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Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-infection and Nonalcoholic Fatty Liver Disease

Year: 2021
Type: article
Abstract: BACKGROUND: The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modulates critical metabolic pathways; however, little is known regarding effects of augmenting pulsatile GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and liver tissue in people with human immunodeficiency virus (HIV) (PWH) and nonalcoholic fatty liver disease (NAFLD). METHODS: 92 biomarkers associated with immunity, chemotaxis, and metabolism were measured in plasma samples from 61 PWH with NAFLD who participated in a double-blind, randomized trial of tesamorelin versus placebo for 12 months. Gene set enrichment analysis was performed on serial liver biopsies targeted to immune pathways. RESULTS: Tesamorelin, compared to placebo, decreased interconnected proteins related to cytotoxic T-cell and monocyte activation. Circulating concentrations of 13 proteins were significantly decreased, and no proteins increased, by tesamorelin. These included 4 chemokines (CCL3, CCL4, CCL13 [MCP4], IL8 [CXCL8]), 2 cytokines (IL-10 and CSF-1), and 4 T-cell associated molecules (CD8A, CRTAM, GZMA, ADGRG1), as well as ARG1, Gal-9, and HGF. Network analysis indicated close interaction among the gene pathways responsible for these proteins, with imputational analyses suggesting down-regulation of a closely related cluster of immune pathways. Targeted transcriptomics using liver tissue confirmed a significant end-organ signal of down-regulated immune activation pathways. CONCLUSIONS: Long-term treatment with a GHRH analog reduced markers of T-cell and monocyte/macrophage activity, suggesting that augmentation of the GH axis may ameliorate immune activation in an HIV population with metabolic dysregulation, systemic and end organ inflammation. Clinical Trials Registration. NCT02196831.
DOI: 10.1093/cid/ciab019
Authors: Takara L Stanley, Lindsay T Fourman, Lai Ping Wong, Ruslan Sadreyev, James M Billingsley, Meghan N Feldpausch, Isabel Zheng, Chelsea S Pan, Autumn Boutin, Hang Lee, Kathleen E Corey, Martin Torriani, David E Kleiner, Raymond T Chung, Colleen M Hadigan, Steven K Grinspoon
Language: English
Field: Medicine
Open Access status: green
Funders: National Institutes of Health, Nutrition Obesity Research Center at Harvard, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: Tesamorelin Effects on Liver Fat and Histology in HIV: A Collaborative U01 Grant, G1597684046, HIV-Associated Macrophage Alterations and Progressive Liver Disease, The Harvard Clinical and Translational Science Center, Growth Hormone Releasing Hormone Analog to Improve Nonalcoholic Fatty Liver Disease and Associated Cardiovascular Risk, Harvard Clinical and Translational Science Center, Harvard University Center for AIDS Research, Boston Area Nutrition Obesity Research Center (NORC)
OpenAlex ID: W3155736455
FWCI: 1.717
Cites: 48
Cited by: 18
Related to: 10