RESUMEN
BACKGROUND: Human immunodeficiency virus (HIV) infection induces epigenetic age acceleration (EAA), but it remains unclear whether epigenetic aging continues to accelerate during successful antiretroviral therapy (ART) and prolonged virological suppression. METHODS: We longitudinally analyzed 63 long-term aviremic HIV-infected adults. Using blood DNA methylation patterns, we calculated EAA measures based on 3 epigenetic clocks (Horvath's clock, PhenoAge, and GrimAge). We recorded the emergence of serious AIDS-related and non-AIDS-related events throughout the study to assess its association with EAA. RESULTS: All participants were on stable ART and were virologically suppressed. After 4 years of follow-up, PhenoAge-EAA and GrimAge-EAA showed no differences, whereas Horvath-EAA slightly decreased (median difference, -0.53 years; P = .015). Longitudinal changes in EAA measures were independent of changes in CD4 cell counts, the ART regimen, or other HIV-related factors. Nineteen percent of participants experienced a serious clinical event during the study. Horvath-EAA was significantly higher at baseline in participants with clinical events (P = .027). After adjusting for confounders, we found a trend toward an association of higher levels of all EAA measures at baseline with serious clinical events. CONCLUSIONS: Epigenetic aging did not accelerate in long-term aviremic HIV-infected adults after 4 years of successful ART. EAA measures deserve further study as potential tools for predicting clinical events.
Asunto(s)
Envejecimiento/genética , Terapia Antirretroviral Altamente Activa/métodos , Epigénesis Genética , Infecciones por VIH/tratamiento farmacológico , Adulto , Antirretrovirales/uso terapéutico , Terapia Antirretroviral Altamente Activa/efectos adversos , Epigenómica , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: To evaluate whether the negative impact of tenofovir on telomere length (TL) is due to immune reconstitution interference or inhibition of telomerase. METHODS: One hundred and twenty-eight long-term aviraemic HIV adults treated with tenofovir-containing (n = 79) or tenofovir-sparing regimens (n = 49) were recruited to compare the following: TL in whole blood, PBMCs, CD4+ T cells and CD8+ T cells by quantitative PCR (qPCR); telomerase activity in PBMCs, CD4+ cells and CD8+ T cells using the TRAPeze RT Telomerase Detection Kit; and T cell maturational subset distribution by flow cytometry. RESULTS: In an adjusted analysis, participants treated with tenofovir for at least 4 years had shorter TL in CD8+ T cells (P = 0.04) and lower telomerase activity in CD4+ (P = 0.012) and CD8+ T cells (P = 0.023). Tenofovir treatment was also associated with lower proportions of recent thymic emigrant (RTE) CD4+ cells (P = 0.031) and PD1 marker expression (P = 0.013). CONCLUSIONS: In long-term aviraemic HIV adults, the inhibition of telomerase by tenofovir could explain telomere shortening in CD8+ T cells. There is no telomere shortening in the CD4+ compartment and the decrease in telomerase activity could be explained both by the inhibition by tenofovir and by the lower proportion of RTE CD4+cells.
