Macrophage Activation and the Tumor Necrosis Factor Cascade in Hepatitis C Disease Progression Among HIV-Infected Women Participating in the Women's Interagency HIV Study

Abstract

Background HIV/hepatitis C coinfected persons experience more rapid liver disease progression than HCV monoinfected persons, even in the setting of potent antiretroviral therapy. Methods We sought to articulate the role of macrophage activation and inflammation in liver disease progression by measuring serial soluble markers in HIV/HCV coinfected women. We compared markers measured during retrospectively defined time periods of rapid liver disease progression to time periods where little or no liver disease progression occurred. Liver disease progression was defined by liver biopsy, liver-related death or the serum markers APRI and FIB-4. Soluble CD14, sCD163, lipopolysaccharide (LPS), TNF receptor II, interleukin-6 (IL-6) and chemokine ligand 2 (CCL 2) were measured at 3 timepoints over 5 years Results One hundred six time intervals were included in the analysis: including 31 from liver disease progressors and 75 from non-progressors. LPS, sCD14, IL-6 and CCL2 levels did not differ in slope or quantity over time between rapid liver disease progressors and non-progressors. TNFRII and sCD163 were significantly higher in liver disease progressors at (p=0.002 and <0.0001 respectively) and preceding (p=0.01 and 0.003 respectively) the liver fibrosis outcome in unadjusted models, with similar values when adjusted for HIV RNA and CD4 count. Conclusions In women with HIV/HCV coinfection, higher sCD163 levels, a marker of macrophage activation, and TNFRII levels, implying activation of the TNF-α system, were associated with liver disease progression. Our results provide an addition to the growing body of evidence regarding the relationship between macrophage activation, inflammation and liver disease progression in HIV/HCV coinfection.

Modulation of Monocyte Activation and Function during Direct Antiviral Agent Treatment in Patients Coinfected with HIV and Hepatitis C Virus

“…The levels of sCD163 decreased after DAA therapy, and no differences compared to HIV-monoinfected patients were observed; this is in accordance with other studies of HIV-coinfected and HCV-monoinfected patients (12,22,23). This points toward decreased macrophage activation in the liver, as CD163 is a cell surface glycoprotein receptor that is highly expressed on most tissue macrophages, including hepatic Kupffer cells, and is cleaved from the cell surface in response to LPS, thus increasing the levels of the shed form of sCD163 in serum (23,24). This improvement has been associated with a regression of liver fibrosis (25).…”

A changing paradigm: management and treatment of the HCV/HIV-co-infected patient

“…Indirectly, HIV can accelerate extracellular matrix production and pro-fibrotic pathways through its alterations in the immune system [29]. Depletion, dysregulation, and activation of immune cells by HIV have all been described, and all seem to play roles in liver inflammation and scarring [30].…”

A genomic variant of ALPK2 is associated with increased liver fibrosis risk in HIV/HCV coinfected women

“…To elucidate the impacts of glycosylation on the pathogenesis of fibrosis in HIV/HCV coinfected patients, we focused on nsSNV affecting the NxS/T sequons required for the attachment of N-glycans to proteins and thus the potential to change the number of glycans on the protein surface [13,14]. The Women's Interagency HIV Study (WIHS) is a longitudinal natural history study of HIV infection that features a sufficient number of HIV/HCV coinfected participants and biomarkers of liver disease to evaluate the impact of risk factors for liver disease progression [15], including genetic risk factors [16][17][18].…”