CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

mean change -10.96, 95% CI -33.33 to 11.41, p=0.270). However, a significant decrease in intestinal inflammation was detected on PET/MRI (-0.3 mean difference in combined activity grade score from six regions, P=0.006), along with a reduction in the bacterial families Enterobacteriaceae (p=0.018) and Erysipelotrichaceae (p=0.037) after probiotic intervention. Comparing individuals with decreased 18F-FDG-uptake on PET/MRI (good responders) with individuals with no change in uptake after intervention (poor responders), there was a significant reduction in the relative abundance of Enterobacteriaceae (p=0.048), but not Erysipelotrichaceae, in the gut microbiome of the good responders. Conclusion: Reduced abundance of Enterobacteriaceae after probiotic intervention could potentially explain the local anti-inflammatory effect in the gut, as this bacterial family contains several known pathogenic strains. These findings are in line with the measured PET/MRI activity in the gut. 258 INVESTIGATING THE EFFECT OF THERAPEUTICS ON THE MICROBIOME OF PATIENTS WITH HIV/AIDS Bryn C. Taylor 1 , David M. Asmuth 2 , Rob Knight 1 1 University of California San Diego, La Jolla, CA, USA, 2 University of California Davis, Davis, CA, USA Background: Here, we investigate the pathways by which maraviroc- treated cohorts experience improved mucosal immunity through changes in host:microbial interactions. We hypothesize that maraviroc therapy-induced improvements in mucosal immunity impacts the microbial mucosal interaction through either a change in the distribution of the microbial communities, their metabolic state, or both. Methods: We previously performed a three-arm, randomized clinical trial (RCT) that examined the impact of maraviroc alone or combined with raltegravir versus efavirenz (each combined with emtricitabine-tenofovir DF) on gastrointestinal-associated lymphoid tissue (GALT) immune reconstitution. Subjects who were naïve to antiretroviral therapy and with CCR5-tropic virus underwent upper endoscopy and flexible sigmoidoscopy before and 9 months after initiating treatment; plasma and fecal samples were also collected at these time points. We performed 16S rRNA sequencing to look first at the composition of the microbial communities in all samples before and after treatment with the regimens tested in the recently completed RCT. Metabolomic analysis of the stool and plasma was performed to explore whether alterations in the metabolic state of the microbial community is a potential mechanism for altering mucosal immune lymphocyte distribution or immune function as has been suggested for other diseases of the gastrointestinal tract that lead to systemic inflammation. Results: Analysis of 16S rRNA sequencing of the samples yielded clearly distinct microbial communities between body sites. Interestingly, the microbial communities remained stable in each of the body sites before and after 9 months of each treatment. Despite the overall community stability, with metabolomics analysis we identified distinct functional profiles between treatment groups and over time. Conclusion: Extensive analysis of the microbial community profiles of the HIV-positive cohort show no community-level differences between treatment groups. Due to the immune reconstitution we see in maraviroc-treated patients, we expected instead to see variation in the functional profile of these microbial communities. We performed metabolomics analysis of these samples to explore the functional output of these stable microbial communities and we determined the metabolic pathways by which maraviroc-treated cohorts achieve improved mucosal immunity.

Poster Abstracts

259 TLR9 AGONIST MODULATED INTESTINAL GLYCOGENE EXPRESSION IMPACTS MICROBIOME DIVERSITY Mohamed Abdel-Mohsen 1 , Phillip A. Engen 2 , Ali Keshavarzian 2 , Stefan J. Green 3 , Alan Landay 2 , Satish K. Pillai 4 , Anders K. Dige 5 , Jørgen Agnholt 5 , Andreas M. Petersen 6 , Thomas Benfield 6 , Lars Østergaard 5 , Line K. Vibholm 5 , Ole S. Søgaard 5 , Martin Tolstrup 5 , Paul W. Denton 5 1 Wistar Institute, Philadelphia, PA, USA, 2 Rush University Medical Center, Chicago, IL, USA, 3 University of Illinois at Chicago, Chicago, IL, USA, 4 Blood Systems Research Institute, San Francisco, CA, USA, 5 Aarhus University Hospital, Aarhus, Denmark, 6 University of Copenhagen, Copenhagen, Denmark Background: An emerging paradigm suggests that the gut-associated glycome is critical to the maintenance of a homeostatic relationship between the host and its gut microbiota. In HIV infection, alterations in glycan metabolismmay contribute to HIV-mediated intestinal damage, microbial translocation, and chronic inflammation. Given that we recently found that the TLR9 agonist lefitolimod (MGN1703, Mologen AG) increased microbiome diversity in HIV-1 infected individuals at multiple phylogenetic levels in Shannon and Simpson indices (PMID: 28766555), we hypothesized that lefitolimod- mediated changes in the gut glycome promoted changes in microbiome diversity. Methods: Sigmoid biopsies and stool samples were collected (at baseline and after the last dose) from 8 HIV+ adults on suppressive antiretroviral therapy who received lefitolimod (60 mg s.c.) twice weekly for 4 weeks. Ribosomal RNA gene amplicon libraries from fecal samples were sequenced, and all datasets were rarefied to 14,500 reads for calculations of both beta and alpha diversity. Sigmoid tissue was digested and percoll-enriched intestinal mononuclear cells were obtained. The tissue expression of 424 glycosylation-associated genes (glycogenes) was measured using RNA-sequencing. False-discovery rate (FDR) was used to correct for multiple comparisons. Results: Overall, we found 51 unique gut-associated glycogenes that significantly correlated with 122 microbiome classifications (FDR<0.05). When we filtered the data to only the glycogenes that were significantly modulated by lefitolimod, we identified 10 glycogenes with diverse functions including: mucin-type O-glycosylation synthesis (N-acetyl-galactosaminyltransferases); mannose synthesis and metabolism; and anti-microbial C-type lectin-mediated innate immunity (p<0.05). The changes in these glycogenes correlated strongly (FDR<0.05) with the longitudinal changes in microbiome diversity in multiple

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CROI 2018