Asunto(s)
Infecciones por VIH , Telomerasa , Adulto , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos , Humanos , Telomerasa/metabolismo , Telómero/metabolismo , Tenofovir/uso terapéuticoRESUMEN
BACKGROUND: Previously selected lamivudine resistance-associated mutations (RAMs) may remain archived within the proviral HIV-DNA. OBJECTIVES: To evaluate the ability of proviral DNA genotyping to detect lamivudine RAMs in HIV-1 virologically suppressed participants; the correlation between Sanger and next generation sequencing (NGS); and predictive factors for detection of lamivudine RAMs in proviral DNA. METHODS: Cross-sectional study of participants on stable antiretroviral therapy and suppressed for ≥1 year. Analysis of proviral DNA was performed by Sanger sequencing in whole blood and by NGS in PBMCs. RESULTS: We analysed samples from 102 subjects (52 with and 50 without lamivudine RAMs in historical plasma RNA-genotypes). Among participants with previous lamivudine resistance, Sanger sequencing detected RAMs in 26.9%. Detection rates significantly increased using NGS: 47.9%, 64.6%, 75% and 87.5% with the 20%, 10%, 5% and 1% thresholds, respectively. As for participants without historical lamivudine resistance, Sanger detected the RAMs in 1/49 (2%), and NGS (5% threshold) in 8/45 (17.8%). Multivariate models fitted to the whole population revealed that having a history of lamivudine resistance was a risk factor for detection of lamivudine RAMs by NGS. Among participants with historical lamivudine resistance, multivariate analysis showed that a longer time since HIV diagnosis was associated with persistence of archived mutations by NGS at thresholds of >10% [OR 1.10 (95% CI: 1.00-1.24)] and >5% [OR 1.16 (95% CI: 1.02-1.32)]. CONCLUSIONS: Proviral DNA Sanger sequencing does not detect the majority of historical lamivudine RAMs. NGS increases the sensitivity of detection at lower thresholds, although the relevance of these minority populations with lamivudine RAMs needs further evaluation.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Fármacos Anti-VIH/uso terapéutico , Estudios Transversales , Farmacorresistencia Viral , Genotipo , Técnicas de Genotipaje , Infecciones por VIH/tratamiento farmacológico , Humanos , Lamivudine/uso terapéutico , Mutación , Carga ViralRESUMEN
Background: Tenofovir is a potent inhibitor of human telomerase. The clinical relevance of this inhibition is unknown. Methods: NEAT001/ANRS143 is a randomized trial that showed noninferiority over 96 weeks of ritonavir-boosted darunavir plus raltegravir versus tenofovir disoproxil fumarate/emtricitabine in 805 antiretroviral antiretrovrial-naive HIV-infected adults. We compared changes in whole-blood telomere length measured with quantitative polymerase chain reaction in 201 randomly selected participants (104 raltegravir and 97 tenofovir disoproxil fumarate/emtricitabine). We performed multivariable estimative and predictive linear regression. Results: At week 96, participants receiving tenofovir disoproxil fumarate/emtricitabine had a statistically significant higher gain in telomere length than participants receiving raltegravir. Difference in mean telomere length change between groups (tenofovir disoproxil fumarate/emtricitabine minus raltegravir) from baseline to week 96 adjusted by baseline telomere length was 0.031 (P = .009). This difference was not significantly confounded by age, gender, known duration of HIV infection, CD4 (baseline/nadir), CD8 cells, CD4/CD8 ratio, HIV viral load (baseline/week 96), tobacco and alcohol consumption, statins, or hepatitis C. Conclusion: Antiretroviral-naive HIV-infected adults receiving ritonavir-boosted darunavir and tenofovir disoproxil fumarate/emtricitabine had a significant higher gain in blood telomere length than those receiving ritonavir-boosted darunavir and raltegravir, suggesting a better initial recovery from HIV-associated immunosenescence.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Telómero/efectos de los fármacos , Adulto , Análisis de Varianza , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , ADN/sangre , Darunavir/administración & dosificación , Darunavir/farmacología , Darunavir/uso terapéutico , Emtricitabina/administración & dosificación , Emtricitabina/farmacología , Emtricitabina/uso terapéutico , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/genética , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Raltegravir Potásico/administración & dosificación , Raltegravir Potásico/farmacología , Raltegravir Potásico/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Ritonavir/administración & dosificación , Ritonavir/farmacología , Ritonavir/uso terapéutico , Tenofovir/administración & dosificación , Tenofovir/farmacología , Tenofovir/uso terapéuticoRESUMEN
Background: Tenofovir is a potent inhibitor of human telomerase. The clinical relevance of this inhibition is unknown. Methods: A prospective cohort of human immunodeficiency virus (HIV)-infected participants with suppressed virological replication was recruited to compare whole-blood telomere length (measured by quantitative multiplex polymerase chain reaction analysis) in participants with current exposure to tenofovir disoproxil fumarate (TDF) to that in participants never exposed to TDF. Results: A total of 172 participants were included: 67 were in the TDF group, and 105 were in the non-TDF group (75 were receiving 2 nucleosides [of whom 69 were receiving abacavir], 25 were receiving a nucleos[t]ide reverse transcriptase inhibitor [N{t}RTI]-sparing regimen, and 5 were receiving lamivudine as the only nucleoside). After 2 years, the mean blood telomere length increased significantly in the whole cohort. The TDF group had significantly smaller gains in telomere length than the non-TDF group. In the analysis restricted to participants receiving N(t)RTIs, TDF exposure was not associated with an independent negative effect. In the non-TDF group, participants treated with 2 nucleosides also had significantly smaller gains in telomere length than those receiving N(t)RTI-sparing regimens or lamivudine as the only nucleoside. Discussion: In HIV-infected adults with prolonged virological suppression, treatment with TDF or abacavir was associated with smaller gains in blood telomere length after 2 years of follow-up.
