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[PMID]:28636951
[Au] Autor:Zheng Y; Han GW; Abagyan R; Wu B; Stevens RC; Cherezov V; Kufareva I; Handel TM
[Ad] Endereço:University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093, USA.
[Ti] Título:Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV.
[So] Source:Immunity;46(6):1005-1017.e5, 2017 Jun 20.
[Is] ISSN:1097-4180
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CCR5 is the primary chemokine receptor utilized by HIV to infect leukocytes, whereas CCR5 ligands inhibit infection by blocking CCR5 engagement with HIV gp120. To guide the design of improved therapeutics, we solved the structure of CCR5 in complex with chemokine antagonist [5P7]CCL5. Several structural features appeared to contribute to the anti-HIV potency of [5P7]CCL5, including the distinct chemokine orientation relative to the receptor, the near-complete occupancy of the receptor binding pocket, the dense network of intermolecular hydrogen bonds, and the similarity of binding determinants with the FDA-approved HIV inhibitor Maraviroc. Molecular modeling indicated that HIV gp120 mimicked the chemokine interaction with CCR5, providing an explanation for the ability of CCR5 to recognize diverse ligands and gp120 variants. Our findings reveal that structural plasticity facilitates receptor-chemokine specificity and enables exploitation by HIV, and provide insight into the design of small molecule and protein inhibitors for HIV and other CCR5-mediated diseases.
[Mh] Termos MeSH primário: Quimiocina CCL5/química
Proteína gp120 do Envelope de HIV/química
Infecções por HIV/imunologia
HIV-1/fisiologia
Modelos Moleculares
Mimetismo Molecular
Receptores CCR5/química
[Mh] Termos MeSH secundário: Animais
Antagonistas dos Receptores CCR5/química
Antagonistas dos Receptores CCR5/farmacologia
Quimiocina CCL5/metabolismo
Clonagem Molecular
Cristalografia por Raios X
Cicloexanos/química
Cicloexanos/farmacologia
Proteína gp120 do Envelope de HIV/metabolismo
Inibidores da Fusão de HIV/química
Infecções por HIV/tratamento farmacológico
Seres Humanos
Ligação Proteica
Conformação Proteica
Receptores CCR5/metabolismo
Células Sf9
Spodoptera
Relação Estrutura-Atividade
Triazóis/química
Triazóis/farmacologia
Internalização do Vírus/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCR5 Receptor Antagonists); 0 (Chemokine CCL5); 0 (Cyclohexanes); 0 (HIV Envelope Protein gp120); 0 (HIV Fusion Inhibitors); 0 (Receptors, CCR5); 0 (Triazoles); MD6P741W8A (maraviroc)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170622
[St] Status:MEDLINE


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[PMID]:28446620
[Au] Autor:Garbelli A; Riva V; Crespan E; Maga G
[Ad] Endereço:DNA Enzymology & Molecular Virology Unit, Institute of Molecular Genetics - CNR, via Abbiategrasso 207, Pavia 27100, Italy.
[Ti] Título:How to win the HIV-1 drug resistance hurdle race: running faster or jumping higher?
