed to optimize treatment for children, ensuring access to existing drugs and speeding up development of newer and better formulations moving forward. SUMMARY: Over the last few years there have been a number of key developments in paediatric ART which offer the opportunity to reconsider the way ART is optimized for children. Additional evidence is needed to ensure optimal options are available from infancy through adulthood.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/uso terapêutico
Infecções por HIV/tratamento farmacológico
Inibidores de Integrase de HIV/uso terapêutico
Compostos Heterocíclicos com 3 Anéis/uso terapêutico
Inibidores de Proteases/uso terapêutico
[Mh] Termos MeSH secundário: Química Farmacêutica
Criança
Seres Humanos
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (HIV Integrase Inhibitors); 0 (Heterocyclic Compounds, 3-Ring); 0 (Protease Inhibitors); DKO1W9H7M1 (dolutegravir)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM; X
[Da] Data de entrada para processamento:170602
[St] Status:MEDLINE
[do] DOI:10.1097/COH.0000000000000378


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[PMID]:28525279
[Au] Autor:Vernekar SKV; Tang J; Wu B; Huber AD; Casey MC; Myshakina N; Wilson DJ; Kankanala J; Kirby KA; Parniak MA; Sarafianos SG; Wang Z
[Ad] Endereço:Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
[Ti] Título:Double-Winged 3-Hydroxypyrimidine-2,4-diones: Potent and Selective Inhibition against HIV-1 RNase H with Significant Antiviral Activity.
[So] Source:J Med Chem;60(12):5045-5056, 2017 Jun 22.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function yet to be exploited as an antiviral target. One of the possible challenges may be that targeting HIV RNase H is confronted with a steep substrate barrier. We have previously reported a 3-hydroxypyrimidine-2,4-dione (HPD) subtype that potently and selectively inhibited RNase H without inhibiting HIV in cell culture. We report herein a critical redesign of the HPD chemotype featuring an additional wing at the C5 position that led to drastically improved RNase H inhibition and significant antiviral activity. Structure-activity relationship (SAR) concerning primarily the length and flexibility of the two wings revealed important structural features that dictate the potency and selectivity of RNase H inhibition as well as the observed antiviral activity. Our current medicinal chemistry data also revealed that the RNase H biochemical inhibition largely correlated the antiviral activity.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/química
Fármacos Anti-HIV/farmacologia
Inibidores Enzimáticos/farmacologia
Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores
[Mh] Termos MeSH secundário: Domínio Catalítico
Linhagem Celular
Técnicas de Química Sintética
Avaliação Pré-Clínica de Medicamentos/métodos
Inibidores Enzimáticos/química
Inibidores de Integrase de HIV/química
Inibidores de Integrase de HIV/farmacologia
Seres Humanos
Pirimidinonas/química
Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Enzyme Inhibitors); 0 (HIV Integrase Inhibitors); 0 (Pyrimidinones); EC 3.1.26.4 (Ribonuclease H, Human Immunodeficiency Virus)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00440



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