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1.
J Virol ; 92(14)2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29743357

RESUMO

Cellular antiviral proteins interfere with distinct steps of replication cycles of viruses. The galectin 3 binding protein (LGALS3BP, also known as 90K) was previously shown to lower the infectivity of nascent human immunodeficiency virus type 1 (HIV-1) virions when expressed in virus-producing cells. This antiviral effect was accompanied by impaired gp160Env processing and reduced viral incorporation of mature Env glycoproteins. Here, we examined the ability of 90K orthologs from primate species to reduce the particle infectivity of distinct lentiviruses. We show that 90K's ability to diminish the infectivity of lentiviral particles is conserved within primate species, with the notable exception of 90K from rhesus macaque. Comparison of active and inactive 90K orthologs and variants uncovered the fact that inhibition of processing of the HIV-1 Env precursor and reduction of cell surface expression of HIV-1 Env gp120 are required, but not sufficient, for 90K-mediated antiviral activity. Rather, 90K-mediated reduction of virion-associated gp120 coincided with antiviral activity, suggesting that 90K impairs the incorporation of HIV-1 Env into budding virions. We show that a single "humanizing" amino acid exchange in the BTB (broad-complex, tramtrack, and bric-à-brac)/POZ (poxvirus and zinc finger) domain is sufficient to fully rescue the antiviral activity of a shortened version of rhesus macaque 90K, but not that of the full-length protein. Comparison of the X-ray structures of the BTB/POZ domains of 90K from rhesus macaques and humans point toward a slightly larger hydrophobic patch at the surface of the rhesus macaque BTB domain that may modulate a direct interaction with either a second 90K domain or a different protein.IMPORTANCE The cellular 90K protein has been shown to diminish the infectivity of nascent HIV-1 particles. When produced in 90K-expressing cells, particles bear smaller amounts of the HIV-1 Env glycoprotein, which is essential for attaching to and entering new target cells in the subsequent infection round. However, whether the antiviral function of 90K is conserved across primates is unknown. Here, we found that 90K orthologs from most primate species, but, surprisingly, not from rhesus macaques, inhibit HIV-1. The introduction of a single amino acid exchange into a short version of the rhesus macaque 90K protein, consisting of the two intermediate domains of 90K, resulted in full restoration of antiviral activity. Structural elucidation of the respective domain suggests that the absence of antiviral activity in the rhesus macaque factor may be linked to a subtle change in protein-protein interaction.


Assuntos
Antígenos de Neoplasias/farmacologia , Antivirais/farmacologia , Biomarcadores Tumorais/farmacologia , Proteínas de Transporte/farmacologia , Glicoproteínas/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Antígenos de Neoplasias/química , Biomarcadores Tumorais/química , Proteínas de Transporte/química , Produtos do Gene env/metabolismo , Glicoproteínas/química , Infecções por HIV/virologia , Humanos , Macaca mulatta , Conformação Proteica , Homologia de Sequência , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Especificidade da Espécie , Montagem de Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
2.
Artigo em Inglês | MEDLINE | ID: mdl-27799217

RESUMO

Rilpivirine (RPV), the latest nonnucleoside reverse transcriptase inhibitor active against HIV-1, is prescribed in a standard dosage of 25 mg once a day in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The aim of this observational study was to characterize the RPV pharmacokinetic profile, to quantify interpatient variability, and to identify potential factors that could influence drug exposure. RPV concentration data were collected from HIV-infected patients as part of routine therapeutic drug monitoring performed in our center (Laboratory of Clinical Pharmacology). A population pharmacokinetic analysis was performed with NONMEM by comparing various structural models. The influence of demographic and clinical covariates, as well as frequent genetic polymorphisms in 5 genes (CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*17, UGT1A1*28, and UGT1A4*2), on RPV elimination was explored. A total of 325 plasma concentration measurements were obtained from 249 HIV-positive patients. Plasma concentrations ranged from 12 to 255 ng/ml. A one-compartment model with zero-order absorption best characterized RPV pharmacokinetics. The average RPV clearance (CL) was 11.7 liters/h, the average volume of distribution was 401 liters, and the mean absorption time was 4 h. The interinterindividual variability (IIV) for CL was estimated to be 33%. None of the available demographic or genetic covariates showed any influence on RPV pharmacokinetics, but 29% of the patients were predicted to present minimal concentrations below the recently identified target cutoff value of 50 ng/ml. The variability in RPV pharmacokinetics appears to be lower than that for most other antiretroviral drugs. However, under the standard regimen of 25 mg daily, a significant number of patients might be underdosed. It remains to be investigated whether the underexposure has an impact on the development of resistance while patients are on maintenance therapy.


