Translocated microbiome composition determines immunological outcome in treated HIV infection

• Type of Material: Article
• Authors: Rafick-Pierre Sekaly, Emory University; Krystelle Nganou-Makamdop, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda; Aarthi Talla, Case Western Reserve University; Ashish Sharma, Emory University; Sam Darko, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda; Amy Ransier, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda; Farida Laboune, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda; Jeffrey G Chipman, University of Minnesota, Minneapolis; Gregory J Beilman, University of Minnesota, Minneapolis; Torfi Hoskuldsson, University of Minnesota, Minneapolis; Slim Fourati, Emory University; Thomas E Schmidt, University of Minnesota, Minneapolis; Sahaana Arumugam, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda; Noemia S Lima, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda; Damee Moon, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda; Samuel Callisto, University of Minnesota, Minneapolis; Jordan Schoephoerster, University of Minnesota, Minneapolis; Jeffery Tomalka, Case Western Reserve University; Peter Mugyenyi, Joint Clinical Research Center; Francis Ssali, Joint Clinical Research Center; Proscovia Muloma, Joint Clinical Research Center; Patrick Ssengendo, Joint Clinical Research Center; Ana R Leda, University of Miami; Ryan K Cheu, University of Miami; Jacob K Flynn, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda; Antigoni Morou, Research Centre of the Centre Hospitalier de l’Université de Montréal; Elsa Brunet-Ratnasingham, Research Centre of the Centre Hospitalier de l’Université de Montréal; Benigno Rodriguez, Case Western Reserve University; Michael M Lederman, Case Western Reserve University; Daniel E Kaufmann, Ctr Hosp Univ Montreal; Nichole R Klatt, University of Miami; Cissy Kityo, Joint Clinical Research Center; Jason M Brenchley, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda; Timothy W Schacker, University of Minnesota, Minneapolis; Daniel C Douek, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda
• Language: English
• Date: 2021-07-22
• Publisher: CELL PRESS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2021.05.023
• Title of Journal or Parent Work: CELL
• Volume: 184
• Issue: 15
• Start Page: 3899
• End Page: +
• Keywords: LIFE EXPECTANCY; Science & Technology; Biochemistry & Molecular Biology; INDIVIDUALS; INFLAMMATION; PLASMA; LIPOPOLYSACCHARIDES; IMMUNE ACTIVATION; PREDICT MORTALITY; GUT MICROBIOTA; ANTIRETROVIRAL THERAPY; Life Sciences & Biomedicine; TH17; Cell Biology

Abstract

The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.