Asunto(s)
Infecciones por VIH , Inhibidores de la Transcriptasa Inversa , Telómero/efectos de los fármacos , Adulto , Didesoxinucleósidos/farmacología , Didesoxinucleósidos/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Telomerasa , Tenofovir/farmacología , Tenofovir/uso terapéutico , Carga ViralRESUMEN
Several factors are involved in the control of HIV transcription/replication, including epigenetic modifications at the promoter level. Analysis of the HIV long terminal repeat (LTR) methylation status in infected patients controlling viremia is scarce. Herein, we show a higher degree of DNA methylation in the 5'-LTR of long-term nonprogressor and elite controller (LTNP/EC) versus progressor patients and a positive correlation with time of infection, indicating a certain contribution of HIV LTR silencing in reducing the number of replicating viruses which may account for a delayed progression.
Asunto(s)
Metilación de ADN , Epigénesis Genética/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Viremia/prevención & control , Terapia Antirretroviral Altamente Activa , Infecciones por VIH/sangre , Duplicado del Terminal Largo de VIH/genética , Sobrevivientes de VIH a Largo Plazo , Humanos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/virología , Filogenia , Provirus/genética , Viremia/genéticaRESUMEN
We investigated whether blood telomere length (TL), epigenetic age acceleration (EAA), and soluble inflammatory monocyte cytokines are associated with cardiovascular events or diabetes (DM) in people living with HIV (PLHIV). This was a case-control study nested in the Spanish HIV/AIDS Cohort (CoRIS). Cases with myocardial infarction, stroke, sudden death, or diabetes after starting antiretroviral therapy were included with the available samples and controls matched for sex, age, tobacco use, pre-ART CD4 cell count, viral load, and sample time-point. TL (T/S ratio) was analysed by quantitative PCR and EAA with DNA methylation changes by next-generation sequencing using the Weidner formula. Conditional logistic regression was used to explore the association with cardiometabolic events. In total, 180 participants (94 cases (22 myocardial infarction/sudden death, 12 strokes, and 60 DM) and 94 controls) were included. Of these, 84% were male, median (IQR) age 46 years (40-56), 53% were current smokers, and 22% had CD4 count ≤ 200 cells/mm3 and a median (IQR) log viral load of 4.52 (3.77-5.09). TL and EAA were similar in the cases and controls. There were no significant associations between TL, EAA, and monocyte cytokines with cardiometabolic events. TL and EAA were mildly negatively correlated with sCD14 (rho = -0.23; p = 0.01) and CCL2/MCP-1 (rho = -0.17; p = 0.02). We found no associations between TL, EAA, and monocyte cytokines with cardiovascular events or diabetes. Further studies are needed to elucidate the clinical value of epigenetic biomarkers and TL in PLHIV.
RESUMEN
BACKGROUND: Previous epigenome-wide association studies have shown that HIV infection can disrupt the host DNA methylation landscape. However, it remains unclear how antiretroviral therapy (ART) affects the HIV-induced epigenetic modifications. METHODS: 184 individuals with HIV from the NEAT001/ANRS143 clinical trial (with pre-ART and post-ART samples [96 weeks of follow-up]) and 44 age-and-sex matched individuals without HIV were included. We compared genome-wide DNA methylation profiles in whole blood between groups adjusting for age, sex, batch effects, and DNA methylation-based estimates of leucocyte composition. FINDINGS: We identified 430 differentially methylated positions (DMPs) between HIV+ pre-ART individuals and HIV-uninfected controls. In participants with HIV, ART initiation modified the DNA methylation levels at 845 CpG positions and restored 49.3% of the changes found between HIV+ pre-ART and HIV-uninfected individuals. We only found 15 DMPs when comparing DNA methylation profiles between HIV+ post-ART individuals and participants without HIV. The Gene Ontology enrichment analysis of DMPs associated with untreated HIV infection revealed an enrichment in biological processes regulating the immune system and antiviral responses. In participants with untreated HIV infection, DNA methylation levels at top HIV-related DMPs were associated with CD4/CD8 ratios and viral loads. Changes in DNA methylation levels after ART initiation were weakly correlated with changes in CD4+ cell counts and the CD4/CD8 ratio. INTERPRETATION: Control of HIV viraemia after 96 weeks of ART initiation partly restores the host DNA methylation changes that occurred before antiretroviral treatment of HIV infection. FUNDING: NEAT-ID Foundation and Instituto de Salud Carlos III, co-funded by European Union.
