CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

Conclusions: Our volumetric results suggest that the putamen may be specifically affected in the first year of HIV infection, and the volume of this structure associates with systemic immune measures and neurocognitive performance during this period. Longitudinal analyses are required to assess whether early introduction of ART might stabilize or reverse these structural changes observed in PHI. 61 IRF4 Transcription Factor AssociatedWith Integrated HIV DNA in Brain Macrophages Benjamin B. Gelman 1 ; Joshua G. Lisinicchia 1 ;Tetyana P. Buzhdygan 1 ;Vipulkumar Patel 1 ;Tyler Clement 1 ; Samantha A.Trevino 1 ; Kristofer R. Jennings 1 ; Dennis L. Kolson 2 1 University of Texas Medical Branch, Galveston, TX, US; 2 University of Pennsylvania, Philadelphia, PA, US Background: Integrated HIV DNA (HIV int ) can become transcriptionally silenced and latently expressed in certain types of resting lymphocytes. In the brain viral infection occurs predominantly in macrophage type cells in which viral latency is not as thoroughly investigated. To identify the cellular targets of eradication therapy in the CNS we compared macrophage markers in human brain specimens containing high and low concentrations of latent HIV DNA. Methods: Integrated HIV DNA, total HIV DNA and HIV RNA were measured in frontal neocortex from 40 patients using qPCR or the O’Doherty two-step Alu-Gag assay. Infected patients were separated into those with less than or greater than 3% HIV int relative to the number of HIV RNA copies. Macrophage-expressed mRNAs were measured using qPCR in these groups and a group of 21 seronegative controls. Differences were evaluated with one-way ANOVA and Tukey tests. Results: High and low HIV int groups had equivalent HIV RNA copies per gram of brain tissue. The group with high HIV int had significantly greater expression interferon regulatory factor 4 ( IRF4 ) (p < 0.03). mRNAs corresponding to macrophage and microglial type marker antigens CD163, CD14, CD16, Mac387 and Iba-1 were not significantly different. IRF4 protein expression in specimens with higher HIV DNA was localized histologically in brain M2 macrophages preferentially and often was co-localized with low Zeste 2 and high JMJD3, which are two critical elements of the Polycomb Repressor Complex (PRC). Conclusions: High macrophage IRF4 mRNA expression is associated with a higher concentration integrated HIV DNA in the brain. IRF4 is a nuclear transcription factor involved in active macrophage polarization towards M2 phenotypes. It is regulated epigenetically by the PRC. The results suggest that HIV-infected macrophages undergoing active polarization toward M2 phenotypes via IRF4 expression contribute disproportionately to the establishment of the latent pool of integrated HIV DNA in the brain. 62 Longitudinal Assessment of Blood Brain Barrier Disruption in Primary HIV Infection Elham Rahimy 1 ; Fang-yong Li 2 ; Alex Russell 4 ; Julia Peterson 4 ; Lars Hagberg 3 ; Henrik Zetterberg 3 ; Richard Price 4 ; Magnus Gisslén 3 ; Serena Spudich 1 1 Yale University School of Medicine, New Haven, CT, US; 2 Yale Center for Analytical Sciences, Yale University, New Haven, CT, US; 3 University of Gothenburg, Gothenburg, Sweden; 4 University of California San Francisco, San Francisco, CA, US Background: Abnormal blood brain barrier (BBB) permeability has been implicated in the neuropathogenesis of chronic HIV infection. As neurocognitive impairment can persist despite effective combination antiretroviral therapy (cART), it is possible that irreversible CNS processes are initiated in early infection. We analyzed the natural history of BBB permeability in primary HIV infection (PHI), as well as the effects of cART initiated during this period. Methods: Blood and CSF were collected from 108 cART-naive participants with PHI (94%male, median age=36, days post-transmission, dpt=91) at baseline and in follow-up visits. 