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

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.

Keywords: HIV-infection; growth hormone; growth hormone releasing hormone; immune activation; nonalcoholic fatty liver disease.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Between group changes in immuno-oncology proteins with tesamorelin treatment. Volcano plot showing the Log2 Fold Change (x-axis) and -(Log10 P-value) (y-axis) for each protein in the immuno-oncology panel. Proteins shown in red and labeled had False Discovery Rate < 0.1. Abbreviations: ADGRG1, adhesion G-protein coupled receptor G1; ARG1, Arginase-1; CCL3, C-C motif chemokine 3; CCL4, C-C motif chemokine 4; CD8A, T-cell surface glycoprotein CD8 alpha chain; CRTAM, cytotoxic and regulatory T-cell molecule; CSF-1, Macrophage colony-stimulating factor 1; Gal-9, Galectin-9; GZMA, Granzyme A; HGF, Hepatocyte growth factor; IL8, Interleukin-8; IL10, Interleukin-10; MCP-4, C-C motif chemokine 13.

Figure 2.

Heatmap comparing within-group changes in immuno-oncology proteins. Heatmap indicating the strength and directionality of the within-group log2 fold changes over 12 months in the tesamorelin (left) and placebo (right) treatment groups. Proteins are ordered from top to bottom according to t-statistic for the between-group comparison, with the lowest t-statistic at the top. Blue indicates decrease and red increase. *Denotes proteins with statistically significant changes over time (FDR-q < 0.1) between tesamorelin and placebo groups. Abbreviations: ADGRG1, adhesion G-protein coupled receptor G1; ARG1, Arginase-1; CCL3, C-C motif chemokine 3; CCL4, C-C motif chemokine 4; CD8A, T-cell surface glycoprotein CD8 alpha chain; CRTAM, cytotoxic and regulatory T-cell molecule; CSF-1, Macrophage colony-stimulating factor 1; FDR, false discovery rate; Gal-9, Galectin-9; GZMA, Granzyme A; HGF, Hepatocyte growth factor; IL8, Interleukin-8; IL10, Interleukin-10; MCP-4, C-C motif chemokine 13.

Figure 3.

Network analysis. Network analysis using GeneMANIA analytical software showing the potential relationships of proteins altered by tesamorelin with false discovery rate