CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

296

Maraviroc and Immune Recovery in Advanced AIDS (CD4 <100) Pablo F. Belaunzarán-Zamudio 1 ; Livio Azzoni 2 ; Juan Sierra-Madero 3 ;Yanink Caro-Vega 4 ; Irini Sereti 5 ; David H. Canaday 6 ; Brian Clagget 7 ; Benigno Rodriguez 8 ; Ian M. Sanne 9 ; Michael M. Lederman 7 1 Inst Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico; 2 The Wistar Inst, Philadelphia, PA, USA; 3 Natl Inst of Med Scis and Nutrition Salvador Zubirán, Mexico City, Mexico; 4 Inst Nacional de Ciencias Médicas y Nutrición, Salvador Subirán, Mexico, Mexico; 5 NIH, Bethesda, MD, USA; 6 Cleveland VA Med Cntr, Cleveland, OH, USA; 7 Case Western Reserve Univ, Cleveland, OH, USA; 8 Case Western Reserve Univ Sch of Med, Cleveland, OH, USA; 9 Univ of the Witwatersrand, Wits Hlth Consortium, Johannesburg, South Africa Background: In the CADIRIS trial 276 ART naïve patients with CD4 <100/uL were randomized to receive maraviroc (MVC) or placebo added to a standard ART regimen to evaluate the effects of CCR5 antagonism on occurrence of IRIS. No effect was demonstrable (Sierra-Madero Lancet HIV 2014). This substudy reports dynamics of phenotypic and functional cellular restoration upon viral suppression with or without CCR5 blockade. Methods: Flow cytometry was used to characterize the maturation phenotype, CCR5 expression and activation status of circulating T cells at weeks 0,4,12,24 and 48. CD4 and CD8 T cell reactivity with peptides of CMV, MTb and Staphylococcal enterotoxin B was assessed by intracellular expression of IFNγ, TNFα and CD40 ligand at weeks 0, 4 and 12. Results: Forty patients were studied (MVC=22; placebo=18). MVC selectively retained CCR5+ CD4 and CD8 T cells in circulation as these proportions increased significantly during the first 4 weeks of MVC but not placebo (18.4% vs 1%, p <0.001 and 23.7% vs -4.3%, p <0.001). This increase was transient, and after week 12 the proportions of CCR5-expressing cells decreased in both arms, but subjects in the MVC group retained significantly higher rates of CCR5+ CD4 and CD8 cells at later time points. CD4 and CD8 T cell maturation subset numbers were similar in the treatment arms. The proportion of activated (CD38+ and HLA-DR+) CD4 and CD8 lymphocytes increased more at Week 4 in patients receiving MVC (10.6% and 6%) versus those receiving placebo (1.3% and -7.6%, p =0.04 and p =0.007). These proportions fell in both treatment arms thereafter. Mycobacterial responses were negligible throughout the study, but subjects on MVC had marginally CD8 cellular responses to SEB at weeks 4 (9.5% CD8 cells expressed IFNα in placebo and 17.4% in MVC, p=0.032) and 12 (9.2% CD8 cells expressed IFNα in placebo and 17.8% in MVC, p=0.032) . Conclusions: During ART administration in advanced AIDS, MVC selectively retained in circulation CCR5+ CD4+ and CD8+ T cells without affecting antigen-specific T-cell responses. Sustained increases in circulating CD8 T cell counts were observed in the MVC arm but treatment had no effect on the occurrence of IRIS

297 Transcriptomic Signature of Atorvastatin Response Among ART-Treated Adults in Africa Damalie Nakanjako 1 ; Khader Ghneim 2 ; Isaac Ssinabulya 1 ; Rose M. Nabantanzi 3 ; Lois Bayigga 1 ; Agnes Kiragga 4 ; Harriet Mayanja-Kizza 1 ; Moses R. Kamya; Andrew Kambugu 4 ; Pontiano Kaleebu 5 ; Alison M. Elliott 6 ; Rafick Sekaly 7 1 Makerere Univ Coll of Hlth Scis, Kampala, Uganda; 2 Case Western Reserve Univ, Ceveland, OH, USA; 3 Coll of Hlth Scis, Makerere Univ, Kampala, Uganda; 4 Infectious Diseases Inst, Kampala, Uganda; 5 Med Rsr Council/Uganda Virus Rsr Inst Uganda Rsr Unit on AIDS, Entebbe, Uganda; 6 Med Researh Council/Uganda Virus Rsr Inst, Entebbe, Uganda; 7 Case Western Reserve Univ, Cleveland, OH, USA Background: 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. Methods: 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] fromweek 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. Results: 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. Conclusions: 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.

Poster Abstracts

114

CROI 2016