57 of the 108 subjects initiated cART during follow-up for reasons independent of the study. BBB permeability was evaluated as CSF:Serum albumin ratio (QAlb). Baseline log 10 QAlb was compared with 39 uninfected age-matched control subjects (82%male, median age=38). The mixed-effects model was used to analyze longitudinal change of log 10 QAlb post transmission, adjusting for baseline age. Longitudinal association between log 10 QAlb and the axonal injury marker neurofilament light chain (NFL) was examined subject (r=0.469, p<0.001) correlations. Conclusions: BBB permeability remains elevated during the course of early HIV infection and does not demonstrate measurable improvement over a year of follow up after cART initiation. Additionally, QAlb was longitudinally associated with increased expression of the neuronal injury biomarker NFL. HIV-associated neuropathogenesis may be initiated and maintained early in the course of infection, and continue despite effective cART. 63 Declining Prevalence of HIV-Associated Neurocognitive Disorders in More Recent Years Carmela Pinnetti ; Raffaella Libertone; Pietro Balestra; Patrizia Lorenzini; Martina Ricottini; Samanta Menichetti; Maria Maddalena Plazzi; Mauro Zaccarelli; Adriana Ammassari; Andrea Antinori National Institute for Infectious Diseases, Lazzaro Spallanzani, Rome, Italy Background: Overall prevalence of neurocognitive impairment (NCI) has been estimated as high even in the cART era. More recently, lower NCI prevalence has been found in MSM, suggesting that it may be previously overestimated. Aim of the study was to evaluate prevalence of HIV-associated neurocognitive disorders (HAND) and predictive factors in more recent years of cART impact. Methods: Single-centre, retrospective, cross-sectional analysis of neurocognitive profile in HIV-infected cART-treated patients. All patients underwent neuropsychological assessment (NPA) by standardized battery of 14 tests on 5 different domains. People were classified as having HAND according to Frascati’s criteria. Chi-square for trend, and multivariable logistic regression were fitted. Results: 569 consecutive HIV-infected cART-treated individuals from 2009 to 2014, contributing a total of 858 NPA tests, were included (male 82%; median age 48 years; MSMs 51%; HCV+ 15%; CD4 nadir >200 cell/ mm 3 61%; current CD4 >350 cell/mm 3 83%; HIV-RNA <40 c/mL 83%). At the time of NPA, 49% of patients were receiving a NNRTI-based, 32% a PIr-based, and 11% a NRTI-sparing regimen, for a median time of exposure to current regimen of 25 months (IQR 9-46). A cognitive complaint of memory loss, attention deficit or concentration difficulties was observed in 313 (36%) tested patients, whereas 545 (64%) were non-complaining. HAND prevalence was 48% in complaining (ANI=23%; MND=21%; HAD=4%) and 16% in non-complaining patients (ANI=12%; MND=4%; HAD=0). By calendar periods, prevalence of HAND in complaining was 50% in 2009/2010, 45% in 2011/2012 and 48% in 2013-2014 (P at chi square for trend=0.74). In non-complaining was 20%, 22% and 9%, respectively (P at chi square for trend=0.004). Factors associated to HAND by multivariable logistic regression are reported in Table. with between-subject correlation and within-subject correlation. Results: At baseline, PHI subjects demonstrated elevated median log 10 of 475 dpt in the PHI cohort (median visits=3.0), log 10 QAlb compared to age-matched uninfected controls (0.721 vs. 0.635, p=0.002). Over a median follow-up QAlb demonstrated a nearly flat trajectory (slope=-4.9E-5, p=0.532). 23 PHI participants with baseline QAlb greater than previously reported age-specific upper limits of normal (ULN) demonstrated statistically significant yet modest decreases in log 10 Levels of those with baseline below the ULN did not change (slope=-7.9E-5, p=0.004). Log 10 QAlb over time (slope=-0.0017, p=0.013). QAlb did not significantly change over time after cART initiated at a median 225 dpt NFL as determined by within-subject (r=0.543, p=0.001) and between- (slope=1.39E-4, p=0.255; median 398 days of treatment, median 2 visits). Log 10 QAlb correlated with log 10

Oral Abstracts

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CROI 2015