Assuntos
Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/patogenicidade , Rilpivirina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP3A/genética , Feminino , Genótipo , Glucuronosiltransferase/genética , Infecções por HIV/genética , Infecções por HIV/metabolismo , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Rilpivirina/uso terapêutico , Adulto Jovem
3.
Nat Commun ; 7: 12412, 2016 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-27510803

RESUMO

Siglec-1/CD169 is a myeloid-cell surface receptor critical for HIV-1 capture and infection of bystander target cells. To dissect the role of SIGLEC1 in natura, we scan a large population genetic database and identify a loss-of-function variant (Glu88Ter) that is found in ∼1% of healthy people. Exome analysis and direct genotyping of 4,233 HIV-1-infected individuals reveals two Glu88Ter homozygous and 97 heterozygous subjects, allowing the analysis of ex vivo and in vivo consequences of SIGLEC1 loss-of-function. Cells from these individuals are functionally null or haploinsufficient for Siglec-1 activity in HIV-1 capture and trans-infection ex vivo. However, Siglec-1 protein truncation does not have a measurable impact on HIV-1 acquisition or AIDS outcomes in vivo. This result contrasts with the known in vitro functional role of Siglec-1 in HIV-1 trans-infection. Thus, it provides evidence that the classical HIV-1 infectious routes may compensate for the lack of Siglec-1 in fuelling HIV-1 dissemination within infected individuals.


Assuntos
Infecções por HIV/genética , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Adulto , Alelos , Linfócitos T CD4-Positivos/metabolismo , Linhagem da Célula , Células Dendríticas/metabolismo , Progressão da Doença , Exoma , Éxons , Feminino , Genética Populacional , Genótipo , HIV-1 , Heterozigoto , Homozigoto , Humanos , Leucócitos Mononucleares/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Suíça , Estados Unidos
4.
Open Forum Infect Dis ; 3(2): ofw101, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27419173

RESUMO

Background. The impact of human genetic background on low-trauma fracture (LTF) risk has not been evaluated in the context of human immunodeficiency virus (HIV) and clinical LTF risk factors. Methods. In the general population, 6 common single-nucleotide polymorphisms (SNPs) associate with LTF through genome-wide association study. Using genome-wide SNP arrays and imputation, we genotyped these SNPs in HIV-positive, white Swiss HIV Cohort Study participants. We included 103 individuals with a first, physician-validated LTF and 206 controls matched on gender, whose duration of observation and whose antiretroviral therapy start dates were similar using incidence density sampling. Analyses of nongenetic LTF risk factors were based on 158 cases and 788 controls. Results. A genetic risk score built from the 6 LTF-associated SNPs did not associate with LTF risk, in both models including and not including parental hip fracture history. The contribution of clinical LTF risk factors was limited in our dataset. Conclusions. Genetic LTF markers with a modest effect size in the general population do not improve fracture prediction in persons with HIV, in whom clinical LTF risk factors are prevalent in both cases and controls.

5.
J Antimicrob Chemother ; 71(7): 1933-42, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27029846

RESUMO

OBJECTIVES: Co-formulated elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine is among the preferred regimens for first-line ART. A population approach was used to characterize the pharmacokinetics of elvitegravir and cobicistat and identify individual factors and co-medications influencing their disposition, taking into consideration the interaction between the two compounds. METHODS: The study population included 144 HIV-infected individuals who provided 186 and 167 elvitegravir and cobicistat plasma concentrations, respectively. First, distinct NONMEM(®) analyses were conducted for elvitegravir and cobicistat, including individual demographic, clinical and genetic factors as potential covariates. Elvitegravir and cobicistat interaction was then assessed through different inhibitory models. Simulations based on the final model served to compare expected drug concentrations under standard and alternative dosage regimens. RESULTS: Clearance with between-subject variability was 7.6 L/h [coefficient of variation (CV) 16.6%] and volume of distribution 61 L for elvitegravir and 16.0 L/h (CV 41.9%) and 88.3 L, respectively, for cobicistat. Concomitant administration of non-ritonavir-boosted atazanavir decreased elvitegravir clearance by 35%, likely due to UDP-glucuronosyl transferase (UGT) 1A1 inhibition. Concomitant administration of non-ritonavir-boosted atazanavir and ritonavir-boosted darunavir decreased cobicistat clearance by 47% and 27%, respectively. The final interaction model included cobicistat exposure (AUC0-24) on elvitegravir clearance. Simulations confirmed that a reduced elvitegravir dose of 85 mg co-administered with cobicistat and atazanavir produces a concentration-time course comparable to the standard regimen without atazanavir. CONCLUSIONS: Elvitegravir and cobicistat pharmacokinetic variability appears to be mainly explained by drug-drug interactions that may be encountered in routine clinical practice. In these cases, therapeutic drug monitoring and surveillance for potential toxicities would be justified.


