CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

THURSDAY, FEBRUARY 26, 2015 Session P-G8 Poster Session

Poster Hall

2:30 pm– 4:00 pm Mitochondrial Dysfunction in HAND and Depression 496 Mitochondrial DNA, Neurologic and Systemic Inflammation, and Immune Dysregulation Josué Pérez-Santiago ; Michelli Faria de Oliveira; Susanna R.Var; Steven P.Woods; Sara GianellaWeibel; Sanjay Mehta; Ben Murrell;Tyler R. Day; Ronald J. Ellis University of California San Diego, La Jolla, CA, US

Background: We recently found that higher levels of cell-free mtDNA in cerebrospinal fluid (CSF) were associated with more neurological and systemic inflammation in a clinically heterogeneous cohort of HIV infected individuals. Here we investigated how CSF mtDNA levels relate to inflammation and immune status in a cohort of virologically suppressed individuals, and in 5 individuals following structured treatment interruption (STI). Methods: Using droplet digital PCR, we quantified cell-free mtDNA levels from the CSF supernatant in 41 HIV-infected individuals with completely suppressed HIV RNA levels in CSF and blood plasma (<50 copies/mL), and in five HIV infected individuals who underwent STI. For each CSF and plasma sample, we also measured markers of inflammation and cellular trafficking (IP-10, MCP-1, IL-6, IL-8, TNF- α , MIP-1 α and sCD14). Statistical analyses were performed in R statistical software. Results: Levels of mtDNA in CSF supernatant were significantly higher in individuals with a diagnosis of AIDS when compared to participants without AIDS (median: 6.34 log 10 copies/mL versus 3.81 log 10 copies/mL, p=0.0003). Using fixed-effects regression analyses, higher levels of mtDNA in CSF were also associated with lower CD4 + T-cell nadir (r=- 0.43, p=0.004). Furthermore, higher levels of mtDNA in CSF were associated with more inflammation in CSF as measured by MCP-1 (r=0.56, p=0.0002), TNF- α (r=0.73, p=0.01), and in blood plasma measured by IL-8 (r=0.44, p=0.004) and TNF- α (r=0.43, p=0.005). In a multivariate analysis, higher levels of mtDNA remained significantly associated with higher levels of MCP-1 (p=0.03) and TNF- α (p=0.01) in CSF when adjusted for AIDS status. In subjects undergoing STI, mtDNA levels in CSF rebounded prior to CSF and blood plasma HIV RNA and prior to pleocytosis in all individuals. Furthermore, pleocytosis was associated with both levels of mtDNA (p=0.03) and HIV RNA in CSF (p=0.01) when evaluated in a multivariate mixed-effects model. Conclusions: In virologically suppressed individuals, higher levels of mtDNA in CSF were strongly associated with more neurologic and systemic inflammation, and with a lower CD4+ nadir and AIDS status. Also after STI, mtDNA levels rose prior to HIV rebound and pleocytosis in CSF. These results suggest that increased levels of cell-free mtDNA in CSF play a role in neuro-inflammation especially in individuals with more advanced HIV disease. Our data provide important insights to the pathophysiology of immune dysregulation in the CNS during AIDS. 497 CSF Metabolomics Implicate Bioenergetic Adaptation as a Neural Mechanism Regulating Shifts in the Cognitive States of HIV-Infected Subjects Norman J. Haughey 1 ; Alex DIckens 1 ; Reena Deutsch 2 ; Michelle Mielke 3 ;Timothy Claridge 4 ; Igor Grant 2 ;Thomas Marcotte 2 ; Scott Letendre 2 ; Justin McArthur 1 1 Johns Hopkins University School of Medicine, Baltimore, MD, US; 2 University of California San Diego, San Diego, CA, US; 3 Mayo Clinic, Rochester, MN, US; 4 University of Oxford, Oxford, United Kingdom Background: Although combinational antiretroviral therapy (ART) has been an effective tool in controlling replication of the Human Immunodeficiency Virus (HIV), ART has not been completely effective to suppress neurological complications. While some cases of cognitive impairment can be attributed to ART failure, many individuals develop HIV- Associated Neurocognitive Disorders (HAND) with stable ART, little or no detectable viral load, and CD4 counts in the normal range. HIV-infection and ART are each associated with disturbances in peripheral and central bioenergetics. Although brain imaging studies have shown the