[So] Source:Biochem J;474(10):1559-1577, 2017 Apr 26.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Infections by the human immunodeficiency virus type 1 (HIV-1), the causative agent of the acquired immunodeficiency syndrome (AIDS), are still totaling an appalling 36.7 millions worldwide, with 1.1 million AIDS deaths/year and a similar number of yearly new infections. All this, in spite of the discovery of HIV-1 as the AIDS etiological agent more than 30 years ago and the introduction of an effective combinatorial antiretroviral therapy (cART), able to control disease progression, more than 20 years ago. Although very effective, current cART is plagued by the emergence of drug-resistant viral variants and most of the efforts in the development of novel direct-acting antiviral agents (DAAs) against HIV-1 have been devoted toward the fighting of resistance. In this review, rather than providing a detailed listing of all the drugs and the corresponding resistance mutations, we aim, through relevant examples, at presenting to the general reader the conceptual shift in the approaches that are being taken to overcome the viral resistance hurdle. From the classic 'running faster' strategy, based on the development of novel DAAs active against the mutant viruses selected by the previous drugs and/or presenting to the virus a high genetic barrier toward the development of resilience, to a 'jumping higher' approach, which looks at the cell, rather than the virus, as a source of valuable drug targets, in order to make the cellular environment non-permissive toward the replication of both wild-type and mutated viruses.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/uso terapêutico
Desenho de Drogas
Farmacorresistência Viral Múltipla
Quimioterapia Combinada
Infecções por HIV/tratamento farmacológico
HIV-1/efeitos dos fármacos
Modelos Biológicos
[Mh] Termos MeSH secundário: Animais
Fármacos Anti-HIV/efeitos adversos
Fármacos Anti-HIV/química
Fármacos Anti-HIV/farmacologia
Terapia Antirretroviral de Alta Atividade/efeitos adversos
Antagonistas dos Receptores CCR5/química
Antagonistas dos Receptores CCR5/farmacologia
Antagonistas dos Receptores CCR5/uso terapêutico
RNA Helicases DEAD-box/antagonistas & inibidores
RNA Helicases DEAD-box/química
RNA Helicases DEAD-box/genética
RNA Helicases DEAD-box/metabolismo
Quimioterapia Combinada/efeitos adversos
Infecções por HIV/metabolismo
Infecções por HIV/virologia
Inibidores da Protease de HIV/efeitos adversos
Inibidores da Protease de HIV/química
Inibidores da Protease de HIV/farmacologia
Inibidores da Protease de HIV/uso terapêutico
HIV-1/genética
HIV-1/crescimento & desenvolvimento
HIV-1/fisiologia
Interações Hospedeiro-Patógeno/efeitos dos fármacos
Proteínas do Vírus da Imunodeficiência Humana/antagonistas & inibidores
Proteínas do Vírus da Imunodeficiência Humana/química
Proteínas do Vírus da Imunodeficiência Humana/genética
Proteínas do Vírus da Imunodeficiência Humana/metabolismo
Seres Humanos
Estrutura Molecular
Terapia de Alvo Molecular
Mutação
Conformação Proteica
Inibidores da Transcriptase Reversa/química
Inibidores da Transcriptase Reversa/farmacologia
Inibidores da Transcriptase Reversa/uso terapêutico
Fenômenos Fisiológicos Virais/efeitos dos fármacos
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (CCR5 Receptor Antagonists); 0 (HIV Protease Inhibitors); 0 (Human Immunodeficiency Virus Proteins); 0 (Reverse Transcriptase Inhibitors); EC 3.6.1.- (DDX3X protein, human); EC 3.6.4.13 (DEAD-box RNA Helicases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170623
[Lr] Data última revisão:
170623
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20160772


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[PMID]:28128944
[Au] Autor:Schwehm C; Kellam B; Garces AE; Hill SJ; Kindon ND; Bradshaw TD; Li J; Macdonald SJ; Rowedder JE; Stoddart LA; Stocks MJ
[Ad] Endereço:School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K.
[Ti] Título:Design and Elaboration of a Tractable Tricyclic Scaffold To Synthesize Druglike Inhibitors of Dipeptidyl Peptidase-4 (DPP-4), Antagonists of the C-C Chemokine Receptor Type 5 (CCR5), and Highly Potent and Selective Phosphoinositol-3 Kinase δ (PI3Kδ) Inhibitors.
[So] Source:J Med Chem;60(4):1534-1554, 2017 Feb 23.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs.
