CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

1 Case Western Reserve Univ, Cleveland, OH, USA, 2 Vanderbilt Univ, Nashville, TN, USA, 3 Univ of California San Diego, San Diego, CA, USA, 4 Univ of California San Diego, La Jolla, CA, USA, 5 Cleveland Clinic Lerner Coll of Med, Cleveland, OH, USA Background: HIV-Associated Neurocognitive Disorder (HAND) is a term established to capture a spectrum of neurocognitive (NC) deficits associated with HIV infection. The genetic underpinnings of HAND are poorly understood. CHARTER is a US-based observational study of neuro-HIV outcomes in ambulatory, HIV+ adults who underwent standardized, comprehensive NC assessment (2003-7) and were assigned a Global Deficit Score (GDS) [normal (GDS<0.5) or impaired (GDS≥0.5)]. In this study, we investigated the impact of genetic variants known to alter the expression of genes in whole blood on GDS outcomes. Methods: We used CHARTER genome-wide association study (GWAS) data (imputed to the 1000 Genomes reference) to predict gene expression using an approach called PrediXcan. It estimates the genetically regulated component of gene expression using reference panels from studies of expression quantitative trait loci (eQTL). In this study, Gene/ Tissue Expression data and CHARTER genome-wide genotype data were used to model the expression profile of 11,000 genes. We then evaluated associations of these “imputed” gene expression traits with two CHARTER NC phenotypes (continuous GDS and GDS impairment). We performed regression analyses to identify predicted gene expression values that associate to continuous GDS and GDS impairment, adjusting for population effects and known clinical covariates (comorbidity status, current CART use, plasma viral load, nadir CD4+ T-cell count). Results: While no genes were significant after multiple testing corrections, the top genes were Ankyrin Repeat Domain 44 (ANKRD44), insulin receptor substrate 2 (IRS2), and Activating Transcription Factor 3 (ATF3). Using a set of 222 genes associated to CHARTER phenotypes at p < 0.01, we performed gene pathway enrichment analysis. Initial analysis suggests overrepresentation of iron ion binding, immune defense response, regulation of inflammatory process and mitochondrial-mediated membrane pathways. Additionally, among the most significant associations (p < 0.01), we found 17 genes with known HIV protein interactions. Conclusion: We identified genes and pathways influencing NC impairment in HIV-infected cases. We hypothesize that individuals with altered regulation of HIV-interacting genes may be predisposed to HAND in the presence of HIV infection. We provide support for a role of iron transport in HAND pathogenesis and evaluates gene expression effects by modeling the mechanisms through which genetic variants influence NC impairment. 394 MRS MEASURES ASSOCIATE WITH IMPAIRED NEUROPSYCHOLOGICAL PERFORMANCE IN ACUTE HIV Joanna Hellmuth 1 , James L. Fletcher 2 , Victor Valcour 1 , Napapon Sailasuta 3 , Somporn Tipsuk 2 , Jintanat Ananworanich 4 , Bonnie Slike 4 , Robert Paul 5 , Serena Spudich 6 , for the SEARCH 010/RV254 Study Group 1 Univ of California San Francisco, San Francisco, CA, USA, 2 SEARCH, Bangkok, Thailand, 3 Univ of Hawaii, Honolulu, HI, USA 4 US Military HIV Rsr Prog, Silver Spring, MD, USA, 5 Univ of Missouri- St. Louis, St. Louis, MO, USA, 6 Yale Univ, New Haven, USA Background: We used magnetic resonance spectroscopy (MRS) to assess the mechanisms underlying impaired neuropsychological performance (defined as ≥1 SD below Thai norms on ≥2 cognitive tests) in untreated acute HIV infection (AHI). Methods: Participants were prospectively identified through laboratory screening at an HIV testing center in Bangkok, Thailand and diagnosed with Fiebig I-V acute HIV. Prior to starting combination antiretroviral therapy (cART), participants completed neuropsychological (NP) testing (Color Trails I, Color Trails II, Grooved pegboard non-dominant hand, Trail Making A), a PHQ-9 depression inventory, phlebotomy, and optional cerebrospinal fluid (CSF) testing for viral and inflammatory markers. A subset of AHI participants and a group of HIV-uninfected individuals underwent 1.5 Tesla brain MRS. Results: 297 participants had NP testing during AHI (median estimated HIV infection duration 21 days, IQR: 10). The proportion of AHI participants with impaired