RÉSUMÉ
OBJECTIVES: To report atypical pathogens from clinical trial data comparing delafloxacin to moxifloxacin in the treatment of adults with community-acquired bacterial pneumonia (CABP). METHODS: Multiple diagnostic methods were employed to diagnose atypical infections including culture, serology, and urinary antigen. RESULTS: The microbiological intent-to-treat (MITT) population included 520 patients; 30% had an atypical bacterial pathogen identified (156/520). Overall, 13.1% (68/520) had a monomicrobial atypical infection and 2.3% (12/520) had polymicrobial all-atypical infections. Among patients with polymicrobial infections, Streptococcus pneumoniae was the most frequently occurring co-infecting organism and Chlamydia pneumoniae was the most frequently occurring co-infecting atypical organism. For Mycoplasma pneumoniae and Legionella pneumophila, serology yielded the highest number of diagnoses. Delafloxacin and moxifloxacin had similar in vitro activity against M. pneumoniae and delafloxacin had greater activity against L. pneumophila. Two macrolide-resistant M. pneumoniae isolates were recovered. No fluoroquinolone-resistant M. pneumoniae were isolated. The rates of microbiological success (documented or presumed eradication) at test-of-cure were similar between the delafloxacin and moxifloxacin groups. There was no evidence of a correlation between minimum inhibitory concentration (MIC) and outcome; a high proportion of favorable outcomes was observed across all delafloxacin baseline MICs. CONCLUSIONS: Delafloxacin may be considered a treatment option as monotherapy for CABP in adults, where broad-spectrum coverage including atypical activity is desirable.
Sujet(s)
Antibactériens/administration et posologie , Infections communautaires/traitement médicamenteux , Fluoroquinolones/administration et posologie , Moxifloxacine/administration et posologie , Pneumopathie bactérienne/traitement médicamenteux , Adulte , Infections communautaires/microbiologie , Femelle , Humains , Legionella pneumophila/effets des médicaments et des substances chimiques , Legionella pneumophila/croissance et développement , Legionella pneumophila/isolement et purification , Macrolides/administration et posologie , Mâle , Tests de sensibilité microbienne , Mycoplasma pneumoniae/effets des médicaments et des substances chimiques , Mycoplasma pneumoniae/croissance et développement , Mycoplasma pneumoniae/isolement et purification , Pneumopathie bactérienne/microbiologie , Streptococcus pneumoniae/effets des médicaments et des substances chimiques , Streptococcus pneumoniae/génétique , Streptococcus pneumoniae/isolement et purification , Jeune adulteRÉSUMÉ
Delafloxacin is a novel fluoroquinolone with activity against Gram-positive, Gram-negative, and atypical pathogens, including fluoroquinolone-nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA). The microbiological results of a phase 3 clinical trial in adults with community-acquired pneumonia (CAP) comparing delafloxacin (300 mg intravenously [i.v.] with the option to switch to 450 mg orally every 12 h) to moxifloxacin (400 mg i.v. with the option to switch to 400 mg orally once a day [QD]) were determined. Patients from 4 continents, predominately Europe but also South America and Asia, were enrolled. The microbiological intent-to-treat (MITT) population included 520 patients, and 60.5% of these patients had a bacterial pathogen identified. Multiple diagnostic methods were employed, including culture, serology, PCR, and urinary antigen tests. Based on baseline MIC90 values, delafloxacin exhibited at least 16-fold greater activity than moxifloxacin for Gram-positive and fastidious Gram-negative pathogens. Delafloxacin retained activity against resistant phenotypes found in Streptococcus pneumoniae (penicillin-, macrolide-, and multiple-drug resistant), Haemophilus species (ß-lactamase producing and macrolide nonsusceptible), and S. aureus (MRSA and fluoroquinolone-nonsusceptible methicillin-susceptible S. aureus [MSSA]). The microbiological success rates were 92.7% for S. pneumoniae (87.5% for penicillin-resistant S. pneumoniae [PRSP]), 92.6% for S. aureus (100% for MRSA), 100% for Escherichia coli, 82.4% for Klebsiella pneumoniae, 100% for Klebsiella oxytoca, 100% for Moraxella catarrhalis, 91.7% for Haemophilus influenzae, 88.6% for Haemophilus parainfluenzae, 96.7% for Mycoplasma pneumoniae, 93.1% for Legionella pneumophila, and 100% for Chlamydia pneumoniae There was little correlation between MICs and outcomes, with a high proportion of favorable outcomes observed across all delafloxacin baseline MIC values. Delafloxacin may be considered a treatment option as monotherapy for CAP in adults, where broad-spectrum coverage including MRSA activity is desirable.
