Journal Article

Impact of HIV kick-and-kill therapy on host epigenetic and transcriptional programs in PBMC, and viral rebound after cART interruption

Riol, M. Ruiz, Clotet, B, Pla, A. Sanchez, Tordera, B. Oriol, Esteller, M, Codina, A. Esteve, Hanke, T, Calle, M.L, Brander, C, Goncalves, E, Combadiere, B, Mothe, B, Berdasco, M, Molto, J

2021

Overview

Background: BCN02 was a pilot kick-and-kill clinical trial that combined therapeutic vaccination (MVA.HIVconsv) with the latency reversing agent romidepsin (RMD) followed by a monitored antiretroviral pause (MAP) in 15 early-treated HIV+ individuals (NCT02616874). Out of 12 evaluable participants for an omics sub-analysis, 8 participants showed early (pVL > 2000 copies/mL < 4 weeks) and 4 a more delayed viral rebound (pVL > 2000 copies/mL > 4 weeks) in MAP. Systems biology analyses identified epigenetic and molecular mechanisms associated with response to vaccination and RMD and viral rebound kinetics. Methods: Genome-wide gene expression (Ilumina HiSeq2500) and DNA Methylation (Infinium HumanMethylation450 BeadChip) were assessed in frozen PBMC-pellets at baseline, 1 week after vaccination and 1 week after the 3rd RMD infusion (post-RMD). After pre-processing and normalization steps we applied principal component analyses (PCA) and differential expression/methylation analyses (limma-R/Biocondcutor). GSEA was used for functional analysis, and sPLS-DA (MixOmics-R/Bioconductor), to identify pathways explicative of differential viral rebound kinetics. Results: The largest impact on host transcriptional and DNA methylation (DNAm) profiles was observed after the combined effect of vaccination and RMD, with 733 differentially expressed genes and 5695 differentially methylated positions being detected between baseline and post-RMD (adjusted p < 0.1). Modulated pathways at gene expression and/or DNAm level, were mainly associated with processes including cell cycle, DNA repair or metabolism and HIV, innate and adaptive immunity (GSEA q-value < 0.15). Of note, PCA revealed that only DNAm levels after the combined intervention segregated participants by their early or late viral rebound kinetics in MAP. We summarized the therapy-modulated pathways with eigenvectors of DNAm at post-RMD, and identified HIV, innate immunity and T-cell pathways among the most relevant to discriminate the two viral rebound profiles in MAP. Interestingly, 3 CpG positions in the HIV category, 37 in the innate immunity group and 10 in the T cell category were differentially methylated between individuals with different viral rebound profile (adjusted p < 0.1). Conclusions: Host transcription and epigenetic programs provide a deeper understanding of the molecular mechanisms induced during HIV cure therapies. While DNAm after a kick-and-kill strategy could be used to predict viral rebound kinetics after ART interruption, further study is warranted in future controlled studies.

• Publisher: International AIDS Society
• Subject: Antiviral agents / Development and progression / Drug therapy / Gene expression / Genetic aspects / Health aspects / HIV infection / Host-virus relationships / Patient outcomes