Assuntos
Fármacos Anti-HIV/farmacocinética , Cobicistat/farmacocinética , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Quinolonas/farmacocinética , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Área Sob a Curva , Cobicistat/administração & dosagem , Estudos de Coortes , Simulação por Computador , Interações Medicamentosas , Feminino , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Quinolonas/administração & dosagem , Adulto Jovem
6.
Genet Med ; 18(8): 814-22, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26765343

RESUMO

PURPOSE: The implementation of genomic-based medicine is hindered by unresolved questions regarding data privacy and delivery of interpreted results to health-care practitioners. We used DNA-based prediction of HIV-related outcomes as a model to explore critical issues in clinical genomics. METHODS: We genotyped 4,149 markers in HIV-positive individuals. Variants allowed for prediction of 17 traits relevant to HIV medical care, inference of patient ancestry, and imputation of human leukocyte antigen (HLA) types. Genetic data were processed under a privacy-preserving framework using homomorphic encryption, and clinical reports describing potentially actionable results were delivered to health-care providers. RESULTS: A total of 230 patients were included in the study. We demonstrated the feasibility of encrypting a large number of genetic markers, inferring patient ancestry, computing monogenic and polygenic trait risks, and reporting results under privacy-preserving conditions. The average execution time of a multimarker test on encrypted data was 865 ms on a standard computer. The proportion of tests returning potentially actionable genetic results ranged from 0 to 54%. CONCLUSIONS: The model of implementation presented herein informs on strategies to deliver genomic test results for clinical care. Data encryption to ensure privacy helps to build patient trust, a key requirement on the road to genomic-based medicine.Genet Med 18 8, 814-822.


Assuntos
Segurança Computacional , Privacidade Genética , Infecções por HIV/genética , Variação Genética , Genômica/ética , Humanos , Modelos Teóricos
7.
Drug Metab Dispos ; 44(1): 151-61, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26553012

RESUMO

Efavirenz (EFV) is principally metabolized by CYP2B6 to 8-hydroxy-efavirenz (8OH-EFV) and to a lesser extent by CYP2A6 to 7-hydroxy-efavirenz (7OH-EFV). So far, most metabolite profile analyses have been restricted to 8OH-EFV, 7OH-EFV, and EFV-N-glucuronide, even though these metabolites represent a minor percentage of EFV metabolites present in vivo. We have performed a quantitative phase I and II metabolite profile analysis by tandem mass spectrometry of plasma, cerebrospinal fluid (CSF), and urine samples in 71 human immunodeficiency virus patients taking efavirenz, prior to and after enzymatic (glucuronidase and sulfatase) hydrolysis. We have shown that phase II metabolites constitute the major part of the known circulating efavirenz species in humans. The 8OH-EFV-glucuronide (gln) and 8OH-EFV-sulfate (identified for the first time) in humans were found to be 64- and 7-fold higher than the parent 8OH-EFV, respectively. In individuals (n = 67) genotyped for CYP2B6, 2A6, and CYP3A metabolic pathways, 8OH-EFV/EFV ratios in plasma were an index of CYP2B6 phenotypic activity (P < 0.0001), which was also reflected by phase II metabolites 8OH-EFV-glucuronide/EFV and 8OH-EFV-sulfate/EFV ratios. Neither EFV nor 8OH-EFV, nor any other considered metabolites in plasma were associated with an increased risk of central nervous system (CNS) toxicity. In CSF, 8OH-EFV levels were not influenced by CYP2B6 genotypes and did not predict CNS toxicity. The phase II metabolites 8OH-EFV-gln, 8OH-EFV-sulfate, and 7OH-EFV-gln were present in CSF at 2- to 9-fold higher concentrations than 8OH-EFV. The potential contribution of known and previously unreported EFV metabolites in CSF to the neuropsychological effects of efavirenz needs to be further examined in larger cohort studies.


Assuntos
Fármacos Anti-HIV/farmacocinética , Benzoxazinas/efeitos adversos , Benzoxazinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Metabolômica/métodos , Inibidores da Transcriptase Reversa/farmacocinética , Espectrometria de Massas em Tandem , Alcinos , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/líquido cefalorraquidiano , Fármacos Anti-HIV/urina , Benzoxazinas/sangue , Benzoxazinas/líquido cefalorraquidiano , Benzoxazinas/urina , Ciclopropanos , Citocromo P-450 CYP2A6/genética , Citocromo P-450 CYP2A6/metabolismo , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Genótipo , Glucuronídeos/sangue , Glucuronídeos/líquido cefalorraquidiano , Glucuronídeos/urina , Infecções por HIV/diagnóstico , Infecções por HIV/metabolismo , Humanos , Hidroxilação , Desintoxicação Metabólica Fase I , Desintoxicação Metabólica Fase II , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Fenótipo , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/líquido cefalorraquidiano , Inibidores da Transcriptase Reversa/urina , Medição de Risco , Sulfatos/sangue , Sulfatos/líquido cefalorraquidiano , Sulfatos/urina
8.
EBioMedicine ; 2(7): 706-12, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26288843