Sujet(s)
Antibactériens/usage thérapeutique , Fluoroquinolones/usage thérapeutique , Humains , Klebsiella pneumoniae/effets des médicaments et des substances chimiques , Klebsiella pneumoniae/pathogénicité , Macrolides/usage thérapeutique , Staphylococcus aureus résistant à la méticilline/effets des médicaments et des substances chimiques , Staphylococcus aureus résistant à la méticilline/pathogénicité , Tests de sensibilité microbienne , Moxifloxacine/usage thérapeutique , Pneumopathie bactérienne/traitement médicamenteux , Staphylococcus aureus/effets des médicaments et des substances chimiques , Staphylococcus aureus/pathogénicité , Streptococcus pneumoniae/effets des médicaments et des substances chimiques , Streptococcus pneumoniae/pathogénicitéRÉSUMÉ
Solithromycin, a novel macrolide and the first fluoroketolide, is being developed as a therapy for community-acquired bacterial pneumonia, with a distinct mechanism that provides activity against macrolide-resistant bacteria. The pharmacokinetics, metabolism, and excretion of solithromycin were studied in healthy male subjects after oral administration of a single 800-mg (â¼100-µCi) dose of [14C]solithromycin. Solithromycin was well tolerated, and absorption from the solution occurred with a median time to peak concentration of 4.0 h. Solithromycin and the total radioactivity had similar profiles with no long-lived metabolites. The whole-blood total radioactivity was approximately 75% of the plasma total radioactivity. Recovery was essentially complete (mean, 90.6%), with 76.5% and 14.1% of the dose recovered in feces and urine, respectively. Unchanged solithromycin (CEM-101) was the predominant circulating radioactive component in plasma (77% of the total radioactivity area under the concentration-time curve [AUC]), with two minor plasma metabolites, CEM-214 and CEM-122 (N-acetyl-CEM-101), each accounting for approximately 5% of the total radioactivity. Urinary excretion was predominantly like that of the parent. Solithromycin was primarily eliminated in the feces after extensive metabolism via a complex metabolic pathway with CEM-262 as the major constituent (27.36% of the administered dose). Overall oxidative pathways, presumably carried out mostly by CYP3A4, represented the majority of the metabolism, with N-acetylation present to a lesser extent. No disproportionate human metabolites were observed.
Sujet(s)
Antibactériens/métabolisme , Antibactériens/pharmacocinétique , Infections communautaires/traitement médicamenteux , Macrolides/métabolisme , Macrolides/pharmacocinétique , Pneumopathie bactérienne/traitement médicamenteux , Triazoles/métabolisme , Triazoles/pharmacocinétique , Adulte , Cytochrome P-450 CYP3A/métabolisme , Humains , Mâle , Taux de clairance métabolique/physiologie , Tests de sensibilité microbienne , Adulte d'âge moyen , Jeune adulteRÉSUMÉ
The activity of solithromycin, a fourth-generation macrolide and novel fluoroketolide, was evaluated by determining its minimum inhibitory concentration (MIC) (via Clinical and Laboratory Standards Institute broth microdilution) against 2797 contemporary clinical respiratory tract isolates collected from North America, Europe, Asia-Pacific and other regions of the world in 2012-13. Solithromycin was very active against Streptococcus pneumoniae and Streptococcus pyogenes, with MIC90 of 0.25 and 0.12 µg/mL, respectively. Isolates with combined macrolide resistance genes ermB and mefE had a higher solithromycin MIC distribution, but the highest MIC recorded was 1 µg/mL for one S. pneumoniae isolate from Japan and one S. pyogenes isolate from China. Solithromycin was active against methicillin-susceptible Staphylococcus aureus (MIC90 0.12 µg/mL) but not against methicillin-resistant S. aureus (MRSA) (MIC90 >32 µg/mL). However, MRSA strains most commonly observed with community-associated infections (i.e. SCCmec IV) were more susceptible than other MRSA SCCmec types. Gram-negative pathogens that cause community-acquired respiratory tract infections (Haemophilus influenzae and Moraxella catarrhalis) were inhibited by solithromycin isolated from worldwide locations (MIC90 2 and 0.25 µg/mL, respectively). These data support the continued development of solithromycin for the treatment of community-acquired pneumonia globally.
