Liver biopsies obtained throughout SIV infection reveal evolving interferon stimulated protein expression within distinct monocyte/macrophage subsets

Abstract

ABSTRACTLiver dysfunction is more common and more severe among people with HIV than in the general population. Our previous transcriptomic analysis identified an increased hepatic type-1 interferon (IFN-1) response in simian immunodeficiency virus (SIV) infected rhesus macaques, including pronounced upregulation of the IFN-1 stimulated gene product MX1. Here, we interrogated the role of different cell types in the IFN-1 response, focusing on macrophage subsets. During the acute phase of SIV infection, the expression of MX1 in liver biopsies was elevated in the resident macrophage Kupffer cells (KCs, CD163+ CD206+) as well as liver sinusoidal endothelial cells (LSECs, CD163- CD206+). Chronic infection was associated with increased MX1 expression both within KCs and the recruited monocyte-derived macrophages (MdMs, CD163+ CD206-) although the KCs were associated with the highest MX1 expression levels. We explored factors in the liver potentially associated with the macrophage IFN-1 response: 1) SIV DNA load, 2) bacterial DNA load (assessed via SIV DNA and 16S bacterial DNA qPCR, respectively), and 3) acute-phase hepatocyte lipid accumulation (steatosis). Both SIV and bacteria were elevated during chronic infection and directly correlated with MdM frequency. KC frequency did not correlate with SIV load but inversely correlated with bacterial load and also correlated directly with hepatocyte microvesicular steatosis in acute infection. Hepatocytes expressed variable levels of MX1 during acute and chronic infection. Overall, our data identify MdMs, LSECs and KCs as contributors to the heightened expression of MX1 in the liver during SIV infection. KCs express the highest levels of MX1 and therefore represent a potential target to reduce liver inflammation in people with HIV. AUTHOR SUMMARYLiver disease disproportionately affects people with HIV (PWH). However, liver biopsies are generally not indicated in humans, making the immune mechanisms underlying HIV-driven liver dysfunction difficult to study. Using a model of HIV infection in which rhesus macaques are infected with SIV, we previously found a strong upregulation of type 1 interferon (IFN-1) signaling as well as an increased number of CD68+ monocyte/macrophage cells in the liver during chronic infection. Here we used longitudinally collected liver biopsies from SIV-infected macaques to describe the kinetics of the IFN-1 response, focusing on MX1, which was a top differentially expressed gene in our previous transcriptomic screen. We also defined two populations of liver macrophages - resident Kupffer cells and recruited monocyte-derived macrophages - to identify which cells produce MX1, what stimuli the cells respond to, and where the cells accumulate within the liver. Our results indicate that Kupffer cells are the major producers of MX1 during acute and chronic infection and that their frequency in the liver correlates with lipid accumulation (steatosis) during acute infection. These data provide insights into how Kupffer cells may promote inflammation and fibrosis and identify Kupffer cells as an important target to limit liver disease in PWH.