RESUMO

BACKGROUND: Efavirenz (EFV) based antiretroviral therapy is expanding worldwide. However discontinuation of EFV containing regimens is common in some patients, particularly black patients, due most often to neuropsychiatric side effects. These adverse drug effects often result in premature drug discontinuation, as well as considerable morbidity. METHODS: We genotyped CYP2A6, CYP2B6 and CYP3A4, which encode enzymes principally involved in EFV metabolism, from patients enrolled in the multinational SMART, FIRST and ESPRIT studies, for whom outcome data of treatment adherence was available. Patients with loss or decrease of function single nucleotide polymorphisms (SNPs) in the above genes were assigned a risk score based upon the number of SNPs present weighted relative to whether CYP2B6 (main metabolism pathway) and/or CYP2A6 and CYP3A4 (accessory pathways) were involved. Cox regression models were used to study the association between high genetic risk and time from initiation to EFV discontinuation. Failure was defined as discontinuation of an antiretroviral regimen other than for virologic failure or protocol determined discontinuation. FINDINGS: Patients with highest pharmacogenetic risk, as defined by cumulative SNPs in CYP2A6, CYP2B6 and CYP3A4, have an increased risk of discontinuation of EFV containing therapy compared to patients with lower genetic risk scores (adjusted HR 1.9, 95% CI 1.2, 3.1, P = 0.009). High genetic risk score was not associated with an increased risk of discontinuing atazanavir or nevirapine. High genetic risk was present more often in blacks compared to non-blacks (Adjusted OR 4.5, 95% CI: 1.9,10.5), and treatment discontinuation was also increased in blacks overall (Adjusted HR 1.4, 95% CI 1.0, 1.9). However, high genetic risk was more associated with treatment discontinuation than race alone for both blacks (Adjusted OR 1.9, 95% CI 0.8, 4.8) and non-blacks (Adjusted OR 5.3, 95% CI 1.5, 18.0). INTERPRETATION: Premature discontinuation of ART delays the time to effective long term viral suppression, and is associated with significant morbidity. Pharmacogenetic testing may predict those with a high risk of EFV discontinuation, and therefore should be considered in patients in whom initiation of EFV based ART is being considered. FUNDING: Funded by NIH.


Assuntos
Benzoxazinas/uso terapêutico , Etnicidade/genética , Predisposição Genética para Doença , Soropositividade para HIV/tratamento farmacológico , Soropositividade para HIV/genética , Suspensão de Tratamento , Adulto , Alcinos , Fármacos Anti-HIV , Ciclopropanos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Suíça , Resultado do Tratamento
9.
PLoS One ; 10(7): e0133879, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26218843

RESUMO

BACKGROUND: Ribavirin (RBV) is an essential component of most current hepatitis C (HCV) treatment regimens and still standard of care in the combination with pegylated interferon (pegIFN) to treat chronic HCV in resource limited settings. Study results in HIV/HCV-coinfected patients are contradicting as to whether RBV concentration correlates with sustained virological response (SVR). METHODS: We included 262 HCV treatment naïve HIV/HCV-coinfected Swiss HIV Cohort Study (SHCS) participants treated with RBV and pegIFN between 01.01.2001-01.01.2010, 134 with HCV genotype (GT) 1/4, and 128 with GT 2/3 infections. RBV levels were measured retrospectively in stored plasma samples obtained between HCV treatment week 4 and end of therapy. Uni- and multivariable logistic regression analyses were used to evaluate the association between RBV concentration and SVR in GT 1/4 and GT 2/3 infections. The analyses were repeated stratified by treatment phase (week 4-12, 13-24, >24) and IL28B genotype (CC versus CT/TT). RESULTS: SVR rates were 35.1% in GT 1/4 and 70.3% in GT 2/3 infections. Overall, median RBV concentration was 2.0 mg/L in GT 1/4, and 1.9 mg/L in GT 2/3, and did not change significantly across treatment phases. Patients with SVR had similar RBV concentrations compared to patients without SVR in both HCV genotype groups. SVR was not associated with RBV levels ≥2.0 mg/L (GT 1/4, OR 1.19 [0.5-2.86]; GT 2/3, 1.94 [0.78-4.80]) and ≥2.5 mg/L (GT 1/4, 1.56 [0.64-3.84]; GT 2/3 2.72 [0.85-8.73]), regardless of treatment phase, and IL28B genotype. CONCLUSION: In HIV/HCV-coinfected patients treated with pegIFN/RBV, therapeutic drug monitoring of RBV concentrations does not enhance the chance of HCV cure, regardless of HCV genotype, treatment phase and IL28B genotype.