Sujet(s)
Antibactériens/pharmacologie , Bactéries/effets des médicaments et des substances chimiques , Infections bactériennes/microbiologie , Macrolides/pharmacologie , Infections de l'appareil respiratoire/microbiologie , Triazoles/pharmacologie , Bactéries/isolement et purification , Santé mondiale , Humains , Tests de sensibilité microbienneRÉSUMÉ
BACKGROUND: Macrolide antibiotics may cause QT prolongation. OBJECTIVES: To study the QT effect of a novel macrolide, solithromycin. METHODS: This was a thorough QT study with a three-way crossover design performed in healthy male and female subjects to evaluate the ECG effects of a novel macrolide, solithromycin. Forty-eight subjects were randomized to receive 800 mg of intravenous (iv) solithromycin, 400 mg of oral moxifloxacin and placebo in three separate treatment periods. Continuous 12 lead ECGs were recorded at a pre-dose baseline and serially after drug administration for 24 h. RESULTS: After the 40 min infusion of 800 mg of solithromycin, the geometric mean solithromycin peak plasma concentration (Cmax) reached 5.9 (SD: 1.30) µg/mL. Solithromycin infusion caused a heart rate increase with a peak effect of 15 bpm immediately after the end of the infusion. The change-from-baseline QTcF (ΔQTcF) was similar after dosing with solithromycin and placebo and the resulting placebo-corrected ΔQTcF (ΔΔQTcF) for solithromycin was therefore small at all timepoints with a peak effect at 4 h of only 2.8 ms (upper bound of the 90% CI: 4.9 ms). Using a linear exposure-response model, a statistically significant, slightly negative slope of -0.86 ms per ng/mL (90% CI: -1.19 to -0.53; Pâ=â0.0001) was observed with solithromycin. The study's ability to detect small QT changes was confirmed by the moxifloxacin response. Solithromycin did not have a clinically meaningful effect on the PR or QRS interval. CONCLUSIONS: The study demonstrated that solithromycin, unlike other macrolide antibiotics, does not cause QT prolongation.
Sujet(s)
Troubles du rythme cardiaque/induit chimiquement , Système de conduction du coeur/effets des médicaments et des substances chimiques , Macrolides/effets indésirables , Triazoles/effets indésirables , Études croisées , Électrocardiographie , Femelle , Fluoroquinolones/usage thérapeutique , Volontaires sains , Humains , Macrolides/sang , Macrolides/usage thérapeutique , Mâle , Moxifloxacine , Placebo/administration et posologie , Triazoles/sang , Triazoles/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Fusidic acid (FA) has been used for decades for bone infection, including prosthetic joint infection (PJI), often in combination with rifampin (RIF). An FA/RIF pharmacokinetic interaction has not previously been described. METHODS: In a phase 2 open-label randomized study, we evaluated oral FA/RIF vs standard-of-care (SOC) intravenous antibiotics for treatment of hip or knee PJI. Outcome assessment occurred at reimplantation (week 12) for subjects with 2-stage exchange, and after 3 or 6 months of treatment for subjects with hip or knee debride and retain strategies, respectively. RESULTS: Fourteen subjects were randomized 1:1 to FA/RIF or SOC. Pharmacokinetic profiles were obtained for 6 subjects randomized to FA/RIF. FA concentrations were lower than anticipated in all subjects during the first week of therapy, and at weeks 4 and 6, blood levels continued to decline. By week 6, FA exposures were 40%-45% lower than expected. CONCLUSIONS: The sponsor elected to terminate this study due to a clearly illustrated drug-drug interaction between FA and RIF, which lowered FA levels to a degree that could influence subject outcomes. Optimization of FA exposure if used in combination with RIF should be a topic of future research. CLINICAL TRIALS REGISTRATION: NCT01756924.