Asunto(s)
Metilación de ADN , Infecciones por VIH , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Epigénesis Genética , Recuento de Linfocito CD4 , Relación CD4-CD8 , ADN , Antirretrovirales/uso terapéuticoRESUMEN
BACKGROUND: Accelerated epigenetic ageing can occur in untreated HIV infection and is partially reversible with effective antiretroviral therapy (ART). We aimed to make a long-term comparison of epigenetic ageing dynamics in people with HIV during untreated HIV infection and during suppressive ART. METHODS: In this longitudinal study, conducted over 17 years in HIV outpatient clinics in Switzerland, we applied 5 established epigenetic age estimators (epigenetic clocks) in peripheral blood mononuclear cells (PBMCs) in Swiss HIV Cohort Study participants before or during suppressive ART. All participants had a longitudinal set of PBMC samples available at four timepoints (T1-T4). T1 and T2 had to be 3 years or longer apart, as did T3 and T4. We assessed epigenetic age acceleration (EAA) and a novel rate of epigenetic ageing. FINDINGS: Between March 13, 1990, and Jan 18, 2018, we recruited 81 people with HIV from the Swiss HIV Cohort Study. We excluded one participant because a sample did not meet quality checks (transmission error). 52 (65%) of 80 patients were men, 76 (95%) were white, and the median patient age was 43 (IQR 37·5-47) years. Per year of untreated HIV infection (median observation 8·08 years, IQR 4·83-11·09), mean EAA was 0·47 years (95% CI 0·37 to 0·57) for Horvath's clock, 0·43 years (0·3 to 0·57) for Hannum's clock, 0·36 years (0·27 to 0·44) for SkinBlood clock, and 0·69 years (0·51 to 0·86) for PhenoAge. Per year of suppressive ART (median observation 9·8 years, IQR 7·2-11), mean EAA was -0·35 years (95% CI -0·44 to -0·27) for Horvath's clock, -0·39 years (-0·50 to -0·27) for Hannum's clock, -0·26 years (-0·33 to -0·18) for SkinBlood clock, and -0·49 years (-0·64 to -0·35) for PhenoAge. Our findings indicate that people with HIV epigenetically aged by a mean of 1·47 years for Horvath's clock, 1·43 years for Hannum's clock, 1·36 years for SkinBlood clock, and 1·69 years for PhenoAge per year of untreated HIV infection; and 0·65 years for Horvath's clock, 0·61 years for Hannum's clock, 0·74 years for SkinBlood clock, and 0·51 years for PhenoAge, per year of suppressive ART. GrimAge showed some change in the mean EAA during untreated HIV infection (0·10 years, 0·02 to 0·19) and suppressive ART (-0·05 years, -0·12 to 0·02). We obtained very similar results using the rate of epigenetic ageing. Contribution of multiple HIV-related, antiretroviral, and immunological variables, and of a DNA methylation-associated polygenic risk score to EAA was small. INTERPRETATION: In a longitudinal study over more than 17 years, epigenetic ageing accelerated during untreated HIV infection and decelerated during suppressive ART, highlighting the importance of limiting the duration of untreated HIV infection. FUNDING: Swiss HIV Cohort Study, Swiss National Science Foundation, and Gilead Sciences.
Asunto(s)
Infecciones por VIH , Leucocitos Mononucleares , Masculino , Humanos , Anciano , Femenino , Estudios Longitudinales , Estudios de Cohortes , Suiza/epidemiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/genética , Envejecimiento/genética , Epigénesis GenéticaRESUMEN
Human immunodeficiency virus type 2 (HIV-2) emerged in West Africa and has spread further to countries that share socio-historical ties with this region. However, viral origins and dispersal patterns at a global scale remain poorly understood. Here, we adopt a Bayesian phylogeographic approach to investigate the spatial dynamics of HIV-2 group A (HIV-2A) using a collection of 320 partial pol and 248 partial env sequences sampled throughout 19 countries worldwide. We extend phylogenetic diffusion models that simultaneously draw information from multiple loci to estimate location states throughout distinct phylogenies and explicitly attempt to incorporate human migratory fluxes. Our study highlights that Guinea-Bissau, together with Côte d'Ivoire and Senegal, have acted as the main viral sources in the early stages of the epidemic. We show that convenience sampling can obfuscate the estimation of the spatial root of HIV-2A. We explicitly attempt to circumvent this by incorporating rate priors that reflect the ratio of human flow from and to West Africa. We recover four main routes of HIV-2A dispersal that are laid out along colonial ties: Guinea-Bissau and Cape Verde to Portugal, Côte d'Ivoire and Senegal to France. Within Europe, we find strong support for epidemiological linkage from Portugal to Luxembourg and to the UK. We demonstrate that probabilistic models can uncover global patterns of HIV-2A dispersal providing sampling bias is taken into account and we provide a scenario for the international spread of this virus.