Assuntos
Antivirais/uso terapêutico , Coinfecção/sangue , Infecções por HIV/sangue , Hepatite C Crônica/sangue , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/sangue , Adulto , Coinfecção/complicações , Coinfecção/tratamento farmacológico , Coinfecção/virologia , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Seguimentos , Genótipo , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Resultado do Tratamento
10.
Antivir Ther ; 20(3): 261-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25032819

RESUMO

BACKGROUND: Vitamin D deficiency is prevalent in HIV-infected individuals and vitamin D supplementation is proposed according to standard care. This study aimed at characterizing the kinetics of 25(OH)D in a cohort of HIV-infected individuals of European ancestry to better define the influence of genetic and non-genetic factors on 25(OH)D levels. These data were used for the optimization of vitamin D supplementation in order to reach therapeutic targets. METHODS: 1,397 25(OH)D plasma levels and relevant clinical information were collected in 664 participants during medical routine follow-up visits. They were genotyped for 7 SNPs in 4 genes known to be associated with 25(OH)D levels. 25(OH)D concentrations were analysed using a population pharmacokinetic approach. The percentage of individuals with 25(OH)D concentrations within the recommended range of 20-40 ng/ml during 12 months of follow-up and several dosage regimens were evaluated by simulation. RESULTS: A one-compartment model with linear absorption and elimination was used to describe 25(OH)D pharmacokinetics, while integrating endogenous baseline plasma concentrations. Covariate analyses confirmed the effect of seasonality, body mass index, smoking habits, the analytical method, darunavir/ritonavir and the genetic variant in GC (rs2282679) on 25(OH)D concentrations. 11% of the inter-individual variability in 25(OH)D levels was explained by seasonality and other non-genetic covariates, and 1% by genetics. The optimal supplementation for severe vitamin D deficient patients was 300,000 IU two times per year. CONCLUSIONS: This analysis allowed identifying factors associated with 25(OH)D plasma levels in HIV-infected individuals. Improvement of dosage regimen and timing of vitamin D supplementation is proposed based on those results.


Assuntos
Suscetibilidade a Doenças , Infecções por HIV/sangue , Infecções por HIV/genética , Polimorfismo de Nucleotídeo Único , Vitamina D/sangue , População Branca , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Estudos de Coortes , Simulação por Computador , Suplementos Nutricionais , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Farmacogenética , Carga Viral , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/tratamento farmacológico , Adulto Jovem
11.
AIDS ; 28(9): 1261-72, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24732774

RESUMO

OBJECTIVE: The study of HIV-1 rapid progressors has been limited to specific case reports. Nevertheless, identification and characterization of the viral and host factors involved in rapid progression are crucial when attempting to uncover the correlates of rapid disease outcome. DESIGN: We carried out comparative functional analyses in rapid progressors (n = 46) and standard progressors (n = 46) early after HIV-1 seroconversion (≤1 year). The viral traits tested were viral replicative capacity, co-receptor usage, and genomic variation. Host CD8(+) T-cell responses, humoral activity, and HLA immunogenetic markers were also determined. RESULTS: Our data demonstrate an unusual convergence of highly pathogenic HIV-1 strains in rapid progressors. Compared with standard progressors, rapid progressor viral strains show higher in-vitro replicative capacity (81.5 vs. 67.9%; P = 0.025) and greater X4/DM co-receptor usage (26.3 vs. 2.8%; P = 0.006) in early infection. Limited or absent functional HIV-1 CD8(+) T-cell responses and neutralizing activity were measured in rapid progressors. Moreover, the increase in common HLA allele-restricted CD8(+) T-cell escape mutations in rapid progressors acts as a signature of uncontrolled HIV-1 replication and early impairment of adaptive cellular responses. CONCLUSION: Our data support a dominant role for viral factors in rapid progressors. Robust HIV-1 replication and intrinsic viral properties limit host adaptive immune responses, thus driving rapid disease progression.


Assuntos
Adaptação Biológica , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Adulto , Linfócitos T CD8-Positivos/imunologia , Estudos de Coortes , Progressão da Doença , Feminino , Variação Genética , Anticorpos Anti-HIV/sangue , HIV-1/classificação , HIV-1/genética , HIV-1/fisiologia , Humanos , Masculino , Receptores de HIV/análise , Internalização do Vírus , Replicação Viral
12.
Blood ; 123(7): 1021-31, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24335234

RESUMO

SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase and a nuclease that restricts HIV-1 in noncycling cells. Germ-line mutations in SAMHD1 have been described in patients with Aicardi-Goutières syndrome (AGS), a congenital autoimmune disease. In a previous longitudinal whole genome sequencing study of chronic lymphocytic leukemia (CLL), we revealed a SAMHD1 mutation as a potential founding event. Here, we describe an AGS patient carrying a pathogenic germ-line SAMHD1 mutation who developed CLL at 24 years of age. Using clinical trial samples, we show that acquired SAMHD1 mutations are associated with high variant allele frequency and reduced SAMHD1 expression and occur in 11% of relapsed/refractory CLL patients. We provide evidence that SAMHD1 regulates cell proliferation and survival and engages in specific protein interactions in response to DNA damage. We propose that SAMHD1 may have a function in DNA repair and that the presence of SAMHD1 mutations in CLL promotes leukemia development.


