CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

464 Bridging Genetics, Histopathology, and Neurocognition in the Context of HAND Andrew Levine 1 ;Virawudh Soontornniyomkij 2 ; Cristian L. Achim 2 ; Ben Gouaux 2 ; Eliezer Masliah 2 ; Janet Sinsheimer 3 ; Elyse Singer 1 ; David J. Moore 2 1 University of California Los Angeles, Long Beach, CA, US; 2 University of California San Diego, San Diego, CA, US; 3 University of California Los Angeles, Los Angeles, CA, US

Background: It is unclear which histopathological features of HIV underlie the symptoms of HIV-associated neurocognitive disorders (HAND). Host-genetic association studies have implicated a variety of risk alleles for HAND, but findings have been difficult to replicate due largely to the fact that the neuropsychological impairments common in HAND are heterogeneous across patients. Instead, focusing on intermediate phenotypes, such as histopathology, may serve two purposes: 1) to clarify which, if any, genetic variants contribute to HAND, and 2) to determine which histopathological markers are most relevant to HAND. This study attempts to bridge the gap between genetics, neuropathology, and behavior in the context of HAND. Methods: We examined 82 HIV+ cases diagnosed within 1 year of death as neuropsychologically normal or as having HAND. Cases whose neuropsychological impairment was better attributed to other factors (e.g., stroke, TBI) were not included. The following histopathological markers were quantified from the frontal cortex, frontal white matter, putamen, and hippocampus: glial fibrillary acid protein (GFAP), ionized calcium binding adapter molecule-1, and amyloid- β (A β ). Synaptophysin (SYP) and microtubule-associated protein-2 (MAP2) were also quantified in frontal cortex of 37 cases. DNA was extracted from occipital lobe and 24 immunological and neurobiological-related genes were genotyped. HIV disease characteristics and neuropsychological data were collected. Non-parametric tests were used due to the non-normal distribution of histopathological data, with Bonferroni correction for multiple comparisons. Results: Global neurocognitive functioning was correlated with MAP2 (r= -.691, p<0001) and SYP (r= -.580, p<.0001) in frontal cortex. Of the virologic variables examined, only estimated years with HIV infection was correlated with GFAP in putamen (r = .421, p<.0001). GFAP in putamen and frontal grey matter was influenced by IL1- α genotype (p=.001). Conclusions: Findings suggest that astrogliosis (GFAP) in subcortical brain structures increases with duration of infection (but not age), and that this is influenced by a pro- inflammatory IL1- α genotype. However, GFAP was not correlated with neurocognitive functioning or HAND. Instead, MAP2 and SYP in frontal cortex and A β in putamen were associated with HAND and neurocognitive functioning, indicating that neuronal integrity and communication are more directly associated with behavioral features of HAND. 2:30 pm– 4:00 pm HAND Diagnosis and Predictors 465 Relative Risk and Factors AssociatedWith Progression to Symptomatic HAND Sean B. Rourke 1 ; John Gill 2 ; Anita Rachlis 1 ; Colin Kovacs 3 ; Gordon Arbess 5 ; Jason Brunetta 3 ; Adriana Carvalhal 5 ; Chris Power 2 ; Ann N. Burchell 4 ;Tsegaye Bekele 4 1 University of Toronto, Toronto, Canada; 2 University of Alberta, Calgary, Canada; 3 Maple Leaf Medical Clinic, Toronto, Canada; 4 The Ontario HIV Treatment Network, Toronto, Canada; 5 St. Michael’s Hospital, Toronto, Canada Background: HIV-associated neurocognitive disorders (HAND) remain prevalent and recent work by Grant and colleagues (2014) demonstrated that asymptomatic neurocognitive impairment (ANI) is associated with a 2-5 risk for the development of symptomatic HAND (mild neurocognitive impairment [MND] or HIV-associated dementia [HAD]) in persons followed in CHARTER. We were interested in replicating and extending