CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

450 NOX-4 ASSOCIATED NITROSATIVE STRESS AND INEPT REDOX ADAPTATION IN AGED HIV-1 TG RAT

William Reid 1 , Swati Shah 1 , Frank Denaro 2 , Dragan Maric 1 , Dima A. Hammoud 1 1 NIH, Bethesda, MD, USA, 2 Morgan State University, Baltimore, MD, USA Background: Due to the success of combined anti-retroviral therapy, HIV-positive (HIV+) patients are living longer with a better quality of life. Nonetheless, human immunodeficiency virus associated neurocognitive disorders (HAND) continue to be a widespread problemwith accelerated progression of neurocognitive impairment caused by aging in HIV+ patients. HAND is characterized by increased reactive oxygen and nitrogen species at the cellular level. Motor and behavioral dysfunction are among the common symptoms and it is believed that oxidative and nitrosative stress contributes to mechanistic changes leading to neurocognitive impairment. Our previous imaging, histological, motor and behavioral assessments support a dysregulation in dopaminergic function as the HIV-1 transgenic (Tg) rat ages. Methods: The goal of this study is to demonstrate the presence of oxidative and nitrosative stress within the neuroanatomic areas associated with dopaminergic dysfunction in the HIV-1 Tg rat brain by using molecular and immunohistological techniques. Results: We report pathology suggestive of pre-synaptic dopaminergic neuronal loss (decreased striatal tyrosine hydroxylase and dopamine transporter staining in the basal ganglia and decreased NeuN staining in the substantia nigra; p<0.05). In the striatum, we also found 2.6 fold increase in Nox4 expression (p<0.05), 1.6 fold increase in neuronal nitric oxide synthase (nNOS) protein levels (p=0.056) and associated significant increase in 3-nitrotyrosine (3-NT) immunostaining (figure 1) and nitrosylation of axonal neurofilament tyrosine residues (p<0.05) in the aged HIV-1 Tg rats compared to age-matched non-Tg controls. This increase in free radical mediated neuronal pathology occurred without significant induction of the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) and redox adaptation of the Nrf2 responsive thioredoxin and glutathione antioxidant systems. Conclusion: Our findings suggest increased Nox4 expression and lack of an appropriate redox adaptation in the aging HIV-1 Tg rat, possibly due to chronic exposure to HIV-1 proteins. Increased nitrosative stress and nitrosylation of striatal axonal neurofilament proteins is increased possibly contributing to dopaminergic neuronal structural changes and secondary dopaminergic dysfunction. We therefore propose the HIV-1 Tg rat as an appropriate model of oxidative stress in the setting of HIV infection.

449 PERIPHERAL AND CSF IMMUNE ACTIVATION AND INFLAMMATION IN HIV+ PATIENTS STARTING cART Esther Merlini 1 , Francesca Iannuzzi 1 , Andrea Calcagno 2 , Francesca Bai 1 , Mattia Trunfio 2 , Antonella D’Arminio Monforte 1 , Stefano Bonora 2 , Giulia Marchetti 1 1 University of Milan, Milan, Italy, 2 University of Turin, Turin, Italy Background: Cerebrospinal Fluid (CSF)/plasma HIV-RNA ratio≥1 has been associated with neurocognitive impairment. We sought to explore whether CSF/plasma HIV-RNA ratio associates with peripheral and CSF inflammation and activation and with neurocognitive screening test performance, in HIV+ patients (pts) before (T0) and after 12 months (T12) of suppressive cART. Methods: We enrolled 70 HIV+ cART-naive pts. 33/70 were followed for 12 months after cART. At T0 and T12 pts underwent lumbar puncture and blood withdrawal. Pts were stratified according to CSF/Plasma ratio: high CSF/plasma HIV-RNA ≥1 (H-C/P); low CSF/plasma HIV-RNA <1 (L-C/P). Immuno-virological analyses: CD38/CD45RA/CD45R0/HLA-DR/CCR7/Ki67, IL-2/IFN- γ after HIV/CMV exposure on CD4/CD8 (flow cytometry); total HIV-DNA (q-PCR) on PBMCs; IFN- γ /IL-6/sCD14/TNF-α/MCP1/IP10/neopterin/S100Beta (Luminex/ELISA) on plasma and CSF. In 22/33 pts at T0 and T12 we also performed screening neurocognitive assessment: international HIV dementia scale, mini-mental state examination, frontal assessment battery. Cognitive impairment defined as ≥2 tests altered. Statistical analyses: Chi-square, Mann-Whitney, Kruskal-Wallis, Wilcoxon paired tests. Results: 61/70 pts (87%) were L-C/P; at T0 L-C/P and H-C/P pts showed comparable peripheral and CSF inflammation, peripheral HIV reservoir, T-cell activation/proliferation and maturation, and HIV/CMV-specific response (Fig.1a). At T12, while both H-C/P and L-C/P significantly reduced T-cell activation, only L-C/P pts showed a reduction in CSF sCD14, IL-6 and MCP-1 and in plasma TNF-α (Fig.1b). Besides, L-C/P pts alone showed an increase in naïve CD4+ and CD8+ and central memory CD4+, with a parallel reduction of effector memory CD8+ (Fig.1b). Having shown changes in peripheral and CSF immune parameters, according to CSF/plasma ratio, we next investigated possible associations with cognitive performance. Indeed, we observed that at T0, 9/22 subjects presented altered cognitive impairment: 5/16 (31%) L-C/P, 4/6 (67%) H-C/P (p=.178), with no significant variation at T12 (L-C/P: 4/16; H-C/P: 4/6; p=.137). Conclusion: Although showing a slower response in terms of peripheral and CSF pro-inflammatory/effector phenotypes on cART, HIV+ pts with high CSF/ plasma HIV-RNA ratio seem to maintain stable cognitive performance, as assessed by screening tests. A longer follow up may be needed in order to assess the time-trends of cognitive functioning in pts presenting with high CSF/plasma HIV RNA ratio.

Poster Abstracts

CROI 2018 160