[Mh] Termos MeSH primário: Antagonistas dos Receptores CCR5/química
Antagonistas dos Receptores CCR5/farmacologia
Classe Ia de Fosfatidilinositol 3-Quinase/antagonistas & inibidores
Inibidores da Dipeptidil Peptidase IV/química
Inibidores da Dipeptidil Peptidase IV/farmacologia
Inibidores de Proteínas Quinases/química
Inibidores de Proteínas Quinases/farmacologia
[Mh] Termos MeSH secundário: Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo
Dipeptidil Peptidase 4/metabolismo
Desenho de Drogas
Seres Humanos
Simulação de Acoplamento Molecular
Subunidades Proteicas/antagonistas & inibidores
Subunidades Proteicas/metabolismo
Receptores CCR5/metabolismo
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCR5 Receptor Antagonists); 0 (CCR5 protein, human); 0 (Dipeptidyl-Peptidase IV Inhibitors); 0 (Protein Kinase Inhibitors); 0 (Protein Subunits); 0 (Receptors, CCR5); 0 (Small Molecule Libraries); EC 2.7.1.137 (Class Ia Phosphatidylinositol 3-Kinase); EC 3.4.14.5 (Dipeptidyl Peptidase 4)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170616
[Lr] Data última revisão:
170616
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01801


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[PMID]:28064231
[Au] Autor:Maggi P; Bruno G; Perilli F; Saracino A; Volpe A; Santoro C; Ladisa N; Angarano G
[Ad] Endereço:Institute of Infectious Diseases, University of Bari, Bari, Italy p_maggi@yahoo.com.
[Ti] Título:Effects of Therapy with Maraviroc on the Carotid Intima Media Thickness in HIV-1/HCV Co-infected Patients.
[So] Source:In Vivo;31(1):125-131, 2017 01 02.
[Is] ISSN:1791-7549
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:AIM: To evaluate, in human immunodeficiency virus-hepatitis C virus co-infected patients, the impact of C-C chemokine receptor type 5 (CCR5) antagonist maraviroc-based antiretroviral therapy on the carotid intima media thickness and on atheromasic plaques. PATIENTS AND METHODS: In this pilot prospective study, 12 HIV-HCV co-infected patients underwent color-Doppler ultrasonography before and 48 weeks after switching to a dual therapy based on maraviroc plus protease inhibitors boosted with ritonavir. Changes of intima media thickness, inflammatory and endothelial adhesion biomarkers levels, Veterans Aging Cohort Study index and Framingham risk score were evaluated. RESULTS: At baseline 11 (91.6%) patients showed pathological ultrasonographic findings. After 48 weeks, two patients showed an amelioration of intima media thickness. Of the remaining patients with plaques, four showed a reduction of the previously diagnosed plaque; no patients worsened. CONCLUSION: Our data suggest that CCR5 inhibition could reduce the development of atherosclerosis especially in the non-calcific stage and could play an important role in the blockade of atheromasic plaque progression.
[Mh] Termos MeSH primário: Espessura Intima-Media Carotídea
Coinfecção/tratamento farmacológico
Cicloexanos/uso terapêutico
Infecções por HIV/tratamento farmacológico
Hepatite C Crônica/tratamento farmacológico
Cirrose Hepática/induzido quimicamente
Triazóis/uso terapêutico
[Mh] Termos MeSH secundário: Biomarcadores/análise
Antagonistas dos Receptores CCR5/farmacologia
Feminino
Infecções por HIV/virologia
HIV-1/efeitos dos fármacos
Hepacivirus/efeitos dos fármacos
Hepatite C Crônica/virologia
Seres Humanos
Masculino
Meia-Idade
Projetos Piloto
Reação em Cadeia da Polimerase
Estudos Prospectivos
Ultrassonografia Doppler em Cores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (CCR5 Receptor Antagonists); 0 (Cyclohexanes); 0 (Triazoles); MD6P741W8A (maraviroc)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170425
[Lr] Data última revisão:
170425
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170109
[St] Status:MEDLINE


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[PMID]:28057639
[Au] Autor:Moy RH; Huffman AP; Richman LP; Crisalli L; Wang XK; Hoxie JA; Mick R; Emerson SG; Zhang Y; Vonderheide RH; Porter DL; Reshef R
[Ad] Endereço:Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
[Ti] Título:Clinical and immunologic impact of CCR5 blockade in graft-versus-host disease prophylaxis.
