Translocated microbiome composition determines immunological outcome in treated HIV infection

Krystelle Nganou-Makamdop, Aarthi Talla, Ashish Arunkumar Sharma, Sam Darko, Amy Ransier, Farida Laboune, Jeffrey G. Chipman, Gregory J. Beilman, Torfi Hoskuldsson, Slim Fourati, Thomas E. Schmidt, Sahaana Arumugam, Noemia S. Lima, Damee Moon, Samuel Callisto, Jordan Schoephoerster, Jeffery Tomalka, Peter Mugyenyi, Francis Ssali, Proscovia MulomaPatrick Ssengendo, Ana R. Leda, Ryan K. Cheu, Jacob K. Flynn, Antigoni Morou, Elsa Brunet-Ratnasingham, Benigno Rodriguez, Michael M. Lederman, Daniel E. Kaufmann, Nichole R. Klatt, Cissy Kityo, Jason M. Brenchley, Timothy W. Schacker, Rafick P. Sekaly, Daniel C. Douek

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3899-3914.e16
JournalCell
Volume184
Issue number15
DOIs
StatePublished - Jul 22 2021

Bibliographical note

Funding Information:
This work was funded in part by the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); NIH grant R01-AI124965 to T.W.S.; Center for AIDS Research and Fasenmyer Foundation ( AI 36219 CWRU to M.M.L.), Canadian Institute for Health Research (CIHR) ( CIHR-168901 and NIH grant R01-HL092565 to D.E.K.); and NIH grants R01-DA043263 , R01-DA042712 , and R37-AI141258 to R.P.S. Bacterial cultures were supported by NIH grant R01-DK112254 to N.R.K. We thank R. Dutt with help processing samples. This work made use of the High Performance Computing Resources in the Core Facility for Advanced Research Computing at Case Western Reserve University.

Publisher Copyright:
© 2021

Keywords

  • antiretroviral therapy
  • HIV
  • inflammation
  • microbiome
  • systems biology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

Fingerprint

Dive into the research topics of 'Translocated microbiome composition determines immunological outcome in treated HIV infection'. Together they form a unique fingerprint.

Cite this