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Human APOBEC3G-mediated hypermutation is associated with antiretroviral therapy failure in HIV-1 subtype C-infected individuals.

ABSTRACT: Human APOBEC3G/F (hA3G/F) restricts retroviral replication through G-to-A hypermutations, which can generate drug-resistant progenies in vitro. The clinical relevance is still inconclusive. To bridge this gap, we aim to study the role of these hypermutations in evolution of drug resistance; we characterised hA3G/F-mediated hypermutations in the RT region of the pol gene of patients with or without antiretroviral therapy (ART).In 88 HIV-1-positive individuals, drug resistance genotyping was carried out in plasma virus and provirus by population sequencing. Hypermutations were determined by three different approaches using Hypermut 2.0 software, cluster analysis and APOBEC3G-mediated defectives indices. Clinical and demographic characteristics of these individuals were studied in relation to these hypermutations.hA3G/F-mediated hypermutated sequences in proviral DNA, but not in plasma virus, were identified in 11.4% (10/88) subjects. Proviral hypermutations were observed more frequently in patients with ART failure than in ART-naïve individuals (p=0.03). In therapy failure patients, proviral hypermutation were associated with greater intra-compartmental genetic diversity (p<0.001). In therapy-naïve individuals, hypermutated proviral DNA with M184I and M230I mutations due to the editing of hA3G, had stop codons in the open reading frames and the same mutations were absent in the plasma virus. Only a limited concordance was found between the drug resistance mutations in plasma RNA and proviral DNA.hA3G lethal hypermutation was significantly associated with ART failure in Indian HIV-1 subtype C patients. It is unlikely that viral variants, which exhibit hypermutated sequences and M184I and/or M230I, will mature and expand in vivo.

SUBMITTER: Neogi U

PROVIDER: S-EPMC3582697 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Human APOBEC3G-mediated hypermutation is associated with antiretroviral therapy failure in HIV-1 subtype C-infected individuals.

Neogi Ujjwal U Shet Anita A Sahoo Pravat Nalini PN Bontell Irene I Ekstrand Maria L ML Banerjea Akhil C AC Sonnerborg Anders A

Journal of the International AIDS Society 20130225

<h4>Introduction</h4>Human APOBEC3G/F (hA3G/F) restricts retroviral replication through G-to-A hypermutations, which can generate drug-resistant progenies in vitro. The clinical relevance is still inconclusive. To bridge this gap, we aim to study the role of these hypermutations in evolution of drug resistance; we characterised hA3G/F-mediated hypermutations in the RT region of the pol gene of patients with or without antiretroviral therapy (ART).<h4>Methods</h4>In 88 HIV-1-positive individuals, ...[more]

PMID: 23443042

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Project description:BACKGROUND:Metabolic complications in human immunodeficiency virus (HIV)-infected individuals are common. Prediabetes represents a high risk for future diabetes development. This study aimed to determine the prevalence, diagnostic methods, and associated factors of prediabetes among HIV-infected individuals receiving antiretroviral therapy (ART). METHODS:A cross-sectional study was conducted among HIV-infected adults without a history of diabetes who were receiving ART. Fasting plasma glucose (FPG), 2-hour plasma glucose (2-h PG) after a 75-g oral glucose tolerance test, and hemoglobin A1c (HbA1c) were assessed. RESULTS:A total of 397 patients with a mean age of 47.0?±?9.8 years and 55.7% male, were studied. All received ART with undetectable plasma viral load. The mean duration of ART was 9.6?±?5.2 years, and the mean CD4 cell count was 554?±?235 cells/mm3. Among the patients, 28 (7.1%) had first-diagnosed diabetes, and 133 (33.5%) patients had prediabetes. Glycemia estimation by FPG, 2-h PG, and HbA1c showed a prediabetes prevalence of 17.4%, 14.7%, and 12.5%, respectively. The kappa statistics for the agreement of FPG and 2-h PG, HbA1c and 2-h PG, and HbA1c and FPG were 0.317, 0.429, and 0.396, respectively. In multivariate analysis, hypertension [odds ratio (OR) 3.38; 95% confidence interval (CI), 1.16-9.91; p?=?0.026), and triglycerides?>?150 mg/dL (OR 2.11; 95% CI, 1.01-4.44; p?=?0.047) were factors significantly associated with prediabetes. CONCLUSIONS:Prediabetes among HIV-infected individuals receiving ART is common. The agreements of glycemia estimation methods are minimal to weak. HbA1c may underestimate prediabetes prevalence. Using FPG together with HbA1c increases the detection rate to approximately three-quarters of prediabetes patients. HIV-infected individuals who had hypertension and hypertriglyceridemia should be regularly assessed for prediabetes. Trial registration ClinicalTrial.gov, NCT03545217. Registered 1 June 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03545217.