[So] Source:Blood;129(7):906-916, 2017 Feb 16.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Lymphocyte trafficking via chemokine receptors such as CCR5 plays a critical role in alloreactive responses, and previous data suggest that CCR5 blockade with maraviroc results in a low incidence of visceral GVHD. However, the full scope of clinical and immunologic effects of CCR5 blockade in HSCT has not been described. We compared a cohort of patients enrolled on a trial of reduced-intensity allo-HSCT with standard GVHD prophylaxis plus maraviroc to a contemporary control cohort receiving standard GVHD prophylaxis alone. Maraviroc treatment was associated with a lower incidence of acute GVHD without increased risk of disease relapse, as well as reduced levels of gut-specific markers. At day 30, maraviroc treatment increased CCR5 expression on T cells and dampened T-cell activation in peripheral blood without impairing early immune reconstitution or increasing risk for infections. Patients who developed acute GVHD despite maraviroc prophylaxis showed increased T-cell activation, naive T-cell skewing, and elevated serum CXCL9 and CXCL10 levels. Collectively, these data suggest that maraviroc effectively protects against GVHD by modulating alloreactive donor T-cell responses, and that CXCR3 signaling may be an important resistance mechanism to CCR5 blockade in GVHD.
[Mh] Termos MeSH primário: Antagonistas dos Receptores CCR5/uso terapêutico
Doença Enxerto-Hospedeiro/prevenção & controle
Transplante de Células-Tronco Hematopoéticas/métodos
Ativação Linfocitária/efeitos dos fármacos
Receptores CCR5/imunologia
Linfócitos T/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adulto
Idoso
Antígenos de Neoplasias/análise
Antígenos de Neoplasias/imunologia
Biomarcadores Tumorais/análise
Biomarcadores Tumorais/imunologia
Feminino
Doença Enxerto-Hospedeiro/imunologia
Doença Enxerto-Hospedeiro/patologia
Transplante de Células-Tronco Hematopoéticas/efeitos adversos
Seres Humanos
Imunidade Celular/efeitos dos fármacos
Interleucina-15/análise
Interleucina-15/imunologia
Lectinas Tipo C/análise
Lectinas Tipo C/imunologia
Masculino
Meia-Idade
Proteínas Associadas a Pancreatite
Linfócitos T/imunologia
Linfócitos T/patologia
Transplante Homólogo
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, Neoplasm); 0 (Biomarkers, Tumor); 0 (CCR5 Receptor Antagonists); 0 (CCR5 protein, human); 0 (Interleukin-15); 0 (Lectins, C-Type); 0 (Pancreatitis-Associated Proteins); 0 (REG3A protein, human); 0 (Receptors, CCR5)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170107
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-08-735076


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[PMID]:27811319
[Au] Autor:Gulick RM; Wilkin TJ; Chen YQ; Landovitz RJ; Amico KR; Young AM; Richardson P; Marzinke MA; Hendrix CW; Eshleman SH; McGowan I; Cottle LM; Andrade A; Marcus C; Klingman KL; Chege W; Rinehart AR; Rooney JF; Andrew P; Salata RA; Magnus M; Farley JE; Liu A; Frank I; Ho K; Santana J; Stekler JD; McCauley M; Mayer KH
[Ad] Endereço:Department of Medicine, Weill Cornell Medicine, New York.
[Ti] Título:Phase 2 Study of the Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Men Who Have Sex With Men (HPTN 069/ACTG A5305).
[So] Source:J Infect Dis;215(2):238-246, 2017 Jan 15.