Sujet(s)
Antibactériens/administration et posologie , Infections bactériennes/traitement médicamenteux , Acide fusidique/administration et posologie , Infections dues aux prothèses/traitement médicamenteux , Rifampicine/administration et posologie , Administration par voie orale , Sujet âgé , Sujet âgé de 80 ans ou plus , Antibactériens/pharmacocinétique , Antibactériens/usage thérapeutique , Interactions médicamenteuses , Association de médicaments , Femelle , Acide fusidique/pharmacocinétique , Acide fusidique/usage thérapeutique , Humains , Mâle , Adulte d'âge moyen , Rifampicine/pharmacocinétique , Rifampicine/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Solithromycin, a novel macrolide antibiotic with both intravenous and oral formulations dosed once daily, has completed 2 global phase 3 trials for treatment of community-acquired bacterial pneumonia. METHODS: A total of 863 adults with community-acquired bacterial pneumonia (Pneumonia Outcomes Research Team [PORT] class II-IV) were randomized 1:1 to receive either intravenous-to-oral solithromycin or moxifloxacin for 7 once-daily doses. All patients received 400 mg intravenously on day 1 and were permitted to switch to oral dosing when clinically indicated. The primary objective was to demonstrate noninferiority (10% margin) of solithromycin to moxifloxacin in achievement of early clinical response (ECR) assessed 3 days after first dose in the intent-to-treat (ITT) population. Secondary endpoints included demonstrating noninferiority in ECR in the microbiological ITT population (micro-ITT) and determination of investigator-assessed success rates at the short-term follow-up (SFU) visit 5-10 days posttherapy. RESULTS: In the ITT population, 79.3% of solithromycin patients and 79.7% of moxifloxacin patients achieved ECR (treatment difference, -0.46; 95% confidence interval [CI], -6.1 to 5.2). In the micro-ITT population, 80.3% of solithromycin patients and 79.1% of moxifloxacin patients achieved ECR (treatment difference, 1.26; 95% CI, -8.1 to 10.6). In the ITT population, 84.6% of solithromycin patients and 88.6% of moxifloxacin patients achieved clinical success at SFU based on investigator assessment. Mostly mild/moderate infusion events led to higher incidence of adverse events overall in the solithromycin group. Other adverse events were comparable between treatment groups. CONCLUSIONS: Intravenous-to-oral solithromycin was noninferior to intravenous-to-oral moxifloxacin. Solithromycin has potential to provide an intravenous and oral option for monotherapy for community-acquired bacterial pneumonia. CLINICAL TRIALS REGISTRATION: NCT01968733.
Sujet(s)
Antibactériens/administration et posologie , Infections communautaires/traitement médicamenteux , Infections communautaires/microbiologie , Fluoroquinolones/administration et posologie , Macrolides/administration et posologie , Pneumopathie bactérienne/traitement médicamenteux , Pneumopathie bactérienne/microbiologie , Triazoles/administration et posologie , Administration par voie intraveineuse , Administration par voie orale , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Antibactériens/effets indésirables , Infections communautaires/diagnostic , Comorbidité , Résistance bactérienne aux médicaments , Femelle , Fluoroquinolones/effets indésirables , Humains , Macrolides/effets indésirables , Mâle , Tests de sensibilité microbienne , Adulte d'âge moyen , Moxifloxacine , Pneumopathie bactérienne/diagnostic , Résultat thérapeutique , Triazoles/effets indésirablesRÉSUMÉ
BACKGROUND: Community-acquired bacterial pneumonia (CABP) is a leading cause of morbidity and mortality, and treatment recommendations, each with specific limitations, vary globally. We aimed to compare the efficacy and safety of solithromycin, a novel macrolide, with moxifloxacin for treatment of CABP. METHODS: We did this global, double-blind, double-dummy, randomised, active-controlled, non-inferiority trial at 114 centres in North America, Latin America, Europe, and South Africa. Patients (aged ≥18 years) with clinically and radiographically confirmed pneumonia of Pneumonia Outcomes Research Team (PORT) risk class II, III, or IV were randomly assigned (1:1), via an internet-based central block randomisation procedure (block size of four), to receive either oral solithromycin (800 mg on day 1, 400 mg on days 2-5, placebo on days 6-7) or oral moxifloxacin (400 mg on days 1-7). Randomisation was stratified by geographical region, PORT risk class (II vs III or IV), and medical history of asthma or chronic obstructive pulmonary disease. The study sponsor, investigators, staff, and patients were masked to group allocation. The primary outcome was early clinical response, defined as an improvement in at least two of four symptoms (cough, chest pain, sputum production, dyspnoea) with no worsening in any symptom at 72 h after the first dose of study drug, with a 10% non-inferiority margin. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT-01756339. FINDINGS: Between Jan 3, 2013, and Sept 24, 2014, we randomly assigned 860 patients to receive solithromycin (n=426) or moxifloxacin (n=434). Patients were followed up to days 28-35 after first dose. Solithromycin was non-inferior to moxifloxacin in achievement of early clinical response: 333 (78·2%) patients had an early clinical response in the solithromycin group versus 338 (77·9%) patients in the moxifloxacin group (difference 0·29, 95% CI -5·5 to 6·1). Both drugs had a similar safety profile. 43 (10%) of 155 treatment-emergent adverse events in the solithromycin group and 54 (13%) of 154 such events in the moxifloxacin group were deemed to be related to study drug. The most common adverse events, mostly of mild severity, were gastrointestinal disorders, including diarrhoea (18 [4%] patients in the solithromycin group vs 28 [6%] patients in the moxifloxacin group), nausea (15 [4%] vs 17 [4%] patients) and vomiting (ten [2%] patients in each group); and nervous system disorders, including headache (19 [4%] vs 11 [3%] patients) and dizziness (nine [2%] vs seven [2%] patients). INTERPRETATION: Oral solithromycin was non-inferior to oral moxifloxacin for treatment of patients with CABP, showing the potential to restore macrolide monotherapy for this indication. FUNDING: Cempra.
Sujet(s)
Antibactériens/usage thérapeutique , Infections communautaires/traitement médicamenteux , Fluoroquinolones/usage thérapeutique , Macrolides/usage thérapeutique , Pneumopathie bactérienne/traitement médicamenteux , Triazoles/usage thérapeutique , Adolescent , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Antibactériens/effets indésirables , Méthode en double aveugle , Europe , Femelle , Fluoroquinolones/effets indésirables , Humains , Amérique latine , Macrolides/effets indésirables , Mâle , Adulte d'âge moyen , Moxifloxacine , Amérique du Nord , République d'Afrique du Sud , Triazoles/effets indésirables , Jeune adulteRÉSUMÉ
We assessed the pharmacokinetics and safety of solithromycin, a fluoroketolide antibiotic, in a phase 1, open-label, multicenter study of 13 adolescents with suspected or confirmed bacterial infections. On days 3 to 5, the mean (standard deviation) maximum plasma concentration and area under the concentration versus time curve from 0 to 24 h were 0.74 µg/ml (0.61 µg/ml) and 9.28 µg · h/ml (6.30 µg · h/ml), respectively. The exposure and safety in this small cohort of adolescents were comparable to those for adults. (This study has been registered at ClinicalTrials.gov under registration no. NCT01966055.).
Sujet(s)
Antibactériens/pharmacocinétique , Infections bactériennes/traitement médicamenteux , Macrolides/pharmacocinétique , Triazoles/pharmacocinétique , Adolescent , Adulte , Antibactériens/sang , Aire sous la courbe , Infections bactériennes/sang , Enfant , Dépistage sur goutte de sang séché , Femelle , Humains , Macrolides/sang , Mâle , Sécurité des patients , Triazoles/sangRÉSUMÉ
Selective histone deacetylase (HDAC) inhibitors have emerged as a potential anti-latency therapy for persistent human immunodeficiency virus type 1 (HIV-1) infection. We utilized a combination of small molecule inhibitors and short hairpin (sh)RNA-mediated gene knockdown strategies to delineate the key HDAC(s) to be targeted for selective induction of latent HIV-1 expression. Individual depletion of HDAC3 significantly induced expression from the HIV-1 promoter in the 2D10 latency cell line model. However, depletion of HDAC1 or -2 alone or in combination did not significantly induce HIV-1 expression. Co-depletion of HDAC2 and -3 resulted in a significant increase in expression from the HIV-1 promoter. Furthermore, concurrent knockdown of HDAC1, -2, and -3 resulted in a significant increase in expression from the HIV-1 promoter. Using small molecule HDAC inhibitors of differing selectivity to ablate the residual HDAC activity that remained after (sh)RNA depletion, the effect of depletion of HDAC3 was further enhanced. Enzymatic inhibition of HDAC3 with the selective small-molecule inhibitor BRD3308 activated HIV-1 transcription in the 2D10 cell line. Furthermore, ex vivo exposure to BRD3308 induced outgrowth of HIV-1 from resting CD4+ T cells isolated from antiretroviral-treated, aviremic HIV+ patients. Taken together these findings suggest that HDAC3 is an essential target to disrupt HIV-1 latency, and inhibition of HDAC2 may also contribute to the effort to purge and eradicate latent HIV-1 infection.