Project description:BackgroundAntiretroviral treatment (ART) regimens in HIV patients commonly cause significant lipid elevations, including increases in both triglycerides and cholesterol. Standard treatments for hypercholesterolemia include the HMG CoA reductase inhibitors, or "statins." Because many ART agents and statins share a common metabolic pathway that uses the cytochrome P450 enzyme system, coadministration of ART with statins could increase statin plasma levels significantly. The oyster mushroom, Pleurotus ostreatus, has been shown in animal models to decrease lipid levels--a finding that has been supported by preliminary data in a small human trial.MethodsTo assess the safety and efficacy of P. ostreatus in patients with HIV and ART-induced hyperlipidemia, a single-arm, open-label, proof-of-concept study of 8 weeks' duration with a target enrollment of 20 subjects was conducted. Study patients with ART-induced elevated non-HDL cholesterol levels (> 160 mg/dL) were enrolled. Participants received packets of freeze-dried P. ostreatus (15 gm/day) to be administered orally for the 8 week trial period. Lipid levels were drawn every two weeks to assess efficacy. Safety assessments included self-reported incidence of muscle aches and measurement of liver and muscle enzymes. Mean within-person change in lipid levels were estimated using generalized estimating equations to account for repeated observations on individuals. A 30 mg/dL decrease in non-HDL cholesterol was deemed clinically significant.Results126 patients were screened to enroll 25, of which 20 completed the 8-week study. The mean age was 46.4 years (36-60). Patients had a mean 13.7 yrs of HIV infection. Mean non-HDL cholesterol was 204.5 mg/dL at day 0 and 200.2 mg/dL at day 56 (mean within-person change = -1.70; 95% confidence interval (CI) = -17.4, 14.0). HDL cholesterol levels increased from 37.8 mg/dL at day 0 to 40.4 mg/dL on day 56 (mean within-person change = 2.6; 95% CI = -0.1, 5.2). Triglycerides dropped from 336.4 mg/dL on day 0 to 273.4 mg/dL on day 56 (mean within-person change = -63.0; 95% CI = -120.9, -5.1). Only 3 individuals achieved a sustained clinically significant (30 mg/dL) decline in non-HDL cholesterol after 8 weeks of therapy. There were no adverse experiences reported other than patients' distaste for the preparation. Liver function tests and muscle enzymes were not affected by the 8 weeks of treatment.ConclusionsPleurotus ostreatus as administered in this experiment did not lower non-HDL cholesterol in HIV patients with ART-induced hypercholesterolemia. Small changes in HDL and triglycerides were not of a clinical magnitude to warrant further study.