[Is] ISSN:1537-6613
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Maraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis. Methods: Phase 2 48-week safety/tolerability study was conducted, comparing 4 regimens: MVC alone, MVC plus emtricitabine (FTC), MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC. Eligible participants were HIV-uninfected men and transgender women reporting condomless anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. At each visit, assessments, laboratory testing, and counseling were done. Analyses were intention to treat. Results: Among 406 participants, 84% completed follow-up, 7% stopped early, and 9% were lost to follow-up; 9% discontinued their regimen early. The number discontinuing and the time to discontinuation did not differ among study regimens (P = .60). Rates of grade 3-4 adverse events did not differ among regimens (P = .37). In a randomly selected subset, 77% demonstrated detectable drug concentrations at week 48. Five participants acquired HIV infection (4 MVC alone, 1 MVC + TDF; overall annualized incidence, 1.4% [95% confidence interval, .5%-3.3%], without differences by regimen; P = .32); 2 had undetectable drug concentrations at every visit, 2 had low concentrations at the seroconversion visit, and 1 had variable concentrations. Conclusions: MVC-containing regimens were safe and well tolerated compared with TDF + FTC; this study was not powered for efficacy. Among those acquiring HIV infection, drug concentrations were absent, low, or variable. MVC-containing regimens may warrant further study for pre-exposure prophylaxis. Clinical Trials Registration: NCT01505114.
[Mh] Termos MeSH primário: Antagonistas dos Receptores CCR5/administração & dosagem
Antagonistas dos Receptores CCR5/efeitos adversos
Cicloexanos/administração & dosagem
Cicloexanos/efeitos adversos
Transmissão de Doença Infecciosa/prevenção & controle
Infecções por HIV/prevenção & controle
Profilaxia Pré-Exposição/métodos
Triazóis/administração & dosagem
Triazóis/efeitos adversos
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Fármacos Anti-HIV/administração & dosagem
Fármacos Anti-HIV/efeitos adversos
Método Duplo-Cego
Homossexualidade Masculina
Seres Humanos
Masculino
Meia-Idade
Estudos Prospectivos
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (CCR5 Receptor Antagonists); 0 (Cyclohexanes); 0 (Triazoles); MD6P741W8A (maraviroc)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171021
[Lr] Data última revisão:
171021
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE
[do] DOI:10.1093/infdis/jiw525


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[PMID]:27998283
[Au] Autor:Döring M; Borrego P; Büch J; Martins A; Friedrich G; Camacho RJ; Eberle J; Kaiser R; Lengauer T; Taveira N; Pfeifer N
[Ad] Endereço:Department for Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, Campus E 1 4, 66123, Saarbrücken, Germany. mdoering@mpi-inf.mpg.de.
[Ti] Título:A genotypic method for determining HIV-2 coreceptor usage enables epidemiological studies and clinical decision support.
[So] Source:Retrovirology;13(1):85, 2016 Dec 20.
[Is] ISSN:1742-4690
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: CCR5-coreceptor antagonists can be used for treating HIV-2 infected individuals. Before initiating treatment with coreceptor antagonists, viral coreceptor usage should be determined to ensure that the virus can use only the CCR5 coreceptor (R5) and cannot evade the drug by using the CXCR4 coreceptor (X4-capable). However, until now, no online tool for the genotypic identification of HIV-2 coreceptor usage had been available. Furthermore, there is a lack of knowledge on the determinants of HIV-2 coreceptor usage. Therefore, we developed a data-driven web service for the prediction of HIV-2 coreceptor usage from the V3 loop of the HIV-2 glycoprotein and used the tool to identify novel discriminatory features of X4-capable variants. RESULTS: Using 10 runs of tenfold cross validation, we selected a linear support vector machine (SVM) as the model for geno2pheno[coreceptor-hiv2], because it outperformed the other SVMs with an area under the ROC curve (AUC) of 0.95. We found that SVMs were highly accurate in identifying HIV-2 coreceptor usage, attaining sensitivities of 73.5% and specificities of 96% during tenfold nested cross validation. The predictive performance of SVMs was not significantly different (p value 0.37) from an existing rules-based approach. Moreover, geno2pheno[coreceptor-hiv2] achieved a predictive accuracy of 100% and outperformed the existing approach on an independent data set containing nine new isolates with corresponding phenotypic measurements of coreceptor usage. geno2pheno[coreceptor-hiv2] could not only reproduce the established markers of CXCR4-usage, but also revealed novel markers: the substitutions 27K, 15G, and 8S were significantly predictive of CXCR4 usage. Furthermore, SVMs trained on the amino-acid sequences of the V1 and V2 loops were also quite accurate in predicting coreceptor usage (AUCs of 0.84 and 0.65, respectively). CONCLUSIONS: In this study, we developed geno2pheno[coreceptor-hiv2], the first online tool for the prediction of HIV-2 coreceptor usage from the V3 loop. Using our method, we identified novel amino-acid markers of X4-capable variants in the V3 loop and found that HIV-2 coreceptor usage is also influenced by the V1/V2 region. The tool can aid clinicians in deciding whether coreceptor antagonists such as maraviroc are a treatment option and enables epidemiological studies investigating HIV-2 coreceptor usage. geno2pheno[coreceptor-hiv2] is freely available at http://coreceptor-hiv2.geno2pheno.org .