Assuntos
Dano ao DNA/genética , Mutação em Linhagem Germinativa , Leucemia Linfocítica Crônica de Células B/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Adulto , Doenças Autoimunes do Sistema Nervoso/complicações , Doenças Autoimunes do Sistema Nervoso/genética , Estudos de Coortes , Hibridização Genômica Comparativa , Frequência do Gene , Células HeLa , Humanos , Leucemia Linfocítica Crônica de Células B/complicações , Masculino , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/genética , Proteína 1 com Domínio SAM e Domínio HD , Adulto Jovem
13.
Antivir Ther ; 18(5): 739-43, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23640958

RESUMO

Here, we describe severe neuropsychiatric symptoms in an HIV-positive Asian man with extremely high efavirenz plasma levels while receiving standard treatment with efavirenz/tenofovir/emtricitabine fixed-dose regimen. Genetic examination revealed compound homozygosity for loss-of-function alleles of CYP2B6, including coding for a rare truncated protein. Neuropsychiatric symptoms resolved completely after efavirenz discontinuation.


Assuntos
Fármacos Anti-HIV/farmacocinética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Benzoxazinas/metabolismo , Inibidores da Transcriptase Reversa/farmacocinética , Adulto , Alcinos , Alelos , Fármacos Anti-HIV/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/genética , Ciclopropanos , Citocromo P-450 CYP2B6 , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/enzimologia , Infecções por HIV/genética , HIV-1 , Humanos , Masculino , Farmacogenética , Polimorfismo de Nucleotídeo Único , Inibidores da Transcriptase Reversa/uso terapêutico
14.
Clin Infect Dis ; 57(1): 112-21, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23532479

RESUMO

BACKGROUND: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. METHODS: In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. RESULTS: A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9 × 10(-4)). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05-2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16-1.96), diabetes (OR = 1.66; 95% CI, 1.10-2.49), ≥ 1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06-1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. CONCLUSIONS: In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.


Assuntos
Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Infecções por HIV/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem
15.
Pharmacogenet Genomics ; 23(1): 9-18, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23111422

RESUMO

OBJECTIVES: Etravirine (ETV) is metabolized by cytochrome P450 (CYP) 3A, 2C9, and 2C19. Metabolites are glucuronidated by uridine diphosphate glucuronosyltransferases (UGT). To identify the potential impact of genetic and non-genetic factors involved in ETV metabolism, we carried out a two-step pharmacogenetics-based population pharmacokinetic study in HIV-1 infected individuals. MATERIALS AND METHODS: The study population included 144 individuals contributing 289 ETV plasma concentrations and four individuals contributing 23 ETV plasma concentrations collected in a rich sampling design. Genetic variants [n=125 single-nucleotide polymorphisms (SNPs)] in 34 genes with a predicted role in ETV metabolism were selected. A first step population pharmacokinetic model included non-genetic and known genetic factors (seven SNPs in CYP2C, one SNP in CYP3A5) as covariates. Post-hoc individual ETV clearance (CL) was used in a second (discovery) step, in which the effect of the remaining 98 SNPs in CYP3A, P450 cytochrome oxidoreductase (POR), nuclear receptor genes, and UGTs was investigated. RESULTS: A one-compartment model with zero-order absorption best characterized ETV pharmacokinetics. The average ETV CL was 41 (l/h) (CV 51.1%), the volume of distribution was 1325 l, and the mean absorption time was 1.2 h. The administration of darunavir/ritonavir or tenofovir was the only non-genetic covariate influencing ETV CL significantly, resulting in a 40% [95% confidence interval (CI): 13-69%] and a 42% (95% CI: 17-68%) increase in ETV CL, respectively. Carriers of rs4244285 (CYP2C19*2) had 23% (8-38%) lower ETV CL. Co-administered antiretroviral agents and genetic factors explained 16% of the variance in ETV concentrations. None of the SNPs in the discovery step influenced ETV CL. CONCLUSION: ETV concentrations are highly variable, and co-administered antiretroviral agents and genetic factors explained only a modest part of the interindividual variability in ETV elimination. Opposing effects of interacting drugs effectively abrogate genetic influences on ETV CL, and vice-versa.