NP performance pre-cART was 20.9%, similar to a report from 36 participants in this cohort. Those with impaired NP performance had higher PHQ-9 depression scores (11.8 vs. 9.9; p=0.02), and a trend towards higher plasma log10HIV RNA (6.0 vs. 5.7; p=0.09). In the 30% of participants with MRS (n=90), those with impaired NP performance had higher frontal gray matter glutamate+glutamine (Glx)/creatine (excitotoxocity and/or glial dysfunction; 2.46 vs. 2.27, p=0.008), lower frontal white matter NAA/creatine (neuronal integrity; 1.42 vs. 1.55; p=0.022), and higher posterior cortical gray choline/creatine (inflammation; 0.180 vs. 0.166; p=0.025) compared to those with normal performance. In a general linear model adjusting for age, AHI participants with impaired performance had higher frontal gray matter Glx/creatine compared to healthy controls (p=0.003) and both AHI groups had higher posterior cortical gray choline/creatine compared to controls (p≤0.001). Conclusion: AHI participants with NP impairment prior to cART exhibit abnormal MRS metabolite measures suggesting increased cortical and subcortical neuronal dysfunction and inflammation compared to those without impairment. This may reflect brain differences prior to HIV infection, or may be due to a differential impact of AHI in the central nervous system. We confirmed that over 20% of participants in AHI have impaired cognitive performance prior to cART. 395 CIRCULATING HIV DNA IS ASSOCIATED WITH WEAKER INTRINSIC BRAIN CONNECTIVITY Background: Monocytes constitute a proviral HIV DNA reservoir contributing to HIV-associated neurocognitive disorder (HAND) that persists despite suppressive antiretroviral therapy (ART). Lymphocyte HIV DNA has also been implicated in HAND. Although HIV DNA in peripheral blood has been linked to subcortical and cortical (e.g., insular) gray matter atrophy, brain function has not been examined in relation to HIV DNA. Methods: We cross-sectionally studied HIV+ and HIV- individuals who underwent resting-state functional connectivity (RSFC) magnetic resonance imaging at 3T and neuropsychological (NP) testing. HIV DNA copy numbers per 106 cells were assessed within CD14+monocyte and CD14- non-monocyte peripheral blood mononuclear cell subsets in HIV+ subjects. Global (NPZ_14) and composite domain-specific NP z-scores were obtained. Analysis of Functional Neuroimages software was used to analyze RSFC data. Age was a covariate in voxelwise analyses. Whole-brain RSFC was computed for seed regions of interest (ROIs) in the insula, caudate, putamen, amygdala and hippocampus; and RSFC differences between HIV+ and HIV- groups assessed. RSFC correlations with HIV DNA were examined. Voxelwise estimates of RSFC were corrected for multiple comparisons using a cluster-based method to achieve a corrected p<0.05. Results: 44 HIV- individuals (55 ± 8 years old) and 38 HIV+ subjects (53 ± 8 years old; all on ART; 87%with plasma HIV RNA < 50 copies/mL; CD4 count=541 ± 279 cells/mm3), of whom 27 had HIV DNA data (log10CD14+ HIV DNA=3.4 ± 1.1; log10CD14- HIV DNA=2.5 ± 1.2), were evaluated. Insular RSFC to prefrontal cortex (PFC) was lower in HIV+ than in HIV- subjects. Decreased RSFC of the left anterior insula to medial PFC correlated with higher CD14+ HIV DNA (Figure). CD14- HIV DNA correlated negatively with the RSFC of left insular and bilateral caudate ROIs to inferior temporal (IT), parietal, cingulate and PFC regions. Average RSFC strength was related to NP z-scores: e.g., RSFC between right caudate and left IT gyrus correlated with NPZ_14 (R= 0.61, p=0.003). CD14- HIV DNA correlated with NPZ_14 (R=−0.59, p<0.01) and with psychomotor speed, working memory and executive function (R~−0.5, p<0.05). Conclusion: These findings directly link peripheral blood HIV DNA burden to brain and cognitive dysfunction in optimally treated HIV disease, underscoring the need to eradicate circulating HIV reservoirs. Our results for CD14- subsets indicate that the role of HIV DNA in T lymphocytes should be a focus of further study. Kalpana J. Kallianpur 1 , Bruce Shiramizu 1 , Melissa Agsalda-Garcia 1 , Robert Paul 2 , Cecilia Shikuma 1 , Gregory Kirk 3 , Rasmus Birn 3 1 Univ of Hawaii–Manoa, Honolulu, HI, USA, 2 Univ of Missouri St. Louis, St. Louis, MO, USA, 3 Univ of Wisconsin Madison, Madison, WI, USA

Poster and Themed Discussion Abstracts

CROI 2017 159