[Mh] Termos MeSH primário: Técnicas de Genotipagem
Proteína gp120 do Envelope de HIV/genética
Infecções por HIV/virologia
HIV-2/genética
Fragmentos de Peptídeos/genética
Receptores CXCR4/metabolismo
Máquina de Vetores de Suporte
[Mh] Termos MeSH secundário: Antagonistas dos Receptores CCR5/uso terapêutico
Sistemas de Apoio a Decisões Clínicas
Genótipo
Proteína gp120 do Envelope de HIV/química
Infecções por HIV/tratamento farmacológico
HIV-2/metabolismo
Seres Humanos
Internet
Fragmentos de Peptídeos/química
Receptores CCR5/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCR5 Receptor Antagonists); 0 (CCR5 protein, human); 0 (CXCR4 protein, human); 0 (HIV Envelope Protein gp120); 0 (HIV envelope protein gp120 (305-321)); 0 (Peptide Fragments); 0 (Receptors, CCR5); 0 (Receptors, CXCR4)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170510
[Lr] Data última revisão:
170510
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161222
[St] Status:MEDLINE
[do] DOI:10.1186/s12977-016-0320-7


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[PMID]:27905841
[Au] Autor:Symonds G; Bartlett JS; Kiem HP; Tsie M; Breton L
[Ad] Endereço:1 Calimmune, Inc. , Tucson, Arizona.
[Ti] Título:Cell-Delivered Entry Inhibitors for HIV-1: CCR5 Downregulation and Blocking Virus/Membrane Fusion in Defending the Host Cell Population.
[So] Source:AIDS Patient Care STDS;30(12):545-550, 2016 Dec.
[Is] ISSN:1557-7449
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV-1 infection requires the presence of the CD4 receptor on the target cell surface and a coreceptor, predominantly CC-chemokine receptor 5 (CCR5). It has been shown that individuals who are homozygous for a defective CCR5 gene are protected from HIV-1 infection. A novel self-inactivating lentiviral vector LVsh5/C46 (Cal-1) has been engineered to block HIV-1 infection with two viral entry inhibitors, conferring resistance to HIV-1 infection from both CCR5 and CXCR4 tropic strains. Cal-1 encodes a short hairpin RNA (sh5) to downregulate CCR5 and C46, an HIV-1 fusion inhibitor. Gene therapy by Cal-1 is aimed at transducing CD4 T cells and CD34 hematopoietic stem/progenitor cells in an autologous transplant setting. Pre-clinical safety and efficacy studies in vitro and in vivo (humanized mouse model and nonhuman primates) have shown that Cal-1 is safe with no indication of any toxicity risk and acts to decrease viral load and increase CD4 counts. Two clinical trials are underway using Cal-1: a phase I/II study to assess safety and feasibility in an adult HIV-1-positive population not on antiretroviral therapy (ART); and a second Fred Hutchinson Investigator Initiated phase I study to assess safety and feasibility in adults with HIV-1-associated non-Hodgkin or Hodgkin lymphoma.
