CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

481 MBL-HIV1gp120 Immunoreactivity Is AssociatedWith Markers of Neuronal Injury Carmen Teodorof 1 ; Damhnien Nguyen 1 ; Nishi Kadakia 1 ; Ricky Maung 2 ; Benchawanna Soontornniyomkij 1 ; Cristian Achim 1 ; David Moore 1 ; Eliezer Masliah 1 ; Marcus Kaul 2 ; Kumud Singh 1 1 University of California San Diego, San Diego, CA, US; 2 The Sanford BurnhamMedical Research Institute, La Jolla, CA, US Background: Mannose-binding lectin (MBL), an innate immune response protein binds directly to the mannose residues on HIV-1 envelope glycoprotein 120 (gp120) via its carbohydrate recognition domain (CRD) and leads to complement activation and virus opsonization. We hypothesized that MBL-gp120 interactions in HIV-1 infected brain will be associated with neuronal damage. Methods: HIV-1 infected frontal cortex brain tissues with or without HIV encephalitis (HIVE) (obtained from California NeuroAIDS Tissue Consortium) and hemi-brain sections from wild type (WT) and gp120 transgenic (gp120tg) mice were used to analyze MBL expression and immunoreactivity with somatodendritic marker MAP2, neurodegeneration marker phospho-Tau (pTau), synaptic marker synaptophysin (SYN) and complement activation product C3d. Furthermore, human primary neuronal cultures (HPNs) were treated with 5nM IIIB-gp120 to determine its effects on neuronal damage. Immunohistochemistry, confocal microscopy, z stacking and immunoblotting were used to analyze expression and immunoreactivity of MBL and gp120 with neuronal markers. Results: Presence of immune complexes (ICs) of MBL and gp120 was associated with a loss of neuronal dendrites (MAP2) and SYN puncta; and an increase of pTau immunoreactivity in HIVE vs. non-HIVE brain (N=5 each). Furthermore, complement activation product C3d was associated with immunodeposition of MBL-gp120 ICs in HIVE tissue. In a gp120tg mouse model, MBL isoforms MBL1 and MBL2 formed ICs with gp120; and compared to the WT mice, hemi-brains from gp120tg mice showed a loss of neuronal dendrites (MAP2) and SYN suggesting MBL-gp120 mediated neuronal damage. Also, 5nM IIIB-gp120 treatment of human primary neurons (HPNs) showed clear immunostaining of MBL-gp120 in perinuclear vesicles and MAP2 along neuronal processes within 30min, followed by a loss of MAP2 and SYN, and an increase of pTau by 6hrs. Confocal microscopy orthogonal view via z-stacking and immunoblots clearly confirmed the immunoreactivity of MBL and gp120. Conclusions: Presence of MBL-gp120 immune complexes was associated with a loss of MAP2 and SYN, and in an increase of pTau and C3d in HIV-1 infected brain, gp120tg mouse model and HPN cultures suggesting a unique role of MBL-gp120 interactions and complement activation in neuronal damage.

WEDNESDAY, FEBRUARY 25, 2015 Session P-G7 Poster Session

Poster Hall

2:30 pm– 4:00 pm Aging and Cognitive Decline

482 Amyloid Uptake by PET Imaging in Older HIV+ Individuals With Cognitive Impairment Ned Sacktor ; Richard Skolasky; Heidi Roosa;Yun Zhou;WeiguoYe; Noble George; DeanWong; Mona Mohamed Johns Hopkins University School of Medicine, Baltimore, MD, US