Assuntos
Infecções por HIV/genética , Inibidores da Protease de HIV/farmacocinética , HIV-1/genética , Modelos Estatísticos , Farmacogenética , Piridazinas/farmacocinética , Adolescente , Adulto , Idoso , Hidrocarboneto de Aril Hidroxilases/genética , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A/genética , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Estudos Prospectivos , Piridazinas/farmacologia , Pirimidinas , Suíça/epidemiologia , Distribuição Tecidual , Adulto Jovem
16.
Pharmacogenet Genomics ; 23(2): 84-93, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23249875

RESUMO

BACKGROUND: (S)-Methadone, metabolized mainly by CYP2B6, shows a wide interindividual variability in its pharmacokinetics and pharmacodynamics. METHODS: Resequencing of the CYP2B6 gene was performed in 12 and 35 selected individuals with high (S)-methadone plasma exposure and low (S)-methadone plasma exposure, respectively, from a previously described cohort of 276 patients undergoing methadone maintenance treatment. Selected genetic polymorphisms were then analyzed in the complete cohort. RESULTS: The rs35303484 (*11; c136A>G; M46V) polymorphism was overrepresented in the high (S)-methadone level group, whereas the rs3745274 (*9; c516G>T; Q172H), rs2279344 (c822+183G>A), and rs8192719 (c1294+53C>T) polymorphisms were underrepresented in the low (S)-methadone level group, suggesting an association with decreased CYP2B6 activity. Conversely, the rs3211371 (*5; c1459C>T; R487C) polymorphism was overrepresented in the low-level group, indicating an increased CYP2B6 activity. A higher allele frequency was found in the high-level group compared with the low-level group for rs3745274 (*9; c516G>T; Q172H), rs2279343 (*4; c785A>G; K262R) (together representing CYP2B6*6), rs8192719 (c1294+53C>T), and rs2279344 (c822+183G>A), suggesting their involvement in decreased CYP2B6 activity. These results should be replicated in larger independent cohorts. CONCLUSION: Known genetic polymorphisms in CYP2B6 contribute toward explaining extreme (S)-methadone plasma levels observed in a cohort of patients following methadone maintenance treatment.


Assuntos
Analgésicos Opioides/sangue , Hidrocarboneto de Aril Hidroxilases/genética , Metadona/sangue , Transtornos Relacionados ao Uso de Opioides/genética , Oxirredutases N-Desmetilantes/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Analgésicos Opioides/farmacocinética , Cromatografia Líquida , Estudos de Coortes , Citocromo P-450 CYP2B6 , Genótipo , Humanos , Espectrometria de Massas , Taxa de Depuração Metabólica , Metadona/farmacocinética , Transtornos Relacionados ao Uso de Opioides/sangue , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Reação em Cadeia da Polimerase , Distribuição Tecidual
17.
Chimia (Aarau) ; 66(5): 291-5, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22867538

RESUMO

Pharmacokinetic variability in drug levels represent for some drugs a major determinant of treatment success, since sub-therapeutic concentrations might lead to toxic reactions, treatment discontinuation or inefficacy. This is true for most antiretroviral drugs, which exhibit high inter-patient variability in their pharmacokinetics that has been partially explained by some genetic and non-genetic factors. The population pharmacokinetic approach represents a very useful tool for the description of the dose-concentration relationship, the quantification of variability in the target population of patients and the identification of influencing factors. It can thus be used to make predictions and dosage adjustment optimization based on Bayesian therapeutic drug monitoring (TDM). This approach has been used to characterize the pharmacokinetics of nevirapine (NVP) in 137 HIV-positive patients followed within the frame of a TDM program. Among tested covariates, body weight, co-administration of a cytochrome (CYP) 3A4 inducer or boosted atazanavir as well as elevated aspartate transaminases showed an effect on NVP elimination. In addition, genetic polymorphism in the CYP2B6 was associated with reduced NVP clearance. Altogether, these factors could explain 26% in NVP variability. Model-based simulations were used to compare the adequacy of different dosage regimens in relation to the therapeutic target associated with treatment efficacy. In conclusion, the population approach is very useful to characterize the pharmacokinetic profile of drugs in a population of interest. The quantification and the identification of the sources of variability is a rational approach to making optimal dosage decision for certain drugs administered chronically.


Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/metabolismo , Soropositividade para HIV/metabolismo , Nevirapina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/genética , Estudos de Coortes , Simulação por Computador , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP3A/genética , Monitoramento de Medicamentos , Feminino , Genótipo , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Modelos Estatísticos , Nevirapina/administração & dosagem , Nevirapina/uso terapêutico , Oxirredutases N-Desmetilantes/genética , Polimorfismo Genético , População , Resultado do Tratamento , Adulto Jovem
18.
Antimicrob Agents Chemother ; 56(6): 2959-66, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22371894

RESUMO

The objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV(+)) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV(+) than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.