Asunto(s)
Infecciones por VIH/historia , VIH-2/genética , África Occidental , Teorema de Bayes , Cabo Verde , Colonialismo/historia , Côte d'Ivoire , Genes Virales/genética , Genoma Viral/genética , Guinea Bissau , Infecciones por VIH/virología , Historia del Siglo XX , Humanos , Datos de Secuencia Molecular , Filogeografía , SenegalRESUMEN
The antiretroviral treatment (ART) developed to control HIV infection led to a revolution in the prognosis of people living with HIV (PLWH). PLWH underwent from suffering severe disease and often fatal complications at young ages to having a chronic condition and a life expectancy close to the general population. Nevertheless, chronic age-related diseases increase as PLWH age. The harmful effect of HIV infection on the individual's immune system adds to its deterioration during ageing, exacerbating comorbidities. In addition, PLWH are more exposed to risk factors affecting ageing, such as coinfections or harmful lifestyles. The ART initiation reverses the biological ageing process but only partially, and additionally can have some toxicities that influence ageing. Observational studies suggest premature ageing in PLWH. Therefore, there is considerable interest in the early prediction of unhealthy ageing through validated biomarkers, easy to implement in HIV-clinical settings. The most promising biomarkers are second-generation epigenetic clocks and integrative algorithms.
Asunto(s)
Coinfección , Infecciones por VIH , Envejecimiento , Antirretrovirales/uso terapéutico , Biomarcadores , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , HumanosRESUMEN
Interleukin 17 (IL17) secreting T (Th17) cells play a protective role against bacterial infections at mucosal surfaces. Recent reports show Th17 cells are depleted in the gut associated lymphoid tissue of HIV+ patients, but their role in HIV disease progression is not well understood. Expression of the IL17 receptor (IL17R) and the production of IL17 were compared between two groups of HIV patients with different disease progression (long-term-nonprogressors, LTNP and typical-progressors, TP). IL17R expression was similar in LTNP and TP, whereas Th17 cell number was greater in LTNP than TP (p=0.015). An inverse correlation between the plasma HIV-RNA and both IL17R expression and Th17 cell number was found (p=0.001 and p=0.002, respectively). The increased number of Th17 cells in LTNP could lead to a more preserved immune response against bacterial infections. As a result, lower microbial translocation could explain the reduced immune activation and slower disease progression seen in LTNP.
Asunto(s)
Progresión de la Enfermedad , Infecciones por VIH/inmunología , Sobrevivientes de VIH a Largo Plazo , Células Th17/inmunología , Adulto , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Estudios Transversales , Femenino , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Receptores de Interleucina-17/metabolismo , Carga Viral/inmunologíaRESUMEN
Accurate HIV-2 plasma viral load quantification is crucial for adequate HIV-2 patient management and for the proper conduct of clinical trials and international cohort collaborations. This study compared the homogeneity of HIV-2 RNA quantification when using HIV-2 assays from ACHI(E)V(2E) study sites and either in-house PCR calibration standards or common viral load standards supplied to all collaborators. Each of the 12 participating laboratories quantified blinded HIV-2 samples, using its own HIV-2 viral load assay and standard as well as centrally validated and distributed common HIV-2 group A and B standards (http://www.hiv.lanl.gov/content/sequence/HelpDocs/subtypes-more.html). Aliquots of HIV-2 group A and B strains, each at 2 theoretical concentrations (2.7 and 3.7 log(10) copies/ml), were tested. Intralaboratory, interlaboratory, and overall variances of quantification results obtained with both standards were compared using F tests. For HIV-2 group A quantifications, overall and interlaboratory and/or intralaboratory variances were significantly lower when using the common standard than when using in-house standards at the concentration levels of 2.7 log(10) copies/ml and 3.7 log(10) copies/ml, respectively. For HIV-2 group B, a high heterogeneity was observed and the variances did not differ according to the type of standard used. In this international collaboration, the use of a common standard improved the homogeneity of HIV-2 group A RNA quantification only. The diversity of HIV-2 group B, particularly in PCR primer-binding regions, may explain the heterogeneity in quantification of this strain. Development of a validated HIV-2 viral load assay that accurately quantifies distinct circulating strains is needed.