Background: Cognitive impairment among older HIV+ individuals could be due to HIV itself, vascular disease, or the early onset of Alzheimer’s disease. Amyloid deposition, a hallmark of Alzheimer’s, can be detected by brain position emission tomography (PET) imaging. A previous PET study using another marker of amyloid, [ 11 C] Pittsburgh B compound (PIB), in 16 HIV+ subjects (age: mean(SD) =46(3) years) with normal cognition (69%) and HIV-associated neurocognitive disorder (HAND) (31%) did not show increased [ 11 C] PIB uptake. The objective of this study was to determine whether abnormal amyloid deposits measured by PET [ 18 F] AV-45 is present in older HIV+ individuals > age 50 years, and is increased in HIV+ individuals with symptomatic HAND (mild neurocognitive disorder (MND) and dementia), compared to asymptomatic HAND [asymptomatic neurocognitive impairment (ANI)] and normal cognition). Methods: 25 HIV+ individuals (age: mean(SD) = 60.8(6.0) years) received neurological evaluations including neuropsychological testing, functional assessments and high resolution research tomography (HRRT) PET [ 18 F] AV-45 imaging. 6 HIV- individuals [age: mean(SD) = 68.3(7.8)] received similar assessments. AV-45 uptake was measured by cerebellum standardized uptake value ratios (SUVR) in 17 cortical and subcortical regions, and compared 1) between HIV+ individuals with and without symptomatic HAND, and 2) by HIV serostatus using the Wilcoxon test. Qualitative analysis of an abnormal PET scan was also performed. Results: HAND stage for HIV+ individuals was as follows: normal cognition-3, ANI-8, MND-7, HIV dementia-6. 12% of the HIV+ individuals (age range 57-64 years) had increased AV-45 uptake by qualitative analysis. HIV+ individuals with symptomatic HAND (MND and dementia) had increased AV-45 uptake in the hippocampus [median(IQR)= 1.26(1.10- 1.35)] and basal ganglia [median(IQR)= 1.64 (1.39-1.76)], compared to HIV+ individuals with ANI/normal cognition [hippocampus median(IQR) = 1.07(1.03-1.16)], (p= 0.049) and basal ganglia [median(IQR) =1.49(1.41-1.52), (p= 0.049). There were no differences in regional uptake by HIV serostatus though HIV- individuals were older than HIV+ individuals (p= 0.015). Conclusions: Amyloid deposition is increased in a minority of HIV+ individuals > age 50. Amyloid deposition in HIV+ individuals with symptomatic HAND is increased compared to individuals with asymptomatic HAND or normal cognition in specific regions which could account for cognitive impairment. 483 Lower CSF Amyloid- β Levels Are AssociatedWithWorse Neurocognitive Functioning in HIV-Infected Adults With a Family History of Dementia Background: Studies of HIV-infected (HIV+) patients have shown that independently both family history of dementia (FHD) and lower levels of A β -42 are associated with worse neurocognitive functioning. We measured cerebrospinal fluid (CSF) levels of A β -42 in a convenience sample of 184 HIV+ adults currently on antiretroviral therapy (ART) (90 with FHD and 94 demographically-matched without FHD) and examined the relationship between these variables and HIV-associated neurocognitive disorders (HAND). Methods: All participants underwent comprehensive neuropsychological and neuromedical assessments, and determination of CSF concentration of A β -42. FHD was defined as a self-reported first or second-degree relative with a dementia diagnosis. Univariate analyses were used to determine whether HAND status was associated with FHD, CSF A β -42, or any potential covariates (e.g., demographics, HIV disease characteristics) and to examine if CSF A β -42 levels differed by FHD. Multivariable logistic regressions then examined the association of CSF A β -42, FHD, and their interaction on HAND. Results: FHD did not differ between those with and without HAND ( p = 0.24); however, CSF A β -42 levels were significantly ( p = 0.03) lower in the HAND group. Further, CSF A β -42 was not associated with FHD ( p = 0.89). Multivariable models controlling for race and comorbidity rating showed a significant main effect of CSF A β -42 ( p = 0.03) and a trend ( p = 0.06) towards an interaction between FHD and CSF A β -42, such that lower CSF A β -42 was only associated with HAND in those with FHD ( p < 0.01) as compared to those Pariya L. Fazeli 1 ; David J. Moore 1 ; Donald Franklin 1 ; Robert Heaton 1 ; Christina Marra 2 ; Benjamin B. Gelman 3 ; Allen McCutchan 1 ; Igor Grant 1 ; Scott Letendre 1 1 University of California San Diego, San Diego, CA, US; 2 University of Washington Seattle, Seattle, WA, US; 3 University of Texas Medical Branch, Galveston, TX, US

Poster Abstracts

325

CROI 2015