Abstract Body

Inflammation is a hallmark of chronic HIV disease. Persistent immune activation was associated with suboptimal CD4 count recovery despite four years of suppressive antiretroviral therapy (ART), and has been associated with increased risk of cardiovascular disease and mortality among ART-treated HIV-infected adults. To understand the pathways affected by atorvastatin (ATV) adjunct therapy, which has immune activation properties, we examined the effect of ATV on gene expression among ART suboptimal immune responders.

Within a randomized, double-blind cross-over trial of atorvastatin adjunct therapy among suboptimal immune responders to ART (NCT01766076), paxgene samples were collected from suboptimal immune responders (SO-IR): patients with CD4 count increase <300 cells/µl (difference between pre-ART CD4 count and CD4 count after seven years of suppressive ART) before and after use of atorvastatin 80mg daily for 12 weeks. Using microarrays, atorvastatin responders (ATV-R): patients that had the highest reduction in immune activation [CD4+HLA+CD38+ expression] from week 0 to week 12 of atorvastatin in the parent study were compared with atorvastatin non-responders (ATV-NR): patients with the least reduction in immune activation after week 12. DEG analysis of the top 50 genes and top 50 ISG genes associated with interferon were analyzed. Network inference was done using geneMania algorithm, followed by linear regression analysis using clinical parameters and pathway analysis.

Atorvastatin downregulated the inflammatory genes IL18, IL16 IFN, ATF3, MED14 and IFNA21 among six ATV-R which remained up-regulated in four ATV-NR. Pathways that were down-regulated by ATV-responders include: NF-KAPPAB signaling, NOTCH signaling, TWEAK signaling, RAN signaling, IL-9 signaling, role of Jak1, Jak2, tyk2 in interferon signaling, and role of NFAT in regulating immune response. We demonstrated that NF kappa B genes were significantly upregulated among 17 SO-IR to ART when compared with 19 ART-responders (patients with CD4 increase>500 cells after seven years of ART). Upregulation of inflammatory pathways was significantly associated CD4 and CD8 activation levels.

Atorvastatin downregulates inflammatory genes among suboptimal immune responders to suppressive antiretroviral therapy. Transcriptomic signature of atorvastatin response could be used to assess the effects of atorvastatin when used as adjunct therapy for ART-treated HIV-infected individuals.