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Latency-associated DNA methylation patterns among HIV-1 infected individuals with distinct disease progression courses or antiretroviral virologic response.

ABSTRACT: DNA methylation is one of the epigenetic modifications that configures gene transcription programs. This study describes the DNA methylation profile of HIV-infected individuals with distinct characteristics related to natural and artificial viremia control. Sheared DNA from circulating mononuclear cells was subjected to target enrichment bisulfite sequencing designed to cover CpG-rich genomic regions. Gene expression was assessed through RNA-seq. Hypermethylation in virologic responders was highly distributed closer to Transcription Start Sites (p-value = 0.03). Hyper and hypomethylation levels within TSS adjacencies varied according to disease progression status (Kruskal-Wallis, p < 0.001), and specific differentially methylated regions associated genes were identified for each group. The lower the promoter methylation, the higher the gene expression in subjects undergoing virologic failure (R = - 0.82, p = 0.00068). Among the inversely correlated genes, those supporting glycolysis and its related pathways were hypomethylated and up-regulated in virologic failures. Disease progression heterogeneity was associated with distinct DNA methylation patterns in terms of rates and distribution. Methylation was associated with the expression of genes sustaining intracellular glucose metabolism in subjects undergoing antiretroviral virologic failure. Our findings highlight that DNA methylation is associated with latency, disease progression, and fundamental cellular processes.

SUBMITTER: Mantovani N

PROVIDER: S-EPMC8626465 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAccess to routine virologic monitoring, critical to ensuring treatment success, remains limited in low- and middle-income countries. We report on implementation of routine viral load (VL) monitoring and risk factors for virologic failure among HIV-infected children on antiretroviral treatment (ART) in Western Kenya.MethodsRoutine VL testing was introduced in western Kenya in November 2013. We performed a case-control study among 1190 HIV-infected children ≤15 years on ART who underwent routine VL testing June 2014-May 2015. A random sample of 98 cases (virologic failure define as VL >1000 cps/mL) and 201 controls (VL <1000 cps/mL) from five facilities in three high HIV prevalence counties in Kenya were followed for a minimum of 12 months. Data from patient charts were analyzed using logistic regression to determine factors associated with failure to attain virologic suppression at initial routine and subsequent VL testing among cases.ResultsOverall, 1190 (94%) children with a median age of 8 years underwent routine VL testing of whom (37%) had virological failure. Among the 299 cases and controls, WHO stage, baseline CD4 count and time since ART initiation were not associated with virologic failure during the follow-up period. In multivariable analysis, unsuppressed children at initial test were more likely to be male (adjusted Odds Ratio (aOR) 2.1, 95% Confidence Interval (CI) 2.1-3.6) and have had an ART regimen change (aOR 2.0, CI 1.0-3.7) than controls. Of the two-thirds of children 201/299 who had a subsequent VL performed, VL suppression was greater among those suppressed at initial test 126/135 (93.3%) compared to children with virologic failure 15/66 (22.7%, p<0.0001). Among those failing at first test who achieved viral suppression in follow up, 12/15 (80%) were on a protease inhibitor (PI)-based regimen. In the multivariable analysis of children with subsequent VL testing, children on PI-based 2nd line regimens were 10-fold more likely to achieve viral suppression than children on first-line NNRTI-based ART (adjusted Odds Ratio [aOR] 0.1; 95%CI 0.0-0.4).ConclusionCoverage of initial routine viral load testing among children on ART in western Kenya is high. However, subsequent testing and virologic suppression are low in children with virologic failure on initial routine viral load test. There is an urgent need to improve management and viral load monitoring of children living with HIV experiencing treatment failure to ensure improved long-term outcomes.

Project description:BackgroundContemporary data on the immunologic, haematologic and virologic responses and predictors of virologic failure after initiation of free antiretroviral treatment in Cameroon are needed to evaluate the current treatment-monitoring algorithm and to complement efforts to scale-up and improve on the management of HIV infections.MethodsThis was a cross-sectional study conducted between October 2010 and June 2012. A total of 951 participants aged 18-74 years were recruited from selected approved HIV treatment centres of the Northwest and Southwest regions. This comprised 247 males and 704 females. Demographic, self-reported risk behaviours and socioeconomic data were obtained using a structured questionnaire. Full blood and CD4 + T-cell counts were done using standard automated techniques. Determination of viral load (VL) was done using Abbott RealTime HIV-1 m2000™ system. Data was analysed using SPSS version 17. The statistical significance level was P < 0.05.ResultsThe median duration of antiretroviral therapy (ART) was 24 months. The population mean CD4 + T-cell count was 255.3 cells/μL [95% CI, 236.8 - 273.9]. Overall, 45.9%, 43.8% and 10.2% of the participants had CD4 + T-cell counts of < 200 cells/μL, 200-499 cells/μL and > 500 cells/μL respectively. Anaemia was present in 26.2% of the participants with 62.3%, 25.7% and 12% described as mild, moderate and severe anaemia respectively. Virologic failure occurred in 23.2% of the participants with 12.3% having VL > 10,000 RNA copies/mL. Meanwhile 76.8% of patients attained adequate viral suppression with 40.8% having undetectable viral load. The age group 18-29 years (p = 0.024), co-infection with tuberculosis (p = 0.014), anaemia (p = 0.028) and distance from the treatment centre (p = 0.011) independently predicted virologic failure.ConclusionThe majority of the participants achieved adequate viral suppression after ≥ 6 months of ART. Despite these favourable immuno-haematologic and virologic outcomes, the National AIDS Control Program should step-up efforts to improve on antiretroviral drug distribution, as well as proper assessment and management of anaemia, foster early diagnosis and treatment of tuberculosis and enhance treatment adherence counselling especially in younger patients.

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Latency-associated DNA methylation patterns among HIV-1 infected individuals with distinct disease progression courses or antiretroviral virologic response.

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