Project description:BackgroundCoenzyme Q10 (CoQ10) deficiency has been associated with statin-induced myopathy, and supplementation with CoQ10 may reduce inflammation markers. The effects of statins on CoQ10 and its anti-inflammatory properties have not been investigated in HIV-positive patients.ObjectiveThe objectives of this study were to examine the effect of rosuvastatin on CoQ10 and CoQ10/LDL ratio over 24-week SATURN-HIV trial, explore the associations between CoQ10 levels and markers of vascular disease, inflammation, and immune activation, and assess whether changes in CoQ10 affected the anti-inflammatory effects of statin therapy or were associated with myalgia symptoms.MethodsThis was a secondary analysis of the SATURN-HIV trial, a 96-week randomized clinical trial of 10 mg daily rosuvastatin vs. placebo in HIV-infected patients on antiretroviral therapy. We assessed the statin treatment effect on CoQ10 levels and CoQ10/LDL ratios and whether changes in these markers were related to myalgias. Relationships between CoQ10, subclinical vascular disease, and biomarkers of inflammation and immune activation were explored using Spearman correlations and multivariable regression models.ResultsOverall, 147 patients were included. Median age was 46 years; 78% were male and 68% African American. At baseline, CoQ10 levels and CoQ10/LDL ratio were modestly correlated with markers of HIV disease, immune activation, and carotid distensibility. After 24 weeks of statin therapy, CoQ10 levels decreased (p = 0.002 for between group difference) and CoQ10/LDL ratio increased (p = 0.036). In the statin treatment arm, we did not find evidence of a relationship between changes in CoQ10 or CoQ10/LDL ration and changes in markers of inflammation or immune activation. There was a borderline statistically significant association between changes in CoQ10 and myalgia symptoms [OR 4.0 per 0.1 mg/L decrease in CoQ10, p = 0.07].ConclusionTwenty-four weeks of 10 mg daily rosuvastatin decreases CoQ10 concentration and increases CoQ10/LDL ratio in HIV-infected patients on antiretroviral therapy.

Project description:Cardiovascular disease and non-AIDS malignancies have become major causes of death among HIV-infected individuals. The relative impact of lifestyle and HIV-related factors are debated.We estimated associations of smoking with mortality more than 1 year after antiretroviral therapy (ART) initiation among HIV-infected individuals enrolled in European and North American cohorts. IDUs were excluded. Causes of death were assigned using standardized procedures. We used abridged life tables to estimate life expectancies. Life-years lost to HIV were estimated by comparison with the French background population.Among 17,995 HIV-infected individuals followed for 79,760 person-years, the proportion of smokers was 60%. The mortality rate ratio (MRR) comparing smokers with nonsmokers was 1.94 [95% confidence interval (95% CI) 1.56-2.41]. The MRRs comparing current and previous smokers with never smokers were 1.70 (95% CI 1.23-2.34) and 0.92 (95% CI 0.64-1.34), respectively. Smokers had substantially higher mortality from cardiovascular disease, non-AIDS malignancies than nonsmokers [MRR 6.28 (95% CI 2.19-18.0) and 3.31 (95% CI 1.80-5.45), respectively]. [corrected]. Among 35-year-old HIV-infected men, the loss of life-years associated with smoking and HIV was 7.9 (95% CI 7.1-8.7) and 5.9 (95% CI 4.9-6.9), respectively. The life expectancy of virally suppressed, never-smokers was 43.5 years (95% CI 41.7-45.3), compared with 44.4 years among 35-year-old men in the background population. Excess MRRs/1000 person-years associated with smoking increased from 0.6 (95% CI -1.3 to 2.6) at age 35 to 43.6 (95% CI 37.9-49.3) at age at least 65 years.Well treated HIV-infected individuals may lose more life years through smoking than through HIV. Excess mortality associated with smoking increases markedly with age. Therefore, increases in smoking-related mortality can be expected as the treated HIV-infected population ages. Interventions for smoking cessation should be prioritized.

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Human APOBEC3G-mediated hypermutation is associated with antiretroviral therapy failure in HIV-1 subtype C-infected individuals.

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Human APOBEC3G-mediated hypermutation is associated with antiretroviral therapy failure in HIV-1 subtype C-infected individuals.

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