Abstract
Although certain individuals with HIV infection can stop antiretroviral therapy (ART) without viral load rebound, the mechanisms under-pinning ‘post-treatment control’ remain unclear. Using RNA-Seq we explored CD4 T cell gene expression to identify evidence of a mechanism that might underpin virological rebound and lead to discovery of associated biomarkers. Fourteen female participants who received 12 months of ART starting from primary HIV infection were sampled at the time of stopping therapy. Two analysis methods (Differential Gene Expression with Gene Set Enrichment Analysis, and Weighted Gene Co-expression Network Analysis) were employed to interrogate CD4+ T cell gene expression data and study pathways enriched in post-treatment controllers versus early rebounders. Using independent analysis tools, expression of genes associated with type I interferon responses were associated with a delayed time to viral rebound following treatment interruption (TI). Expression of four genes identified by Cox-Lasso (ISG15, XAF1, TRIM25 and USP18) was converted to a Risk Score, which associated with rebound (p < 0.01). These data link transcriptomic signatures associated with innate immunity with control following stopping ART. The results from this small sample need to be confirmed in larger trials, but could help define strategies for new therapies and identify new biomarkers for remission.
Highlights
Most people with HIV who are receiving antiretroviral therapy (ART) will experience rebound viraemia if they stop treatment
We identified 14 female participants who had received 12 months of ART commenced during Primary HIV Infection (PHI) followed by treatment interruption (TI)
All had viable samples of peripheral blood mononuclear cells (PBMCs) taken at the point of TI (Week 48) and for 11 participants samples were available at pre-therapy Baseline (Week 0)
Summary
Most people with HIV who are receiving antiretroviral therapy (ART) will experience rebound viraemia if they stop treatment. A small proportion of ART-treated individuals can stop therapy and maintain undetectable viremia—or ‘post-treatment control’ (PTC)—for months and, in some cases, years[1,2,3]. Other individuals spontaneously suppress HIV viraemia in the absence of therapy and maintain undetectable viral loads for many years. These ‘elite controllers’ or ‘long-term non-progressors’ are likely protected by strong T cell responses restricted by protective HLA alleles[4]. We studied participants who received 12 months of ART started in primary HIV infection (PHI), and analysed CD4+ T cell mRNA at the time of TI. Our aim was to identify genes or gene-sets expressed by CD4+ T cells that might associate with longer periods of post-treatment control
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