CROI 2016 Abstract eBook

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Poster Abstracts

sVCAM-1, sICAM-1, MMP-9, tPA-1, hsCRP, IL-6, IL-8, IL-10, TNF-α, MCP-1, IFN-α) were assessed by multiplex Luminex assay. Analysis of covariance was used to determine group differences. Results: 79 HIV-infected subjects (45 Non-Frail, 28 Pre-Frail, 6 Frail): 90%men, median age of 51 years, median CD4 count of 479.0 cells/mm 3 , 84%with plasma HIV RNA < 50 copies/mL. The three groups had similar clinical and laboratory assessments except for body mass index (BMI). Median BMI (Q1,Q3) for the Non-Frail, Pre-Frail, and Frail groups was 26.1 (24.5,27.5), 25.8 (24.1,27.2), and 29.8 (26.0,37.5) kg/m 2 , respectively, with a difference noted between Pre-Frail and Frail groups. There were no differences in biomarkers except for IL-6. Median IL-6 for the Non-Frail, Pre-Frail, and Frail groups was 1.26 (1.02,1.68), 2.20 (0.90,3.61), 2.54 (2.46,5.75) pg/mL, respectively, with differences between Non- Frail and Frail groups. Glucose measures at 90 and 120 min of the OGTT were significantly higher in the Frail than in the Non-Frail group. HOMA-IR and DIo were higher in the Frail group compared to the Non-Frail and Pre-Frail groups even after adjustment for age and BMI. IL-6 correlated with HOMA-IR (β=0.26, p=0.03) but not DIo. Conclusions: Frailty in HIV-infected subjects was associated with increased insulin resistance. IL-6 was elevated in frailty and correlated with HOMA-IR. The roles of inflammatory processes and insulin resistance in frailty require further study.

724 HIV gp120 in the Lungs of HAART-Treated Individuals Impairs Pulmonary Immunity Paul J. Collini 1 ; Martin Bewley 1 ; Julia M. Greig 2 ; Christine Bowman 2 ; David H. Dockrell 1 1 Univ of Sheffield, Sheffield, UK; 2 Sheffield Teaching Hosps, Sheffield, UK

Background: Antiretroviral therapy (ART) has improved overall survival but HIV+ individuals remain at increased susceptibility to chronic lung disease and pneumonia. HIV associated immune activation and oxidative stress persist despite ART and HIV proteins have been implicated in this process. We hypothesised that gp120 plays a role in dysregulating lung immunity in HIV+ individuals despite ART. Methods: We recruited 14 healthy, viral hepatitis-uninfected, ART treated HIV+ non-smokers (9 male, 9 white, mean age 42, mean 372 weeks ART) and 10 matched HIV- controls for bronchoalveolar lavage (BAL) to obtain lung mononuclear cells and fluid (BALF). Cells were analysed by flow cytometry and gp120 measured by ELISA. Alveolar macrophages (AM) and 14-day human monocyte derived macrophages (hMDM) exposed to 10-100ng/mL of gp120 were challenged with pneumococci, and responses characterised by microscopy, flow cytometry and viable bacterial counts. Data were compared with t test and if non-parametric Mann-Whitney or Wilcoxon test and considered significant if p<0.05. Results: gp120 was detected by ELISA in the BALF of 45% of HIV+ at concentrations 13 to 78 ng/mL. Of the HIV+ individuals, those with detectable BALF gp120 had significantly lower plasma CD4 counts (mean 470± SEM43 vs 756±80 cells/mL, p=0.0087). HIV+ individuals had a significant BAL lymphocytosis compared with controls (12.4±1.9 vs 7.6±1.1 %, p=0.043), with increased BAL CD8+ T cells (45.0±4.0 vs 22.3±4.0 %, p=0.0006), and reduced BAL CD4:CD8 ratios (3.79±0.76 vs 1.16±0.15, p=0.0019). HIV+ AM demonstrated impaired intracellular killing of pneumococci (1.3±0.4 vs 0.5±0.5 log CFU/mL), a finding reproduced in hMDM treated with gp120 (1.2±0.3 vs 0.7±0.3 log CFU/mL, p=0.019), and associated with reduced apoptosis (18.1±4.8 vs. 33.5±7.0 %, p=0.039). However, apoptosis-associated killing was not reduced when hMDM were co-cultured with activated autologous CD8 T cells. gp120 also induced the generation of mitochondrial reactive oxygen species in hMDM (mROS, 1.86±0.5 fold change MFI, p=0.016) in hMDM but blunted the induction of mROS with pneumococci (p=0.047). Conclusions: The immune environment of the lung fails to normalise during ART with persistence of gp120 and a CD8 lymphocytosis. gp120 causes macrophage oxidative stress and impairs apoptosis-associated killing of pneumococci. gp120 appears to play a role in HIV associated lung disease despite ART. 725 The Host Response to the HIV Airway Epithelial Cell Microbiome Janice Leung 1 ; Marc Sze 2 ; Stella Xu 1 ; EmilyVucic 3 ;Wan Lam 3 ; Stephen Lam 3 ; Corey Nislow 1 ; Julio Montaner 4 ; Don Sin 1 ; S. F. Paul Man 1 1 Univ of British Columbia, Vancouver, BC, Canada; 2 Univ of Michigan, Ann Arbor, MI, USA; 3 BC Cancer Rsr Cntr, Vancouver, BC, Canada; 4 BC Cntr for Excellence in HIV/AIDS, Vancouver, BC, Canada Background: Chronic Obstructive Pulmonary Disease (COPD) is an important comorbidity in patients living with HIV. Previous bacterial microbiome studies have shown increased abundance of specific bacteria like Tropheryma whipplei in bronchoalveolar lavage samples, but few studies have evaluated the microbiome of airway epithelial cells. Moreover, few studies have determined whether the microbiome can elicit a specific host response. Methods: Two bronchial brush samples were obtained during bronchoscopy from 21 HIV-infected patients. One was used for bacterial microbiome analysis using the Illumina MiSeq platform as well as DNA methylation analysis using the Illumina Infinium 450K Human Methylation array. The other brush was used to evaluate gene expression patterns of the host using the Affymetrix Human Gene ST 2.0 array. Microbiome composition, Shannon diversity, evenness, and operational taxonomic unit (OTU) richness were assessed comparing HIV-infected patients with and without COPD by spirometry, and with and without emphysema by computed tomographic imaging. Weighted gene co-expression network analysis was used to determine the relationship between the bacterial microbiome and host DNA methylation and gene expression patterns. Results: There was no difference in Shannon diversity, evenness, or bacterial community composition between HIV patients with and without COPD or HIV patient with and without emphysema. However, OTU4, OTU15, and OTU38 were able to discriminate between subjects with and without COPD. OTU4 and OTU30 were also able to discriminate between those with and without severe emphysema. 14 gene expression modules correlated significantly to at least one measure of the bacterial microbiome (Table) including modules involved in cilia function, immune response, and antigen presentation. 10 methylation modules correlated significantly to at least one measure of the bacterial microbiome (Table). The turquoise module (representing lung and respiratory tubule development) had the most significant correlations with the microbiome, being negatively correlated with Actinobacteria, Firmicutes and overall OTU richness, and positively correlated with Proteobacteria. Conclusions: Within HIV, certain OTUs are able to distinguish between COPD and non-COPD airway epithelial cells, as well as between those with and without severe emphysema. Microbiome features are additionally related to cilia function, immune response, and lung and respiratory tubule development.

Poster Abstracts

301

CROI 2016