CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Results: Levels of MCP-1 (p = 0.02) but not DKK1 (p = 0.65) were higher in HIV+ subjects than in HIV- subjects. Among HIV+ subjects, higher levels of DKK-1 (d=0.63, p = 0.05) but not MCP-1 (p = 0.59) were associated with NCI. The association between DKK1 and NCI strengthened when recursive partitioning was used to identify an informative threshold value in DKK1: among the 41 HIV+ subjects, those who had plasma DKK1 levels of at least 1,129 pg/ml had a 6.0-fold increased odds of having NCI (75% vs 33%, 2-tail FET p=0.04). The effect size was large and the association between DKK1 and NCI was highly specific (92%), although the sensitivity was poor (35%). In comparison, recursive partitioning failed to identify a statistically significant threshold value for MCP-1. Multivariable analysis among HIV+ subjects identified that the association between higher DKK1 levels and NCI remained statistically significant after accounting for the effects of nadir CD4+ T-cell counts, drugs of abuse, and ART use . Conclusions: These findings underscore the potential specificity of DKK1 as a biomarker for NCI in HIV+ adults. Based on our prior work, the mechanism driving this relationship is via HIV and inflammatory responses that mediate elevation in DKK1 which in turn reduces Wnt/ β -catenin signaling in astrocytes and diminish glutamate/glutamine cycling by astrocytes, leading to neurotoxicity. 479 Markers of HIV-Associated Cognitive Impairment Are Elevated in HIV-Infected Patients With Neurosyphilis Emily Ho ; LaurenTantalo; Sharon Sahi;Trudy Jones; Shelia Dunaway; Christina Marra University of Washington, Seattle, WA, US Background: Despite combination antiretroviral therapy (cART), cognitive impairment is common in HIV-infected patients. Compared to those without cognitive impairment, cerebrospinal fluid (CSF) concentrations of IP-10, MCP-1, neurofilament light chain (Nfl) are higher in cognitively impaired HIV-infected patients. Blood concentrations of activated monocytes are also higher in HIV-infected patients with dementia. Cognitive impairment may be more common in HIV-infected patients with past syphilis. The goal of this study was to determine if markers of HIV-associated cognitive impairment were higher in HIV-infected patients with neurosyphilis. Methods: Banked frozen CSF and cryopreserved CSF cells and peripheral blood mononuclear cells (PBMCs) were collected from 109 individuals: 48% HIV-infected (72% on cART), 95%men, 76% Caucasian; 64% early syphilis; 35 had neurosyphilis (reactive CSF-Venereal Disease Research Laboratory [VDRL]), 74 had uncomplicated syphilis (syphilis; CSF white blood cells [WBCs] ≤ 5/ul, nonreactive CSF-VDRL). CSF concentrations of HIV RNA were measured by RT-PCR; MCP-1, IP-10 were measured by multiplex assay (Mesoscale Discovery), Nfl by ELISA, % activated monocytes (coexpressing CD14 and CD16) by flow cytometry. Differences between groups were assessed by Mann-Whitney U test. The influence of covariates was assessed using linear regression. Results: The results in the four groups are shown in the Table. Among the groups with syphilis and with neurosyphilis, CSF IP-10 concentrations were higher in the HIV-infected patients than in the HIV-uninfected patients. Among patients with syphilis, CSF NFL was higher in the HIV-infected patients than the HIV-uninfected patients, but CSF NFL did not differ between the neurosyphilis patients. Among patients with HIV, CSF HIV RNA, IP-10 and MCP1; and blood % activated monocytes were higher in those with NS than in those with syphilis. Taking into account CSF WBCs, CSF IP-10 but not MCP1, HIV RNA or blood activated monoctyes remained significantly higher in HIV-infected patients with neurosyphilis than in HIV-infected patients with syphilis (P<0.001). Table: Markers of HIV-associated Cognitive Impairment in the Patient Groups Conclusions: Compared to HIV-infected patients with syphilis and patients with neurosyphilis alone, HIV-infected patients with neurosyphilis have higher concentrations of CSF and peripheral blood biomarkers that are associated with cognitive impairment. These studies suggest that patients with concomitant HIV and neurosyphilis may be at higher risk of cognitive impairment. 480 CD14+ PBMC Secrete Cytokines Linked to HIV-Associated Neurocognitive Disorders Melissa A. Agsalda-Garcia 4 ;Victor G.Valcour 1 ; Pasiri Sithinamsuwan 2 ; Guangxiang G. Zhang 4 ; Cecilia M. Shikuma 4 ; James L. Fletcher 3 ; Nicholas Hutchings 1 ; Alexandra Schuetz 5 ; Jintanat Ananworanich 3 ; Bruce Shiramizu 4 1 University of California San Francisco, San Francisco, CA, US; 2 Phramongkutklao Hospital, Bangkok, Thailand; 3 The Thai Red Cross AIDS Research Centre, Bangkok, Thailand; 4 University of Hawaii, John A. Burns School of Medicine, Honolulu, HI, US; 5 Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand Background: HIV-associated neurocognitive disorders (HAND) persist despite the availability of combined antiretroviral therapy (cART) and believed to be at least partially the consequence of mechanisms associated with monocytes. In addition to transporting HIV into the brain, monocytes secrete pro-inflammatory cytokines that lead to neuronal damage. In this study, we analyzed cytokines that were secreted from CD14-selected peripheral blood mononuclear cells (PBMC) from HIV-infected individuals with HAND and normal cognition (NC) at baseline (cART naïve) and after one year on cART to determine which cytokines were associated with HAND. Methods: The study population consisted of 61 HIV-infected Thais who were enrolled in SEARCH011 (NCT00782808); 28 diagnosed with HAND and 33 with NC at entry. PBMC were collected at baseline and 12 months post cART initiation. CD14+ PBMC were separated by magnetic beads and cultured overnight (median 91.4% purity by flow cytometry). Cytokine secretions were measured from the supernatants captured after 24 hour culture and using a custom 10-plex Milliplex MAP kit detecting fractalkine, IFN-g, IL-2, IL-4, IL-6, IL-8, IL-10, IP-10, MCP-1, and TNF- α . HIV DNA copies were also analyzed from the CD14+ PBMC using a real-time qPCR. Non-parametric Spearman correlation and Wilcoxon rank-sum test were conducted. Results: Of the cytokines analyzed, only IL-8 and MCP-1 levels were significantly higher in those with HAND in comparison to NC at baseline (p<0.003). HIV DNA levels were directly correlated to IL-8 (r=0.33; p=0.01) and MCP-1 (r=0.39; p=0.003) at baseline but not after one year. Conclusions: This study demonstrated that individuals with HAND experience continued inflammation and the type of cytokine supports monocyte involvement consistent with their likely role as viral reservoirs that continue to persist despite cART. High levels of IL-8 and MCP-1 continued to be secreted by CD14+ PBMC in individuals with HAND despite initiation of cART. We hypothesize that secretion of these cytokines may play an important role in promoting the continued transmigration of monocytes into the brain that leads to the persistence of HAND despite cART.

Poster Abstracts

324

CROI 2015