CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Conclusions: At baseline, PHI subjects had ADMA levels higher than values from uninfected and chronically infected ART-treated historical comparisons, and ADMA elevation correlated with levels of blood CD8+ T cells, but not CNS measures. In contrast to prior findings in cross sectional studies of treated, suppressed chronic HIV subjects, ADMA levels in our subjects did not change after more than 9 months on ART initiated during early infection, suggesting ongoing endothelial dysfunction. 476 Platelet-Endothelial Interactions in SIV-Associated CNS Disease Claire E. Lyons 2 ; Hannah Schneider 3 ; Liz Engle 1 ; Suzanne E. Queen 1 ; Craig N. Morrell 4 ; Joseph L. Mankowski 1 ; Kelly A. Pate 1 1 Johns Hopkins University School of Medicine, Baltimore, MD, US; 2 Tufts University, North Grafton, MA, US; 3 Colorado State University, Fort Collins, CO, US; 4 University of Rochester, Rochester, NY, US Background: Platelet decline is associated with increased risk for the development of HIV-associated neurocognitive deficits. Interaction of activated platelets with brain microvascular endotheliummay contribute to platelet decline and directly influence the permeability of the blood brain barrier. We sought to determine whether these interactions occur in the SIV-infected pigtailed macaque model of HIV-associated CNS disease. Methods: SIV-infected macaques and mock-inoculated controls (N=4) were euthanized and perfused to clear the organs of blood during acute (N=6) or terminal (N=10) infection. Immunohistochemistry for resident (CD68) and non-resident (CD163, Mac387) macrophages, SIV (KK41) and platelets (CD42b) was used to visualize platelet-endothelial interactions in the brain and perivascular macrophage infiltrates characteristic of CNS disease. Platelet rich plasma was harvested during terminal infection (N = 10) and frommock inoculated controls (N=6). Platelets were stimulated with the thromboxane agonist U46619 then assayed for surface expression of the activation marker p-selectin using flow cytometry. Confluent monolayers of brain microvascular endothelial cells (BMECs) were exposed to washed platelets from SIV infected macaques (N=5), uninfected macaques (N=6) or media alone in transwells and permeability quantified with FITC-inulin. Results: Brains from SIV-infected macaques were more likely than brains from uninfected controls to have platelets bound to vascular endothelium during acute (RR 4.0, P=0.03) and terminal (RR 3.6, P=0.04) infection. 6 of the 10 SIV+macaques had CNS disease during terminal infection and resident Mac387+ (RR 3.4, P=0.0001) or CD163+macrophages (RR 1.44, P=0.0005) but not non-resident CD68+macrophages (RR 1.2, P=0.2) were observed in these animals with increased likelihood around platelet-lined vessels. SIV- infected macrophages were similarly observed with increased likelihood around platelet-lined vessels (RR 1.5, P=0.007). Platelets harvested from infected macaques with CNS disease demonstrated more activation from U46619 stimulation (91.1%) than macaques without CNS disease (15.7%, P=0.036). Permeability of BMECs decreased two-fold following incubation with platelets from SIV infected macaques compared with uninfected macaques (P=0.01). Conclusions: Activated platelet-endothelial interactions may represent a protective mechanism against development of macrophage infiltrates in CNS disease that is removed in the context of HIV-associated thrombocytopenia. 477 Microbial Translocation Is AssociatedWith Neuroinflammation in HIV Subjects on ART Jaime H. Vera 1 ; Qi Guo 2 ; Adriano Boasso 1 ; Louise Greathead 1 ; James Cole 1 ; Courtney Bishop 2 ; Rabiner Ilan 2 ; Roger Gunn 2 ; Paul Matthews 1 ; AlanWinston 1 1 Imperial College London, London, United Kingdom; 2 Imanova Centre for Imaging Sciences, London, United Kingdom Background: Circulating microbial products such as bacterial 16s ribosomal DNA have been associated with immune activation in otherwise effectively treated HIV-infected subjects. The impact of microbial translocation on cerebral parameters remains unknown. The aim of this study was to examine the relationship between a marker of microbial translocation and brain biomarkers of inflammation, function and structure in treated HIV-infected individuals Methods: Plasma bacterial 16s ribosomal DNA (r16s DNA) was measured by quantitative polymerase chain reaction (qPCR) in 12 neurologically asymptomatic HIV-infected subjects on ART (viral load <50 copies/mL). All subjects underwent the following investigations: cerebral PET CT imaging assessing neuroinflammation using the 18kDA translocator protein (TSPO) radioligand [ 11 C]PBR28, diffusion tensor imaging (DTI) for the evaluation of white matter integrity and a lumbar puncture for the analysis of cerebrospinal fluid (CSF) chemokines. Relationships between plasma r16s DNA and [ 11 C]PBR28 binding, DTI fractional anisotropy (FA) and mean diffusivity (MD) and CSF chemokines were explored by correlation analyses Results: Median (range) for age and CD4 count were 41(26-49) years and 645(350-1240) cells/uL, respectively. Plasma r16s DNA median(range) was 4.2(41-2) copies/mL. Significant associations between increase concentration of plasma r16s DNA and greater [ 11 C]PBR28 binding were observed across several brain regions (Table 1). r16s DNA was also associated with greater MD in the forceps major (r=0.532; P= 0.07), right inferior longitudinal fasciculus (r=0.601; P= 0.03) and right inferior fronto-occipital fasciculus (r=0.509; P= 0.09). Finally, r16s DNA level was positively correlated with the proinflammatory chemokine IL-8 in the CSF (r=0.599; P= 0.024, CI=0.152 to 0.956)

Poster Abstracts

Conclusions: In neuroasymptomatic treated HIV-infected individuals microbial translocation is associated with markers of neuroinflammation and abnormalities in white matter integrity. The potential contribution of microbial translocation to the pathogenesis of HIV-associated cognitive impairment warrants further investigation. 478 DKK1 Is AssociatedWith HIV-Associated Neurocognitive Impairment ChunjiangYu 1 ; Melanie Seaton 1 ; Scott Letendre 2 ; Robert Heaton 2 ; Lena Al-Harthi 1 1 Rush University Medical Center, Chicago, IL, US; 2 University of California at San Diego, San Diego, CA, US Background: DKK1 is a soluble antagonist of the Wnt/ β -catenin pathway. It binds to LRP5/6 (a co-receptor of Wnts) and sequesters it away fromWnts. We demonstrated that Wnt/ β -catenin is a critical regulator of the glutamate/glutamine cycle in astrocytes, and diminished Wnt/ β -catenin signaling perturbs their neuroprotective properties. As a consequence, we hypothesized that increased DKK1 would increase the risk for neurocognitive impairment (NCI) in an HIV-infected (HIV+) cohort. Methods: To assess the relationship between plasma DKK-1 and NCI, blood plasma samples from 41 HIV+ and 43 HIV- adults were obtained from the UCSD TMARC cohort. DKK1 and MCP-1 plasma levels were measured by immunoassay. MCP-1 was included as a comparison marker; it is a neuroinflammatory chemokine driving monocyte/macrophage infiltration into the brain. All subjects were assessed using a standardized comprehensive NC battery that adhered to Frascati guidelines. NC performance was summarized using the global deficit score (GDS) method.

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CROI 2015