importance of metabolic abnormalities in HAND, the underlying bioenergetic pathways modified by infection and ART are not well understood. Methods: The metabolic composition of CSF was analysed using 1 H-NMR spectroscopy, which focused on energy metabolites. Metabolic biomarkers for cognitive states were identified using multivariate PLS regression modelling of the acquired spectra, combined with non-parametric analyses of metabolites with clinical features. Results: Multivariate modeling and cross-validated recursive partitioning identified several energy metabolites that, when combined with clinical variables, classified subjects based on change in neurocognitive states. Prognostic identification for worsening was achieved with 4 features that included 1 clinical measure (no change in a detectable plasma viral load), and 3 metabolites (elevated citrate and acetate; decreased creatine), to produce a model with a predictive accuracy of 92%, sensitivity of 88%, and 96% specificity. Prognosis for improvement contained 7 features that included 2 clinical measures (first visit age <47 years, new or continued use of antiretrovirals), and 5 metabolites (elevated glutamine and glucose; decreased myo -inositol, b-glucose, and creatinine) to generate a model with a predictive accuracy of 92%, sensitivity of 100% and specificity of 84%. Conclusions: These CSF metabolic results suggest that worsening cognitive status in HIV-infected patients is associated with increased aerobic glycolysis, and improvements in cognitive status are associated with a shift to anaerobic glycolysis. Dietary, lifestyle and pharmacologic interventions that promote anaerobic glycolysis may protect the brain in setting of HIV infection with ART. 498 Altered Monoamine and Acylcarnitine Metabolites in HIV Patients with Depression Edana Cassol 1 ;Vikas Misra 2 ; Susan Morgello 3 ; Gregory D. Kirk 4 ; Shruti H. Mehta 4 ; Dana H. Gabuzda 2 1 Carleton University, Ottawa, Canada; 2 Dana-Farber Cancer Institute, Boston, MA, US; 3 Mount Sinai Hospital, New York, NY, US; 4 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US Background: Depression is a frequent comorbidity in HIV infection and an important predictor of poor treatment outcomes and increased mortality. Accumulating evidence suggests that inflammation and increased tryptophan catabolism are associated with increased risk of developing major depressive disorder in HIV infection, but the mechanisms leading to depression remain poorly understood. Methods: The severity of depressive symptoms was assessed by Beck Depression Inventory or Center for Epidemiological Studies Depression Scale. Untargeted metabolomic profiling of plasma from 104 subjects across three independent cohorts (32 HIV+ subjects on ART from NNTC and CHARTER [median CD4 288 cells/ul, median plasma VL 50 copies/ ml; n=15 and n=17 with and without depressive symptoms], 36 HIV+ [median CD4 350 cells/ul, median plasma VL 630 copies/ml; n=13 and n=23 with and without depressive symptoms] and 36 HIV- [n=12 and n=24 with and without depressive symptoms] subjects from ALIVE) was performed using liquid or gas chromatography followed by mass spectrometry to detect > 400 metabolites. Cytokine profiling was performed by Bioplex array. Bioinformatic analysis were performed in Metaboanalyst and R. Results: Decreased monoamine metabolites of phenylalanine/tyrosine catabolism (phenylacetate and 4-hydroxyphenylacetate) and acylcarnitines (propionylcarnitine, isobutyrylcarnitine, isovalerylcarnitine, and 2-methylbutyrylcarnitine) in plasma distinguished between subjects with and without depressive symptoms in both HIV+ and HIV- cohorts (FC>1.2, p<0.05, FDR<10%), and these alterations correlated with the severity of depression. In HIV+ subjects, depressive symptoms were associated with augmented IFN responses (IFN-gamma, CXCL9, CXCL10) and tryptophan catabolism (increased kynurenine to tryptophan ratio), and these changes correlated with metabolite alterations associated with depression (p<0.05, FDR<10%). Altered metabolites mapped to pathways involved in monoamine metabolism, mitochondrial function, and inflammation,

Poster Abstracts

331

CROI 2015