P9. Tryptophan metabolites are involved in the pathogenesis of HIV-1 infection.

Babilonia Barqasho1, Ujjwal Neogi1, Lilly Schwieler3, Göran Engberg3, Anders Sönnerborg1,2, Piotr Nowak2

Affiliates: 1Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden 2Department of Medicine Huddinge, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden 3Department of Physiology and Pharmacology, Unit of Electrophysiological Neuropharmacology, Karolinska Institutet, Stockholm, Sweden

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Background
The catabolism of tryptophan (TRP) into kynurenine (kyn) by indoleamine 2,3-dioxygenase-1 (IDO-1), is a possible contributor to the immune dysfunction during chronic human immunodeficiency virus (HIV) infection. An increased IDO-1 activity has been associated with microbial translocation (MT), gut microbiota dysbiosis and HIV progression. In our study, we aimed to investigate the association between downstream catabolites of TRP, inflammation markers and gut microbiota during the chronic HIV-1 infection. Additionally we studied effect of antiretroviral treatment (ART).

Methods
We conducted an observational study including 29 HIV-1 infected patients and nine uninfected controls. Peripheral blood and fecal samples were collected from antiretroviral treatment (ART) naïve patients at baseline and for 16 patients at follow up (after introduction of ART). Levels of the TRP metabolites were evaluated by high-throughput LC-tandem MS assay and microbiota composition was determined by 16s rRNA sequencing. Soluble markers were analyzed by ELISA or Limulus Amebocyte Lysate assay.

Results
We found significantly higher levels of KYNA in healthy individuals as compared to ART naïve patients, p<0.05, and significantly increased levels of IDO-1 activity was detected at follow up as compared to healthy subjects, p<0.05. Additionally, elevated levels of kyn (p<0.005), IDO-1 activity (p<0.0005), quinolinic acid (QA, p<0.0005), 3-hydroxykynurenine (3-HK, p<0.05) and Nicotinamide (NAM, p<0.005) were reduced in HIV patients after ART introduction. Levels of kyn and IDO-1 activity were positively correlated to CD8+ T cells (R-value=0.40; p<0.05). In ART naïve patients, kyn was positively associated to the following genera: Granulicatella (0.484; p<0.05), Butyricimonas (0.430; p<0.05) and Escherichia (0.512; p<0.05). IDO-1 activity was positively associated to Granulicatella (0.433; p<0.05), Lachnobacterium (0.376; p<0.05), while negatively correlated to Sutterella (-0.382; p<0.05). Several catabolites of the TRP pathway were positively associated to Butyricimonas: HAA (0.611; p<0.05), XA (0.442; p<0.05), KA (0.417; p<0.05), QA (0.469; p<0.05) and NAM (0.430; p<0.05). After ART introduction, new associations between the gut microbiota composition and the catabolites of tryptophan pathway were revealed. Thus, kyn was positively correlated to Blautia (0.629; p<0.05) and Rothia (0.587; p<0.05) and negatively associated to Heamophilus (-0.521; p<0.05) and Bilophila (-0.555; p<0.05). Moreover, IDO-1 activity was positively correlated to Blautia (0.663; p<0.05), but negatively correlated to Oscillospira (-0.624; p<0.05) and Oxalobacter (-0.774; p<0.05).

Conclusions
The present study shows that ART decreases the levels of downstream TRP pathway catabolites in viremic patients. We found several significant associations between the TRP catabolites and the gut microbiota which changed after ART introduction. Our findings imply close interplay between gut microbiota and TRP pathway during HIV-1 infection.