CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

variables were adjusted for age, scanner, genetic ancestry, CD4 + T-cell nadir, HIV RNA detectability in plasma, and trait-specific covariates. Analyses stratified by the presence of neurocognitive impairment (Global Deficit Score <0.5 or ≥ 0.5), virus detectability, or comorbidities were also performed, and two levels of correction for multiple statistical tests were applied. Results: Of 22 common SNPs that were significantly associated with structural and/or metabolic traits after correction for the 37 haplotype blocks represented ( p <0.05), 5 SNP associations also survived the most conservative correction (for 37 haplotype blocks and 21 ROI) and demonstrated biologically plausible patterns of association with traits previously linked to aging and/or HAND (Table). Iron-regulatory genes with significant associations included: TFRC in subjects with detectable HIV RNA, SLC40A1 in subjects with undetectable viral RNA, SLC11A1 in subjects without neurocognitive impairment, and CP and ACO2 in subjects with comorbidities.

Conclusions: Iron-regulatory gene variation is associated with degenerative neuroimaging traits in HIV-infected persons, such as abnormal WM and subcortical GM volumes, and with regional metabolite levels that reflect brain inflammation and neuronal integrity. Further studies are needed to replicate these findings, incorporate iron-sensitive neuroimaging ( e.g. , T2*), and assess contributions of these variants to neurodegenerative sequelae of HIV infection, including HAND. 462 Synergistic Effects of MBL2 / APP Polymorphisms on Neurocognitive Impairment in CHARTER Kumud Singh ; Qianqian Deng; Christine Fennema-Notestine; FlorinVaida; Ronald Ellis; Scott Letendre; Donald Franklin; Debralee Rosario; Robert Heaton; Igor Grant CHARTER University of California San Diego, La Jolla, CA, US Background: Mannose binding lectin (MBL), coded by MBL2 , recognizes mannose laden glycans on HIV-1 gp120 and activates complement for virus opsonization. Also, via its cysteine rich region, MBL interacts with amyloid beta (coded by APP ) presumably for clearing it by complement mediated lyses. We hypothesized that the synergistic effects of polymorphisms in APP promoter (rs364048) that enhances APP expression and MBL2 variants with lower MBL ( A/O : rs1800450; rs1800451; rs5030737; H/L : rs11003125; Y/X : rs7096206; and P/Q : rs7095891), will predict neurocognitive (NC) outcomes in HIV-infected adults. Methods: Of 563 subjects from the CHARTER (CNS HIV AntiRetroviral Therapy Effects Research) longitudinal cohort, 399 were on highly active antiretroviral therapy (HAART), 79 on non-HAART and 85 were antiretroviral-naive. 244 subjects were evaluated with single voxel magnetic resonance spectroscopy for brain metabolites choline (CHO), creatine (CR), N-Acetylaspartate (NAA) and myo-inositol (MI) in frontal white matter (FWM), frontal gray matter (FGM) and basal ganglia using LC Model. Associations of g enotypes with neuroimaging outcomes were cross-sectionally examined by multivariate linear regression. Analyses adjusted for comorbidity, current CD4>=200, nadir CD4>=200, detectable plasma/CSF HIV RNA, and HCV serostatus. NC endpoints included global deficit score (0-5), global neurocognitive impairment (NCI, yes/no), and HIV-associated neurocognitive disorders (HAND). Logistic regression for comparing genotypes and Bonferroni correction were used. Results: Of 563 subjects, 79%were males; 54%White and 43% Black. Presence of APP rs364048 and MBL2-A/O variants was associated with abnormal FWM (p=0.014) and a strong trend for HAND in subjects on HAART (p=0.06). Presence of MBL2-P/Q and rs364048 in those with HAART predicted worse NCI (p=0.013) and HAND (Unimpaired MBL2-Y/X and rs364048, and on HAART were associated with NCI (p=0.047), HAND (p=0.033), and strong trends for higher FWM-NAA (p=0.047) and FWM-CR (p=0.06). Presence of MBL2-H/L and rs364048 in those on HAART also predicted higher FGM-NAA (p=0.012). Conclusions: Synergistic effects of higher APP and lower MBL expression due to presence of MBL2/APP polymorphisms, potentially facilitate complement activation, neuroinflammation and brain abnormalities leading to neurocognitive impairment. MBL2/APP genotypes are potential predictive biomarkers for HAND. 463 No Association Between Apo ε 4 , HIV Infection, Age, Cognitive Outcome or Death James T. Becker 1 ; Jeremy J. Martinson 1 ; Sudhir Penugonda 2 ; Lawrence Kingsley 1 ; Samantha A. Molsberry 1 ; Sandra Reynolds 3 ; Andrew Levine 4 ; Eileen Martin 5 ; Cynthia A. Munro 6 ; Ned Sacktor 6 1 University of Pittsburgh, Pittsburgh, PA, US; 2 Northwestern University, Feinberg School of Medicine, Chicago, IL, US; 3 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US; 4 David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, US; 5 Rush University Medical Center, Chicago, IL, US; 6 Johns Hopkins University School of Medicine, Baltimore, MD, US Background: The ε 4 allele of the ApoE gene may have important interactions with physical health and cognitive function among individuals with HIV disease. The purpose of this study is to examine the relationships between ε 4, HIV disease, age, incident neuropsychological impairment and death in a large, well-characterized study sample. Methods: Among the men participating in the Multicenter AIDS Cohort Study (MACS) 2,846 had ApoE genotyping and neuropsychological test data available for analysis. Classifications of cognitive impairment were operationalized using the criteria outlined by Woods et al. (2004) and Antinori et al. (2007). We examined the unadjusted associations between ApoE and other variables using t-tests and contingency tables. Time to death or incident cognitive impairment was tested using Cox proportional hazard models. Results: There was a significant association between race and ApoE genotype; 23.2% of the men who identified themselves as White had at least one copy of the ε 4 allele, whereas 31.2% of the men in other races (primarily African-American) had at least one ε 4 allele. We found a significant association between time to death and HIV infection status, as well as older age, race, and education; ApoE status was not significantly associated with time to death. We found a significant association between HIV infection and time to incident cognitive impairment, as well as age, and education; Apo ε 4 status was not related to incident cognitive impairment. There were no significant two-way interactions between ApoE, HIV, and age on cognitive impairment. Conclusions: Our analysis found no association between ApoE genotype and the development of cognitive dysfunction or time to death. This does not preclude the possibility that ApoE may have an impact on specific cognitive functions or cognitive domains; however, our findings indicate that the transition from normal to impaired cognition is unaffected by ApoE ε 4. These data replicate and strengthen prior findings of the lack of association between ApoE genotype and cognitive outcomes in HIV disease. We conclude that within the specific constraints of an exclusively male sample in which the majority of participants were younger than 65 years of age, the ApoE ε 4 allele does not interact with HIV serostatus.

Poster Abstracts

317

CROI 2015