Asunto(s)
Infecciones por VIH/virología , VIH-2/aislamiento & purificación , Carga Viral/métodos , Humanos , Cooperación Internacional , Variaciones Dependientes del Observador , Plasma/virología , Control de Calidad , Estándares de Referencia , Reproducibilidad de los Resultados , Carga Viral/normasRESUMEN
BACKGROUND: DNA methylation-based estimators of biological age are reliable biomarkers of the ageing process. We aimed to investigate a range of epigenetic ageing biomarkers in a substudy of the NEAT001/ANRS143 clinical trial, which compared ritonavir-boosted darunavir with either raltegravir or tenofovir disoproxil fumarate and emtricitabine in antiretroviral therapy (ART)-naive adults. METHODS: We analysed frozen whole blood samples from 168 ART-naive participants with HIV from the NEAT001/ANRS143 trial, before ART initiation and after 2 years of ART (84 participants on ritonavir-boosted darunavir with raltegravir and 84 participants on ritonavir-boosted darunavir with tenofovir disoproxil fumarate and emtricitabine). We also included 44 participants without HIV with a similar age and sex distribution. We analysed DNA methylation. Epigenetic age estimators (Horvath's clock, Hannum's clock, GrimAge, and PhenoAge) and estimated leucocyte compositions were generated using Horvath's New Online Methylation Age Calculator and Houseman's method. We calculated epigenetic age acceleration measures for each estimator of epigenetic age. The NEAT001/ANRS143 trial is registered with ClinicalTrials.gov, NCT01066962. FINDINGS: Compared with the HIV-uninfected group, ART-naive participants with HIV showed higher epigenetic age acceleration (EAA) according to all EAA estimators (mean 2·5 years, 95% CI 1·89-3·22 for Horvath-EAA; 1·4 years, 0·74-1·99 for Hannum-EAA; 2·8 years, 1·97-3·68 for GrimAge-EAA; and 7·3 years, 6·40-8·13 for PhenoAge-EAA), with all differences being statistically significant except for Hannum-EAA (Horvath-EAA p=0·0008; Hannum-EAA p=0·059; GrimAge-EAA p=0·0021; and PhenoAge-EAA p<0·0001). Epigenetic ageing was more pronounced in participants who had CD4 counts less than 200 cells per µL (significant for PhenoAge and Hannum's clock, p=0·0015 and p=0·034, respectively) or viral loads over 100â000 copies per mL at baseline (significant for PhenoAge, p=0·017). After 2 years of ART, epigenetic age acceleration was reduced, although PhenoAge and GrimAge remained significantly higher in participants with HIV compared with participants without HIV (mean difference 3·69 years, 95% CI 1·77-5·61; p=0·0002 and 2·2 years, 0·47-3·99; p=0·013, respectively). There were no significant differences in the ART effect on epigenetic ageing between treatment regimens. At baseline, participants with HIV showed dysregulation of DNA methylation-based estimated leucocyte subsets towards more differentiated T-cell phenotypes and proinflammatory leucocytes, which was also partly restored with ART. INTERPRETATION: ART initiation partly reversed epigenetic ageing associated with untreated HIV infection. Further studies are needed to understand the long-term dynamics and clinical relevance of epigenetic ageing biomarkers in people with HIV. FUNDING: NEAT-ID Foundation.
