Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART

Abstract

Liver disease is a leading contributor to morbidity and mortality during HIV infection, despite the use of combination antiretroviral therapy (cART). The precise mechanisms of liver disease during HIV infection are poorly understood partially due to the difficulty in obtaining human liver samples as well as the presence of confounding factors (e.g. hepatitis co-infection, alcohol use). Utilizing the simian immunodeficiency virus (SIV) macaque model, a controlled study was conducted to evaluate the factors associated with liver inflammation and the impact of cART. We observed an increase in hepatic macrophages during untreated SIV infection that was associated with a number of inflammatory and fibrosis mediators (TNFα, CCL3, TGFβ). Moreover, an upregulation in the macrophage chemoattractant factor CCL2 was detected in the livers of SIV-infected macaques that coincided with an increase in the number of activated CD16+ monocyte/macrophages and T cells expressing the cognate receptor CCR2. Expression of Mac387 on monocyte/macrophages further indicated that these cells recently migrated to the liver. The hepatic macrophage and T cell levels strongly correlated with liver SIV DNA levels, and were not associated with the levels of 16S bacterial DNA. Utilizing in situ hybridization, SIV-infected cells were found primarily within portal triads, and were identified as T cells. Microarray analysis identified a strong antiviral transcriptomic signature in the liver during SIV infection. In contrast, macaques treated with cART exhibited lower levels of liver macrophages and had a substantial, but not complete, reduction in their inflammatory profile. In addition, residual SIV DNA and bacteria 16S DNA were detected in the livers during cART, implicating the liver as a site on-going immune activation during antiretroviral therapy. These findings provide mechanistic insights regarding how SIV infection promotes liver inflammation through macrophage recruitment, with implications for in HIV-infected individuals.

Bone Marrow-Derived CD4 + T Cells Are Depleted in Simian Immunodeficiency Virus-Infected Macaques and Contribute to the Size of the Replication-Competent Reservoir

“…A recent study looking at myeloid-derived suppressor cells (MDSC) revealed that depletion of these cells in BM could contribute to systemic immune activation and exacerbate SIV pathogenesis (22). In our paper, we focus on the CD4 ϩ T cell contribution to viral persistence; however, others have shown that other cellular subsets in the bone marrow may harbor virus as well (23).…”

Liver function test abnormalities in a longitudinal cohort of Thai individuals treated since acute HIV infection

“…Other studies have hypothesized that HIV results in hepatocellular damage through cellular activation, although data on its potential to infect hepatocytes and Kuppfer cells are limited . Recent work using a simian immunodeficiency virus model in macaques suggested that macrophage and T cell activation were primary drivers of hepatic inflammation . In our analysis, ALT levels correlated with soluble CD163, a marker specific to activated macrophages that has been associated with Kupffer cell activation .…”

Liver bacterial dysbiosis occurs in SIV-infected macaques and persists during antiretroviral therapy

“…The microbiome is in uenced by numerous factors such as age, environment, food and antibiotics [25][26][27][28][29]. With regard to the liver during SIV infection, prior studies have identi ed elevated bacterial loads during SIV infection [30,31], as well as in the context of cART [32], and have shown that bacteria may increase immune cell in ltration [30]. During cART-treated SIV infection, the liver microbiome has been shown to be enriched for in ammatory Proteobacteria that preferentially translocate out of the gut and into the colonic lamina propria [24].…”