Assuntos
Infecções por HIV/tratamento farmacológico , Farmacogenética/métodos , Ritonavir/farmacologia , Adolescente , Adulto , Idoso , Fármacos Anti-HIV , Feminino , Genótipo , Infecções por HIV/genética , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Modelos Teóricos , Ritonavir/uso terapêutico , Adulto Jovem
19.
PLoS One ; 7(1): e29186, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22235271

RESUMO

BACKGROUND: Good adherence to antiretroviral therapy (ART) is critical for successful HIV treatment. However, some patients remain virologically suppressed despite suboptimal adherence. We hypothesized that this could result from host genetic factors influencing drug levels. METHODS: Eligible individuals were Caucasians treated with efavirenz (EFV) and/or boosted lopinavir (LPV/r) with self-reported poor adherence, defined as missing doses of ART at least weekly for more than 6 months. Participants were genotyped for single nucleotide polymorphisms (SNPs) in candidate genes previously reported to decrease EFV (rs3745274, rs35303484, rs35979566 in CYP2B6) and LPV/r clearance (rs4149056 in SLCO1B1, rs6945984 in CYP3A, rs717620 in ABCC2). Viral suppression was defined as having HIV-1 RNA <400 copies/ml throughout the study period. RESULTS: From January 2003 until May 2009, 37 individuals on EFV (28 suppressed and 9 not suppressed) and 69 on LPV/r (38 suppressed and 31 not suppressed) were eligible. The poor adherence period was a median of 32 weeks with 18.9% of EFV and 20.3% of LPV/r patients reporting missed doses on a daily basis. The tested SNPs were not determinant for viral suppression. Reporting missing >1 dose/week was associated with a lower probability of viral suppression compared to missing 1 dose/week (EFV: odds ratio (OR) 0.11, 95% confidence interval (CI): 0.01-0.99; LPV/r: OR 0.29, 95% CI: 0.09-0.94). In both groups, the probability of remaining suppressed increased with the duration of continuous suppression prior to the poor adherence period (EFV: OR 3.40, 95% CI: 0.62-18.75; LPV/r: OR 5.65, 95% CI: 1.82-17.56). CONCLUSIONS: The investigated genetic variants did not play a significant role in the sustained viral suppression of individuals with suboptimal adherence. Risk of failure decreased with longer duration of viral suppression in this population.


Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Cooperação do Paciente/estatística & dados numéricos , Autorrelato , Adulto , Infecções por HIV/genética , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Fatores de Tempo
20.
J Clin Invest ; 121(6): 2391-400, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21555857

RESUMO

High levels of HIV-1 replication during the chronic phase of infection usually correlate with rapid progression to severe immunodeficiency. However, a minority of highly viremic individuals remains asymptomatic and maintains high CD4⁺ T cell counts. This tolerant profile is poorly understood and reminiscent of the widely studied nonprogressive disease model of SIV infection in natural hosts. Here, we identify transcriptome differences between rapid progressors (RPs) and viremic nonprogressors (VNPs) and highlight several genes relevant for the understanding of HIV-1-induced immunosuppression. RPs were characterized by a specific transcriptome profile of CD4⁺ and CD8⁺ T cells similar to that observed in pathogenic SIV-infected rhesus macaques. In contrast, VNPs exhibited lower expression of interferon-stimulated genes and shared a common gene regulation profile with nonpathogenic SIV-infected sooty mangabeys. A short list of genes associated with VNP, including CASP1, CD38, LAG3, TNFSF13B, SOCS1, and EEF1D, showed significant correlation with time to disease progression when evaluated in an independent set of CD4⁺ T cell expression data. This work characterizes 2 minimally studied clinical patterns of progression to AIDS, whose analysis may inform our understanding of HIV pathogenesis.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Cercocebus atys/genética , Perfilação da Expressão Gênica , Regulação Viral da Expressão Gênica , Infecções por HIV/genética , Sobreviventes de Longo Prazo ao HIV , HIV-1 , Macaca mulatta/genética , Síndrome de Imunodeficiência Adquirida dos Símios/genética , Vírus da Imunodeficiência Símia , Animais , Cercocebus atys/metabolismo , Progressão da Doença , Suscetibilidade a Doenças , Infecções por HIV/metabolismo , HIV-1/fisiologia , Humanos , Macaca mulatta/metabolismo , Fenótipo , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo , Vírus da Imunodeficiência Símia/fisiologia , Especificidade da Espécie , Regulação para Cima , Carga Viral , Viremia/genética , Viremia/metabolismo , Replicação Viral
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