Asunto(s)
Envejecimiento/efectos de los fármacos , Fármacos Anti-VIH/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Adulto , Envejecimiento/genética , Biomarcadores/análisis , Recuento de Linfocito CD4 , Metilación de ADN , Quimioterapia Combinada , Femenino , Infecciones por VIH/genética , Infecciones por VIH/patología , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Carga ViralRESUMEN
AIM: To evaluate the association between DNA methylation and frailty in the HIV-infected population and to investigate the usefulness of assessing frailty as a clinical marker to identify age acceleration. METHODS: Frailty was assessed according to Fried's frailty phenotype. DNA methylation was analyzed in 10 frail patients, and compared with 10 robust control patients, all with HIV. Predicted age was inferred using the Weidner's formula. Age acceleration was assessed using the difference between predicted and chronological age. RESULTS: HIV-infected frail patients had significantly higher biological predicted ages than chronological ages (mean acceleration: 10.3 years; p = 0.012). CONCLUSIONS: We link age acceleration and frailty in an older HIV population. Frailty could be used in this population for implementing specific clinical approaches.
Asunto(s)
Biomarcadores/metabolismo , Infecciones por VIH/patología , Anciano , Envejecimiento , Antirretrovirales/uso terapéutico , Metilación de ADN , Femenino , Fragilidad , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
Human immunodeficiency virus type 2 (HIV-2) RNA quantification assays used in nine laboratories of the ACHI(E)V(2E) (A Collaboration on HIV-2 Infection) study group were evaluated. In a blinded experimental design, laboratories quantified three series of aliquots of an HIV-2 subtype A strain, each at a different theoretical viral load. Quantification varied between laboratories, and international standardization of quantification assays is strongly needed.
Asunto(s)
Infecciones por VIH/virología , VIH-2/fisiología , ARN Viral/normas , Juego de Reactivos para Diagnóstico/normas , Carga Viral/normas , Conducta Cooperativa , VIH-2/genética , VIH-2/aislamiento & purificación , Humanos , Internacionalidad , Laboratorios/normas , Control de Calidad , ARN Viral/sangre , Reproducibilidad de los ResultadosRESUMEN
Despite the varying disease progression rates, the majority of HIV-infected individuals eventually progress to AIDS. There is a subset of HIV-positive individuals, who maintain high CD4+ and CD8+ T-cell counts, remain therapy naive and persistently infected with HIV-1 for more than 15 to 20 years. In light of current observations, this subset can be divided into two groups. One shows low detectable plasma viremia (< 5000 HIV-RNA copies/ml), termed long-term nonprogressors. A second group shows plasma HIV-RNA values persistently below 50 copies/ml throughout the course of infection, and termed "elite" or "natural controllers". The features common between both groups are the presence of high CD4+ and CD8+ T-cell counts, strong immune responses, and low but variable cellular proviral DNA load. The group of HIV-positive long-term nonprogressor individuals comprises about 1% of the total HIV population in the world, whereas the "elite" controllers may be much less. Why do some people deteriorate faster, while others remain normal both symptomatically and immunologically for decades? There is a renewed interest in HIV-positive individuals who have survived since the period close to the earlier part of the HIV pandemic in the 1980s and have remained drug-naive. As very little is known about "elite" controllers, the findings discussed here are largely based on previously known and newly emerging aspects of HIV pathogenesis in the context of the long-term nonprogressor group. It is believed that data emerging on long-term nonprogressors will allow us to make scientific inferences to further our research on "elite" controllers. Aspects dealing with cellular, humoral, innate, and adaptive immunity, which are relevant to nonprogressive HIV disease, are beyond the scope of this review.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/virología , Sobrevivientes de VIH a Largo Plazo , VIH/patogenicidad , Desaminasas APOBEC , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Síndrome de Inmunodeficiencia Adquirida/genética , Síndrome de Inmunodeficiencia Adquirida/inmunología , Citidina Desaminasa , Citosina Desaminasa/genética , Citosina Desaminasa/fisiología , Progresión de la Enfermedad , VIH/genética , Antígenos HLA/genética , Antígenos HLA/metabolismo , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Carga Viral , Replicación ViralRESUMEN
Background: Integration of human immunodeficiency virus type 1 (HIV-1) into the host genome causes global disruption of the chromatin environment. The abundance level of various chromatin-modifying enzymes produces these alterations and affects both the provirus and cellular gene expression. Here, we investigated potential changes in enzyme expression and global DNA methylation in chronically infected individuals with HIV-1 and compared these changes with non-HIV infected individuals. We also evaluated the effect of viral replication and degree of disease progression over these changes. Results: Individuals with HIV-1 had a significant surge in the expression of DNA and histone methyltransferases (DNMT3A and DNMT3B, SETDB1, SUV39H1) compared with non-infected individuals, with the exception of PRMT6, which was downregulated. Some histone deacetylases (HDAC2 and HDAC3) were also upregulated in patients with HIV. Among individuals with HIV-1 with various degrees of progression and HIV control, the group of treated patients with undetectable viremia showed greater differences with the other two groups (untreated HIV-1 controllers and non-controllers). These latter two groups exhibited a similar behavior between them. Of interest, the overexpression of genes that associate with viral protein Tat (such as SETDB1 along with DNMT3A and HDAC1, and SIRT-1) was more prevalent in treated patients. We also observed elevated levels of global DNA methylation in individuals with HIV-1 in an inverse correlation with the CD4/CD8 ratio. Conclusions: The current study shows an increase in chromatin-modifying enzymes and remodelers and in global DNA methylation in patients with chronic HIV-1 infection, modulated by various levels of viral control and progression.
