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HIV affects polyamine metabolism and T cell lineages

How HIV induces alterations in polyamine metabolism and could affect T cells and their functions in the oral mucosa of HIV-infected individuals.
Published in Healthcare & Nursing
Go to the profile of Pushpa Pandiyan
Pushpa Pandiyan
Professor, Case Western Reserve University
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Nature
Nature Nature

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

Polyamine metabolism is a determinant of T helper cell polarization. Here, Mahalingam et al analyse the metabolic and transcriptomic profile of oral mucosa from people living with HIV to demonstrate the effect of polyamine synthesis on T cell dysfunction during HIV-1 infection.

Polyamines are organic polycations that work together with DNA, RNA, and proteins, and control cell growth and death. Polyamines come from food and can be produced by our cells and the microbiome in our mucosa. Aberrant changes in their levels in cells are associated with aging and diseases. A study by Dr. Pandiyan's team at Case Western Reserve University has explored polyamines' role in HIV infection and has shown that HIV could damage our immune system by increasing T-cell polyamine metabolism. (Nature Communications; DOI 10.1038/s41467-023-36163-2; https://doi.org/10.1038/s41467-023-36163-2 or https://www.nature.com/articles/s41467-023-36163-2.pdf).

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 (ODC-1). HIV-1 also led to a heightened expression of polyamine synthesis intermediates including ODC-1 as well as an elevated dysfunctional regulatory T cell (TregDys) /T helper 17 (Th17) cell ratios. The loss of Th17 cells was due to pyroptotic cell death. 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. The anti- or hyper-inflammatory effect of altered polyamines on other innate immune cells and the role of increased NLRP3 expression remain to be studied in the future. Thus, by revealing the role of excessive polyamine synthesis during HIV infection, this study unveils a mechanism by which chronic viral infections could drive distinct T cell effector programs and Treg dysfunction.

This study could lead to new therapeutic approaches to repair the immune system that is damaged due to aging, chronic infections, inflammation, and cancer.

Go to the profile of Pushpa Pandiyan
Pushpa Pandiyan (She/Her)
Professor, Case Western Reserve University

I am a Mucosal Immunologist, mainly focusing on infection and cancer immunology in the oral mucosa. We are doing omics approaches to study the intricacies of immune cell interactions during health and disease. My research goal is to develop a multidisciplinary research program that is committed to (i) understanding how Tregs and Th17 cells interact with microbiome, innate immunity, and cancer cells in the mucosa (ii) elucidating epigenetic/transcriptomic/metabolomic molecular pathways that determine the population size and function of Tregs, Th17 cells and other immunoregulatory cells, (iii) characterizing them in normal individuals, patients with oral and gut mucosal immune diseases, HIV infection, and cancer (iv) developing immuno-therapeutic agents to control these cells for treating immuno-pathology and cancer. I am thoroughly excited and humbled by our recent findings on novel mechanisms of immune dysfunction during  HIV disease and cancer.

Bhaskaran N, Jayaraman S, Quigley C, Mamileti P, Ghannoum M, Weinberg A, Thuener J, Pan Q, Pandiyan P. The Role of Dectin-1 Signaling in Altering Tumor Immune Microenvironment in the Context of Aging. Frontiers in Oncology. 2021 Apr 22;11:669066. PMID: 33968777, PMCID: PMC8100664, DOI: 10.3389/fonc.2021.669066.

Bhaskaran, N, Schneider, E, Faddoul, F, Paes da Silva, A, Asaad, R, Talla, A, Greenspan, N, Levine, AD, McDonald, D, Karn, J, Lederman, MM, and Pandiyan, P. Oral immune dysfunction is associated with the expansion of FOXP3 + PD-1 + Amphiregulin + T cells during HIV infection. Nature Communications. 2021 Aug 26;12(1):5143. doi: 10.1038/s41467-021-25340-w. PMID: 34446704 PMCID: PMC8390677.

Pandiyan, P and McCormick  TS. Regulation of IL-17A-Producing Cells in Skin Inflammatory Disorders. J Invest Dermatol. 2021 (21) 01673-0.doi: 10.1016/j.jid.2021.06.036. PMID: 34561088.

Mahalingam,SS, Jayaraman, SJ, Pandiyan, P. Fungal Colonization and Infections—Interactions with Other Human Diseases. Review. Pathogens 2022, 11(2), 212; PMID: 35215155; PMCID: PMC8875122. https://doi.org/10.3390/pathogens11020212.

Shive C and Pandiyan P. Inflammation, Immune Senescence, and Dysregulated Immune Regulation in the Elderly. Frontiers in Aging, 2022 Apr 27;3:840827. PMID: 35821823  PMCID: PMC9261323  DOI: 10.3389/fragi.2022.840827.

Mahalingam, SS, Jayaraman, S, Bhaskaran, N, Schneider, E, Faddoul, F, Paes da Silva, A, Lederman, MM, Asaad, R, Adkins-Travis K, Shriver LP, and Pandiyan, P. Polyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV. Nat Communications. 2023 Jan 25;14(1):399.  PMID: 36693889  PMCID: PMC9873639  DOI: 10.1038/s41467-023-36163-2.

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