[Mh] Termos MeSH primário: Terapia Genética/métodos
Infecções por HIV/terapia
HIV-1/fisiologia
Fusão de Membrana
Receptores CCR5
Receptores de HIV/antagonistas & inibidores
Proteínas Recombinantes de Fusão/biossíntese
[Mh] Termos MeSH secundário: Adulto
Animais
Terapia Biológica/métodos
Antagonistas dos Receptores CCR5
Contagem de Linfócito CD4
Ensaios Clínicos como Assunto
Regulação para Baixo
Infecções por HIV/genética
Infecções por HIV/virologia
HIV-1/genética
Células-Tronco Hematopoéticas
Seres Humanos
Receptores CCR5/biossíntese
Receptores CXCR4
Proteínas Recombinantes de Fusão/genética
Carga Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C46 HIV-1 fusion inhibitory peptide); 0 (CCR5 Receptor Antagonists); 0 (CCR5 protein, human); 0 (CXCR4 protein, human); 0 (Receptors, CCR5); 0 (Receptors, CXCR4); 0 (Receptors, HIV); 0 (Recombinant Fusion Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170630
[Lr] Data última revisão:
170630
[Sb] Subgrupo de revista:IM; X
[Da] Data de entrada para processamento:161202
[St] Status:MEDLINE


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[PMID]:27858912
[Au] Autor:Karris MY; Umlauf A; Vaida F; Richman D; Little S; Smith D
[Ad] Endereço:aUniversity of California San DiegobVeterans Affairs Medical Center, San Diego, CA.
[Ti] Título:A randomized controlled clinical trial on the impact of CCR5 blockade with maraviroc in early infection on T-cell dynamics.
[So] Source:Medicine (Baltimore);95(44):e5315, 2016 Nov.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Initiation of antiretroviral therapy (ART) in early HIV infection demonstrates clinical benefits including enhanced CD4 T-lymphocyte recovery and minimization of the latent HIV reservoir. Whether ART intensification with CCR5 blockade provides additional benefits is unknown. TRIAL DESIGN: This randomized controlled trial evaluated the impact of maraviroc (MVC) intensification in persons starting ART in acute and early HIV (AEH, within 3 months of estimated date of infection). METHODS: Twenty persons in AEH in San Diego underwent double-blind randomization to receive either standard of care (SOC) ART or SOC + MVC to evaluate the hypothesis that early CCR5 blockage with a CCR5-containing ART regimen may provide immunologic and clinical benefit. The primary outcome of this study was the difference from baseline to week 48 in the proportion of CCR5 CD4 memory T cells. Blood was drawn at baseline and weeks 12, 24, and 48 to evaluate CCR5 CD4 and CD8 T-cell dynamics using multicolor flow cytometry. RESULTS: MVC intensification (n = 10) did not significantly alter CCR5 T-cell dynamics at week 48 of study compared to SOC (n = 9) in this fully recruited study (mean 1.12 vs 0.63, t = 0.36, df = 16, P = 0.727). Exploratory analyses of additional T-cell subsets suggest that MVC intensification in AEH trended to early greater increases in naïve and activated and proliferating CD4 T cells (P = 0.11, 0.19), and greater decreases in senescent memory CD4 T cells (P = 0.06), but these differences did not remain by week 48. CD8 T-cell evaluations did demonstrate trends to differences at week 48 with slower increases in naïve cells and slower decreases in activated memory cells (P = 0.16, 0.09). There were no reported harms or significantly different adverse events. CONCLUSIONS: We did observe a few trends, but did not find compelling evidence that MVC intensification during AEH significantly impacts CD4 and CD8 T-cell dynamics. Diagnosing and starting persons in AEH on ART may be of greater clinical importance than the regimen initiated.