Asunto(s)
Linfocitos T CD4-Positivos/química , Metilación de ADN , Perfilación de la Expresión Génica/métodos , Infecciones por VIH/genética , Histona Metiltransferasas/genética , Adulto , Relación CD4-CD8 , Estudios de Casos y Controles , Ensamble y Desensamble de Cromatina , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica , Infecciones por VIH/inmunología , VIH-1/fisiología , Humanos , Masculino , Persona de Mediana Edad , Replicación ViralRESUMEN
The acidic repeat protein (arp) genes from three subspecies of the treponeme Treponema pallidum (T. pallidum subsp. pallidum, Nichols strain; T. pallidum subsp. pertenue, CDC-1 and CDC-2 strains; and T. pallidum subsp. endemicum, Bosnia A strain) were cloned and sequenced. The predicted protein sequence contained a high percentage of glutamic acid, hence the name acidic repeat protein, or Arp. The protein had a potential membrane-spanning domain and a signal peptidase I site. The gene from the Nichols strain of T. pallidum subsp. pallidum contained a set of 14 nearly identical repeats of a 60 bp sequence, which occupied approximately 51 % of the length of the gene. Analyses of arp from laboratory strains showed that the 5' and 3' ends of the genes were conserved, but there was considerable heterogeneity in the number of repeats of this 60 bp sequence. Based on amino acid variations, the 14 sequence repeats could be classified into three types, which were named type I, type II and type III repeats. The type II repeat was the most common in the strains examined. The arp gene of the Nichols strain was subsequently cloned into the expression vector pBAD/TOPO ThioFusion. The expressed protein was detected in a Western blot assay using rabbit immune sera produced against T. pallidum, or synthetic peptides derived from the repeat sequences. Using an ELISA, rapid plasma reagin (RPR) test-positive sera reacted with synthetic peptides derived from the repeat region but not with peptides derived from N and C termini of the Arp protein. These results show that the Arp protein is immunogenic and could prove to be a useful target for serological diagnosis of T. pallidum infection.
Asunto(s)
Proteínas Bacterianas/genética , Proteínas Bacterianas/inmunología , Treponema pallidum/genética , Treponema pallidum/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Antibacterianos/inmunología , Secuencia de Bases , Sitios de Unión/genética , Western Blotting , Clonación Molecular , Secuencia Conservada , ADN Bacteriano/química , ADN Bacteriano/genética , Ensayo de Inmunoadsorción Enzimática , Humanos , Proteínas de la Membrana/genética , Datos de Secuencia Molecular , Polimorfismo Genético , Señales de Clasificación de Proteína/genética , Estructura Terciaria de Proteína/genética , Conejos , Secuencias Repetitivas de Aminoácido/genética , Secuencias Repetitivas de Aminoácido/inmunología , Secuencias Repetitivas de Ácidos Nucleicos , Análisis de Secuencia de ADN , Suero/inmunología , Serodiagnóstico de la Sífilis/métodosRESUMEN
We describe the emergence of the proV47A mutation in three out of five HIV-2-infected individuals failing lopinavir/ritonavir-based HAART. The appearance of such mutated variants resulted in high levels of phenotypic resistance to lopinavir, cross-resistance to indinavir, amprenavir, and hypersusceptibility to saquinavir. A search in HIV-2 databases revealed that proV47A is present in 8.6% of protease inhibitor (PI)-experienced patients but absent in all PI-naive patients. Its selection may be a common mutational pathway for developing resistance to lopinavir/ritonavir in HIV-2.