Sujet(s)
Agents antiVIH/pharmacologie , Lymphocytes T CD4+/effets des médicaments et des substances chimiques , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/physiologie , Histone Deacetylase 1/génétique , Histone Deacetylase 2/génétique , Inhibiteurs de désacétylase d'histone/pharmacologie , Histone deacetylases/génétique , Lymphocytes T CD4+/enzymologie , Lymphocytes T CD4+/virologie , Lignée de cellules transformées , Délétion de gène , Régulation de l'expression des gènes , Infections à VIH/traitement médicamenteux , Infections à VIH/enzymologie , Infections à VIH/génétique , Infections à VIH/virologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/pathogénicité , Histone Deacetylase 1/antagonistes et inhibiteurs , Histone Deacetylase 1/déficit , Histone Deacetylase 2/antagonistes et inhibiteurs , Histone Deacetylase 2/déficit , Histone deacetylases/déficit , Interactions hôte-pathogène , Humains , Régions promotrices (génétique) , Petit ARN interférent/génétique , Petit ARN interférent/métabolisme , Transduction du signal , Latence viraleRÉSUMÉ
Latent HIV proviruses are silenced as the result of deacetylation and methylation of histones located at the viral long terminal repeat (LTR). Inhibition of histone deacetylases (HDACs) leads to the reemergence of HIV-1 from latency, but the contribution of histone lysine methyltransferases (HKMTs) to maintaining HIV latency remains uncertain. Chromatin immunoprecipitation experiments using latently infected Jurkat T-cell lines demonstrated that the HKMT enhancer of Zeste 2 (EZH2) was present at high levels at the LTR of silenced HIV proviruses and was rapidly displaced following proviral reactivation. Knockdown of EZH2, a key component of the Polycomb repressive complex 2 (PRC2) silencing machinery, and the enzyme which is required for trimethyl histone lysine 27 (H3K27me3) synthesis induced up to 40% of the latent HIV proviruses. In contrast, there was less than 5% induction of latent proviruses following knockdown of SUV39H1, which is required for H3K9me3 synthesis. Knockdown of EZH2 also sensitized latent proviruses to external stimuli, such as T-cell receptor stimulation, and slowed the reversion of reactivated proviruses to latency. Similarly, cell populations that responded poorly to external stimuli carried HIV proviruses that were enriched in H3K27me3 and relatively depleted in H3K9me3. Treating latently infected cells with the HKMT inhibitor 3-deazaneplanocin A, which targets EZH2, led to the reactivation of silenced proviruses, whereas chaetocin and BIX01294 showed only minimal reactivation activities. These findings suggest that PRC2-mediated silencing is an important feature of HIV latency and that inhibitors of histone methylation may play a useful role in induction strategies designed to eradicate latent HIV pools.
Sujet(s)
Protéines de liaison à l'ADN/métabolisme , Épigenèse génétique , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/pathogénicité , Histone-lysine N-methyltransferase/métabolisme , Histone/métabolisme , Lysine/métabolisme , Facteurs de transcription/métabolisme , Latence virale , Immunoprécipitation de la chromatine , Protéines de liaison à l'ADN/génétique , Protéine-2 homologue de l'activateur de Zeste , Techniques de knock-down de gènes , Infections à VIH/virologie , Humains , Cellules Jurkat , Complexe répresseur Polycomb-2 , Facteurs de transcription/génétiqueRÉSUMÉ
Given the scope of the human immunodeficiency virus (HIV) pandemic, millions of people will need of chronic antiretroviral therapy (ART) for decades into the future. It is hoped that progress in prevention of HIV infection can be made, but there have been few successes in this effort thus far. ART also presents formidable problems. Therefore, research must continue on improvements in prevention and treatment, but future HIV research should now also seek to develop temporally contained therapies capable of eradicating HIV infection. This review will explore what is known about the mechanisms that restrain HIV expression and result in persistent, latent proviral infection, and what these mechanisms tell us about potential approaches towards eradication of HIV infection.