[Mh] Termos MeSH primário: Antagonistas dos Receptores CCR5/uso terapêutico
Cicloexanos/uso terapêutico
Infecções por HIV/tratamento farmacológico
Linfócitos T/efeitos dos fármacos
Triazóis/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Método Duplo-Cego
Feminino
Infecções por HIV/imunologia
Seres Humanos
Masculino
Linfócitos T/imunologia
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (CCR5 Receptor Antagonists); 0 (Cyclohexanes); 0 (Triazoles); MD6P741W8A (maraviroc)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161119
[St] Status:MEDLINE


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[PMID]:27809912
[Au] Autor:Borm K; Jakobsen MR; Cashin K; Flynn JK; Ellenberg P; Ostergaard L; Lee B; Churchill MJ; Roche M; Gorry PR
[Ad] Endereço:Center for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia.
[Ti] Título:Frequency and Env determinants of HIV-1 subtype C strains from antiretroviral therapy-naive subjects that display incomplete inhibition by maraviroc.
[So] Source:Retrovirology;13(1):74, 2016 Nov 03.
[Is] ISSN:1742-4690
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Entry of human immunodeficiency virus type 1 (HIV-1) into cells involves the interaction of the viral gp120 envelope glycoproteins (Env) with cellular CD4 and a secondary coreceptor, which is typically one of the chemokine receptors CCR5 or CXCR4. CCR5-using (R5) HIV-1 strains that display reduced sensitivity to CCR5 antagonists can use antagonist-bound CCR5 for entry. In this study, we investigated whether naturally occurring gp120 alterations in HIV-1 subtype C (C-HIV) variants exist in antiretroviral therapy (ART)-naïve subjects that may influence their sensitivity to the CCR5 antagonist maraviroc (MVC). RESULTS: Using a longitudinal panel of 244 R5 Envs cloned from 20 ART-naïve subjects with progressive C-HIV infection, we show that 40% of subjects (n = 8) harbored viruses that displayed incomplete inhibition by MVC, as shown by plateau's of reduced maximal percent inhibitions (MPIs). Specifically, when pseudotyped onto luciferase reporter viruses, 16 Envs exhibited MPIs below 98% in NP2-CCR5 cells (range 79.7-97.3%), which were lower still in 293-Affinofile cells that were engineered to express high levels of CCR5 (range 15.8-72.5%). We further show that Envs exhibiting reduced MPIs to MVC utilized MVC-bound CCR5 less efficiently than MVC-free CCR5, which is consistent with the mechanism of resistance to CCR5 antagonists that can occur in patients failing therapy. Mutagenesis studies identified strain-specific mutations in the gp120 V3 loop that contributed to reduced MPIs to MVC. CONCLUSIONS: The results of our study suggest that some ART-naïve subjects with C-HIV infection harbor HIV-1 with reduced MPIs to MVC, and demonstrate that the gp120 V3 loop region contributes to this phenotype.
[Mh] Termos MeSH primário: Antagonistas dos Receptores CCR5/farmacologia
Cicloexanos/farmacologia
Proteína gp120 do Envelope de HIV/genética
HIV-1/efeitos dos fármacos
Fragmentos de Peptídeos/genética
Receptores CCR5/metabolismo
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Terapia Antirretroviral de Alta Atividade
Antígenos CD4/metabolismo
Células HEK293
Proteína gp120 do Envelope de HIV/química
Infecções por HIV/virologia
HIV-1/classificação
HIV-1/genética
HIV-1/fisiologia
Seres Humanos
Mutagênese
Fragmentos de Peptídeos/química
Internalização do Vírus
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCR5 Receptor Antagonists); 0 (CD4 Antigens); 0 (Cyclohexanes); 0 (HIV Envelope Protein gp120); 0 (HIV envelope protein gp120 (305-321)); 0 (Peptide Fragments); 0 (Receptors, CCR5); 0 (Triazoles); MD6P741W8A (maraviroc)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE



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