these results in a Canadian sample. Methods: Study sample included 575 adults who are enrolled in the Ontario HIV Treatment Network Cohort Study (OCS) and who were either neuropsychologically normal (NP-Normal; n=299) or had ANI (n=276) at baseline. Neuropsychological testing was done every 12 months (median follow-up time: 30 months) using a brief test battery that included Hopkins Verbal Learning Test- Revised (HVLT-R), Grooved Pegboard, and WAIS-R Digit Symbol. Cognitive complaints were assessed with four-itemMedical Outcomes Study Cognitive Functioning scale. HAND status was assigned according Antinori et al., (2007) criteria. We used proportional hazards regression modelling to generate risk ratios for progression to MND or HAD after adjusting for baseline and time-varying covariates. Results: Participants: 82%men, 64% Caucasian, 86% on cART, and 73% had undetectable HIV viral load at baseline. Over the follow-up period, 99 individuals (39 who were NP-N and 60 who had ANI at baseline) showed progression to MND or HAD. Participants with ANI had shorter time of progression to MND or HAD than those who were NP-Normal at baseline after adjusting for baseline and time-varying predictors: adjusted hazards ratio 1.85 (95% confidence interval: 1.12-2.82; p=0.005). Among the covariates examined, depression and current smoking were significant predictors of higher risk of progression, while undetectable plasma HIV viral load was significantly associated with lower risk of progression to MND or HAD . Low nadir CD4 (<200 cells/mm 3 ) was not a significant predictor of progression in adjusted analyses although it was associated with higher risk prior to adjustment for covariates. Conclusions: Asymptomatic Neurocognitive Impairment is associated with almost two-fold increased risk of progression to symptomatic HAND. Early treatment with cART and addressing medical and mental comorbidities may delay or lower risk of the development and progression of symptomatic HAND. 466 Monocytes Activation Characterizes Immune Failure but Not Cognitive Impairment on ART Antonio Muscatello 1 ; Davide Mangioni 1 ; Paolo Perseghin 2 ; Arianna Incontri 2 ; Alessandro Soria 1 ; Nicola Squillace 1 ; Giuseppe Lapadula 1 ; Sebastiano Leone 1 ; Andrea Gori 1 ; Alessandra Bandera 1 1 S. Gerardo Hospital, Monza, Italy; 2 San Gerardo Hospital–UOS Aferesi e Nuove Tecnologie Trasfusionali–SIMT, Monza, Italy Background: Neurocognitive impairment (NCI) in HIV+ patients can occur despite effective ART and has been linked to increased CD16-bearing monocytes in circulation. We evaluated monocytes (M/M) phenotypes and activation markers in HIV+ patients under ART, aiming to define the role of innate immune activation on CD4+ T cell recovery and NCI. Methods: Cross sectional study: 84 HIV+ patients whit actual CD4+ T cell count <350/ μ l (n=39, Immune failure-IF) or >500/ μ l (n=45,Immune success-IS) after ≥ 18 months of ART and with VL<50 copies/ml for at least 12 months. The two groups were matched both by age and CD4+ T cell nadir. All patients participated in blood studies and a battery of 8 neuropsychological tests (NPZ8). Peripheral M/M phenotypes (distinguished based on CD14 and CD16 surface expression on “classical” CD14++CD16-, “intermediate” CD14++CD16+ and “non classical” CD14+CD16++) as well as surface activation markers (CD163, CD11b, HLA-DR, CD38, CD69) were evaluated by flow cytometry. Statistical analyses were performed using Wilcoxon and Chi-square. Results: Compared to IS subjects, IF patients showed significantly lower levels of “classical”(p=0.05) and higher levels of “intermediate” monocytes (p=0.04). “Non classical” monocytes were not significantly different between groups. IF patients displayed significantly lower expression of CD163 compared to IS patients, both on total (p=0.02) TUESDAY, FEBRUARY 24, 2015 Session P-G5 Poster Session Poster Hall

Poster Abstracts

318

CROI 2015