Polyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV

  • Nat Commun. 2023 Jan 25;14(1):399. doi: 10.1038/s41467-023-36163-2.
S S Mahalingam  1 ,  S Jayaraman  1 ,  N Bhaskaran  1  2 ,  E Schneider  1 ,  F Faddoul  3 ,  A Paes da Silva  4 ,  M M Lederman  5  6 ,  R Asaad  6 ,  K Adkins-Travis  7 ,  L P Shriver  7 ,  P Pandiyan  8  9  10
Affiliations
  • 1. Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • 2. Faculty of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, Chennai, India.
  • 3. Advanced Education in General Dentistry, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • 4. Department of Periodontics, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • 5. Department of Medicine, Division of Infectious Diseases & HIV Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • 6. University Hospitals Cleveland Medical Center AIDS Clinical Trials Unit, Cleveland, OH, 44106, USA.
  • 7. Department of Chemistry, Center for Metabolomics and Isotope Tracing, Washington University, Saint Louis, MO, 63110, USA.
  • 8. Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA. [email protected].
  • 9. Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA. [email protected].
  • 10. Center for AIDS Research, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA. [email protected].
PMID: 36693889 DOI: 10.1038/s41467-023-36163-2
Abstract

Metabolic changes in immune cells contribute to both physiological and pathophysiological outcomes of immune reactions. Here, by comparing protein expression, transcriptome, and salivary metabolome profiles of uninfected and HIV+ individuals, we found perturbations of polyamine metabolism in the oral mucosa of HIV+ patients. Mechanistic studies using an in vitro human tonsil organoid Infection model revealed that HIV Infection of T cells also resulted in increased polyamine synthesis, which was dependent on the activities of Caspase-1, IL-1β, and ornithine decarboxylase-1. HIV-1 also led to a heightened expression of polyamine synthesis intermediates including ornithine decarboxylase-1 as well as an elevated dysfunctional regulatory T cell (TregDys)/T helper 17 (Th17) cell ratios. Blockade of Caspase-1 and polyamine synthesis intermediates reversed the TregDys phenotype showing the direct role of polyamine pathway in altering T cell functions during HIV-1 Infection. Lastly, oral mucosal TregDys/Th17 ratios and CD4 hyperactivation positively correlated with salivary putrescine levels, which were found to be elevated in the saliva of HIV+ patients. Thus, by revealing the role of aberrantly increased polyamine synthesis during HIV Infection, our study unveils a mechanism by which chronic viral infections could drive distinct T cell effector programs and Treg dysfunction.

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