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Indoleamine 2,3 dioxygenase, age, and immune activation in people living with HIV
  1. Stephanie L Baer1,2,
  2. Rhonda E Colombo2,3,4,
  3. Maribeth H Johnson5,
  4. Sushama Wakade2,
  5. Gabriela Pacholczyk2,
  6. Cheryl Newman-Whitlow2,
  7. Stuart A Thompson2,
  8. Michael S Saag6,
  9. Jeffrey N Martin7,
  10. Michelle Floris-Moore8,
  11. Lei Huang9,10,
  12. Andrew L Mellor9,10
  1. 1Infection Control, Charlie Norwood VA Medical Center, Augusta, Georgia, USA
  2. 2Department of Medicine, Augusta University, Augusta, Georgia, USA
  3. 3Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
  4. 4Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, Maryland, USA
  5. 5Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, Georgia, USA
  6. 6Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
  7. 7Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA
  8. 8Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  9. 9Institute of Cellular Medicine, Faculty of Medical Science, Newcastle University, Newcastle upon Tyne, UK
  10. 10Immunotherapy Discovery Institute, Augusta University, Augusta, Georgia, USA
  1. Correspondence to Dr Stephanie L Baer, Augusta University, Augusta, Georgia 30904, USA; stephanie.baer{at}va.gov

Abstract

Immune activation complicates HIV despite antiretroviral therapy (ART). Indoleamine 2,3 dioxygenase (IDO) catabolizes tryptophan (T) to kynurenine (K), regulating immune activity, and IDO activity increases with age. This study examines the relationship of IDO activity, bacterial translocation, and aging in people living with HIV (PLWH) on ART. Samples and data from PLWH on ART from the Centers for AIDS Research Network of Integrated Clinical Systems and from matched HIV-uninfected patients (controls) from the Multicenter AIDS Cohort Study and the Women’s Interagency HIV Study were analyzed. The ratio of K to T (K:T) and neopterin were indicators of inflammation; 16S ribosomal DNA (16S rDNA) and lipopolysaccharide (LPS) were markers of bacterial translocation. Samples and data from 205 PLWH and 99 controls were analyzed. PLWH had higher K:T values across all ages, with a significant relationship between age and K:T for both groups. CD4 count or CD4 nadir had no association with K:T. There was no positive association between level of 16S rDNA or LPS detection and K:T. K:T and neopterin were associated. PLWH had elevated IDO activity, at younger ages, despite ART. This study suggests K:T ratio increases with age in both groups and is elevated in PLWH at all ages compared with age-matched controls.

  • aging
  • immune tolerance
  • inflammation

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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Footnotes

  • Presented at The results presented in this paper were presented at IDWeek October 2018, San Francisco, California (poster #639).

  • Contributors SLB, REC, CN-W, MSS, JNM, MF-M, and ALM contributed to research conception, design, and procurement of funding. ST, CN-W, MSS, ALM, LH, SLB, REC and MHJ contributed to statistical methods and interpretation. ST, SW, GP, LH and ALM performed the laboratory assays. Collaboration with the repositories and acquisition of specimens involved SW, GP, SLB, JNM and MF-M. SLB drafted the manuscript and all authors contributed to critical revision and have approved the manuscript, contributed significantly to the work, and approved its submission to the Journal of Investigative Medicine. All authors agree to be accountable for all aspects of the work ensuring questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding This work was supported by an Augusta University Department of Medicine Research Initiative Grant, an Augusta University Immunotherapy Discovery Institute Seed Grant, P30 AI027763, and R24 AI067039. The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH). Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and other Communication Disorders (NIDCD), and the NIH Office of Research on Women’s Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA), UL1-TR000454 (Atlanta CTSA), P30-AI-050410 (UNC CFAR), and P30-AI-027767 (UAB CFAR).

  • Disclaimer The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M Jackson Foundation for the Advancement of Military Medicine, the Department of Defense (DoD), the Department of Veterans Affairs, or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the US Government. Investigator time was supported with resources from the Charlie Norwood VA Medical Center. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH), the federal government, or affiliated institutions. The authors assume full responsibility for analyses and interpretations of these data. Data in this manuscript were collected by the CFAR Network of Integrated Clinical Systems (CNICS) and MACS/WIHS Combined Cohort Study (CCS).

  • Competing interests SB is an Editorial Board Member of the Journal of Investigative Medicine. ALM is a shareholder in NewLink Genetics and receives licensing income from this source. All other authors declare no conflicts.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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