Sujet(s)
Agents antiVIH/usage thérapeutique , Thérapie antirétrovirale hautement active/méthodes , Infections à VIH/traitement médicamenteux , Animaux , Agents antiVIH/pharmacologie , Systèmes de délivrance de médicaments , VIH (Virus de l'Immunodéficience Humaine)/effets des médicaments et des substances chimiques , VIH (Virus de l'Immunodéficience Humaine)/métabolisme , Infections à VIH/prévention et contrôle , Infections à VIH/virologie , HumainsRÉSUMÉ
OBJECTIVES: A family of histone deacetylases (HDACs) mediates chromatin remodeling, and repression of gene expression. Deacetylation of histones within the HIV-1 long terminal repeat (LTR) by HDACs plays a key role in the maintenance of latency, whereas acetylation of histones about the LTR is linked to proviral expression and escape of HIV from latency. Global HDAC inhibition may adversely affect host gene expression, leading to cellular toxicities. Potent inhibitors selective for HDACs that maintain LTR repression could be ideal antilatency therapeutics. METHODS: We investigated the ability of selective HDAC inhibitors to de-repress the HIV-1 LTR in both a cell line model of latency and in resting CD4 T cells isolated from patients who were aviremic on antiretroviral therapy (ART). RESULTS: We found that inhibition of class I HDACs increased acetylation of histones at the LTR, but that LTR chromatin was unaffected by class II HDAC inhibitors. In a latently infected cell line, inhibitors selective for class I HDACs were more efficient activators of the LTR than inhibitors that target class II HDACs. Class I HDAC inhibitors were strikingly efficient inducers of virus outgrowth from resting CD4 T cells of aviremic patients, whereas HIV was rarely recovered from patient's cells exposed to class II HDAC inhibitors. CONCLUSIONS: Further development of selective HDAC inhibitors as part of a clinical strategy to target persistent HIV infection is warranted.
Sujet(s)
Antienzymes/pharmacologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , Inhibiteurs de désacétylase d'histone , Latence virale/effets des médicaments et des substances chimiques , Lymphocytes T CD4+/virologie , Cellules cultivées , Chromatine/métabolisme , Évaluation préclinique de médicament/méthodes , Répétition terminale longue du VIH/effets des médicaments et des substances chimiques , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/enzymologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/génétique , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/physiologie , Cellules HeLa , Histone Deacetylase 1/antagonistes et inhibiteurs , Histone Deacetylase 1/physiologie , Humains , Cellules Jurkat , Réplication virale/effets des médicaments et des substances chimiquesRÉSUMÉ
Silencing of the integrated human immunodeficiency virus type 1 (HIV-1) genome in resting CD4(+) T cells is a significant contributor to the persistence of infection, allowing the virus to evade both immune detection and pharmaceutical attack. Nonselective histone deacetylase (HDAC) inhibitors are capable of inducing expression of quiescent HIV-1 in latently infected cells. However, potent global HDAC inhibition can induce host toxicity. To determine the specific HDACs that regulate HIV-1 transcription, we evaluated HDAC1 to HDAC11 RNA expression and protein expression and compartmentalization in the resting CD4(+) T cells of HIV-1-positive, aviremic patients. HDAC1, -3, and -7 had the highest mRNA expression levels in these cells. Although all HDACs were detected in resting CD4(+) T cells by Western blot analysis, HDAC5, -8, and -11 were primarily sequestered in the cytoplasm. Using chromatin immunoprecipitation assays, we detected HDAC1, -2, and -3 at the HIV-1 promoter in Jurkat J89GFP cells. Targeted inhibition of HDACs by small interfering RNA demonstrated that HDAC2 and HDAC3 contribute to repression of HIV-1 long terminal repeat expression in the HeLa P4/R5 cell line model of latency. Together, these results suggest that HDAC inhibitors specific for a limited number of class I HDACs may offer a targeted approach to the disruption of persistent HIV-1 infection.