CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

the Roche 454 FLX Titanium platform. Analyses of viral genetic compartmentalization and evolution in CNS and blood were used to identify the likely source compartment (blood or CSF, with the latter representing the CNS anatomical compartment) of HIV RNA rebound following ART interruption. At the same time-points, we measured levels of different soluble markers of inflammation and cellular trafficking (i.e. soluble [s]CD14, sCD163, IL-2, IL-6, IL-8, TNF- α , IL-10, MCP-1 and MIP-1 α in blood and CSF). Results: In ten out of 14 participants viral rebound populations were compartmentalized between blood and CSF (F st , p ≤ 0.05 for at least one gene). Seven participants were sampled within three weeks of the first detectable HIV RNA in CSF, suggesting that rebound originated within CNS rather than migrating from blood. At the second sampled time- point, three additional participants became compartmentalized. Only one participant remained panmictic (genetically mixed populations) for the entire study follow-up. Levels of four cytokines (IL-2, IL-6, sCD163 in blood and TNF- α in CSF) were higher in non-compartmentalized participants (p ≤ 0.05), but none was significant after adjusting for multiple testing. Conclusions: Our study suggests that HIV reservoirs in the CNS contribute to viral rebound in most HIV-infected subjects interrupting ART. Reservoirs in all anatomic compartments need to be actively targeted to achieve a complete functional cure. 59 Impaired Blood-Brain Barrier Integrity Is AssociatedWith Neuronal Injury in HIV Birgitta Anesten 1 ; Lars Hagberg 1 ; Henrik Zetterberg 2 ; Staffan Nilsson 3 ; Bruce J. Brew 4 ; Dietmar Fuchs 5 ; Richard Price 6 ; Magnus Gisslén 1 1 University of Gothenburg, Gothenburg, Sweden; 2 University of Gothenburg, Gothenburg, Sweden; 3 Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden, Gothenburg, Sweden; 4 University of New South Wales, Sydney, Australia; 5 Division of Biological Chemistry, Biocenter, Medical University, Innsbruck, Austria, Inssbruck, Austria; 6 University of California San Francisco, San Francisco, CA, US Background: Blood-brain barrier (BBB) damage is prevalent in HIV. The aim of this study was to assess the prevalence of BBB disruption in different stages of HIV-infection and study risk factors and potential association with neuronal injury. Methods: Using a cross-sectional design and archived CSF samples from three cohorts (Gothenburg, Sweden; San Francisco, USA; Sydney, Australia), we compared BBB integrity (CSF/plasma albumin ratio) with CSF and blood concentrations of HIV RNA and neopterin, CSF WBC count, and CSF neurofilament light protein (NFL) in 7 HIV-infected groups (n=657 ): 4 groups of untreated ‘neuroasymtpomatic’ (NA) subjects defined by blood CD4+ T cells of >350, 200-349, 50-199, and <50 cells/ m L; 2 groups of untreated patients with HIV-associated dementia (HAD) staged by severity (stage 1 vs 2-4); subjects on antiretroviral treatment (ART) with P HIV-RNA <50 copies/mL >6 months. An HIV-uninfected control group was also examined (n=53). Results: The albumin ratio was significantly increased in HAD as compared to all other groups with highest levels in those with more severe dementia. 68 % of patients with HAD had increased albumin ratio compared to 16 % of NA subjects without ART. No significant difference in albumin ratio was found between NA untreated subjects, subjects on ART, and HIV-negative controls. Significant correlations between BBB integrity and CSF WBC count (p<0.01, r s =0.16), CSF HIV RNA levels (p<0.01, r s =0.14), blood (r s =0.20) and CSF (r s =0.25) neopterin, and age (r s =0.24; all p<0.001) were found in NA untreated subjects. In a multiple linear regression analysis only age and CSF neopterin stood out as independent predictors to albumin ratio with adjusted estimates in the multivariate analysis. Furthermore, a significant correlation was found between albumin ratios and CSF NFL concentrations in untreated patients (p<0.001, r s =0.40) as wells as in patients on ART (p<0.001, r s =0.57). Albumin ratio was confirmed as an independent predictor of CSF NFL together with age, CD4 and CSF WBC count. Conclusions: BBB disruption is mainly found in patients with HAD. Neither untreated neuroasymtpomatic subjects, nor patients on antiretroviral treatment had albumin ratios that were significantly different from HIV-negative controls. Intrathecal immunoactivation is a risk factor of BBB impairment and the association with CSF NFL suggest a pathogenic pathway between inflammation, BBB disruption and neural injury before development of dementia. 60 Cortical and Subcortical Brain Volumes in Primary HIV Infection PatrickW. Wright 1 ; Ashmit Pyakurel 3 ; Kevin Robertson 4 ; Julia Peterson 5 ; Henrik Zetterberg 7 ; Dietmar Fuchs 6 ; Richard Price 5 ; Dieter Meyerhoff 5 ; Serena Spudich 2 ; Beau Ances 1 1 Washington University School of Medicine, Saint Louis, MO, US; 2 Yale University School of Medicine, New Haven, CT, US; 3 Louisiana Tech University, Ruston, LA, US; 4 University of North Carolina, Chapel Hill, NC, US; 5 University of California San Francisco, San Francisco, CA, US; 6 Innsbruck Medical University, Innsbruck, Austria; 7 University of Gothenburg, Gothenburg, Sweden Background: HIV enters the nervous system soon after seroconversion. Though effects of chronic HIV infection on volumes of cortical and subcortical brain regions are well characterized, little is known about the extent of volumetric alterations that may occur within the first year of infection. We assessed brain volumes in antiretroviral therapy (ART)- naïve subjects with primary HIV infection (PHI, <1 year after initial infection) and age-matched HIV-uninfected participants (HIV-). We correlated volumes with neuropsychological performance (NP), blood, and cerebrospinal fluid (CSF) biomarkers to examine mechanisms of and clinical associations with regional brain volumes during PHI. Methods: CSF, blood, NP testing, and structural T1 magnetic resonance imaging scans were acquired from 18 HIV- and 48 PHI male participants. Volumetric measurements were obtained (using Freesurfer 5.1) from the following regions of interest (ROIs): caudate, amygdala, corpus callosum, ventricles, putamen, thalamus, cortical white matter, and total grey matter. Student’s t-test assessed volumetric differences in these ROIs between the two groups. Pearson correlations examined relationships during PHI between volumetric measures and biomarkers in CSF [viral load (VL), neopterin, and neurofilament light-chain (NFL)], and blood (VL, CD4+, and CD8+ T cell count), and NP tests [digit-symbol (DSST), grooved pegboard (GPD), finger-tapping (FT), and timed gait (TG)]. Results: PHI (median 106 days after estimated infection) and HIV- participants were similar in age (36.7 and 35.2 years, respectively) and education (16.1 years and 15.42 years). Only the putamen was significantly different (decreased volume) in PHI compared to HIV- ( p =0.05). Within the PHI group, putamen volume associated directly with decreasing CD4+ count ( p =0.004, Fig. 1A). Trends for inverse correlations were noted for CSF/plasma albumin ratio ( p =0.07) and CSF NFL ( p =0.09). Reductions in putamen volume in PHI participants were associated with worse performance on the DSST ( p =0.05), FT ( p =0.05), and TG ( p =0.02, Fig. 1B) tests.

Oral Abstracts

Figure 1. In primary HIV infection, the volume of the putamen (in cubic milimeters) is significantly positively correlated with CD4+ T cell count (A) and inversely associated with decreasing performance on the timed gait neuropsychological task (B).

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CROI 2015