Thrombospondin Regulation Differentiates HIV Patients with Natural and Therapy-Mediated Control of Plasma Viremia: A Genome-Wide Transcriptomic Analysis

The genomic mechanisms underlying natural and effective control of viremia in HIV+ long-term non-progressors (LTNP) and elite controllers (ECs) remain obscured and poorly understood. We performed genome-wide transcriptomic expression analysis (Bead-Studio; 25,000 genes) on peripheral blood mononuclear cells from nine therapy-naïve LTNPs compared with 15 newly diagnosed HIV+ patients before and after > one year of control of viremia by HAART. Only significantly differentially expressed (DE) genes with p-value <0.01 and FDR (false discovery rate (FDR) of <1% were considered for further analysis. Pathway analysis was performed using MetaCoreTM to derive the functional annotations. Functionally significant genes were validated using quantitative real-time PCR, flow cytometry, and confocal and deltavision microscopy. Although LTNP had naturally controlled viremia (low to undetectable), gene expression levels in these LTNP were distinct from those in HIV+ patients with viremia controlled by HAART (below detection), highlighting the critical role and uniqueness of enriched pathways in the natural control of viremia in the LTNPs and ECs. Thrombospondin (THBS1) (R2 = 0.942) was identified as a POTENTIAL biomarker in our study, discriminating between viremic patients and LTNPs at the genomic (R2 = 0.942, p = 2.654e-08) and proteomic (p = 0.003761) levels. The expression levels of THBS1 were correlated with plasma viremia (R² = 0.81557; p = 0.0003761). Our results suggest a significant distinction between immune pathways in patients with therapy-mediated control of HIV replication compared to those with natural control of viremia in LTNPs, as identified by enriched genomic expression in immune activation, cytoskeletal remodeling, apoptosis, and T-cell signaling pathways. Thrombospondin plays an essential role in apoptosis; therefore, the downregulation of this marker in viremic patients MAY OFFER POTENTIAL AS A BIOMARKER for characterizing pathways of immunological control in untreated LTNP, in addition to predicting optimal treatment response in newly diagnosed HIV+ patients.