Liver Biopsies Reveal Temporal Changes in Pathology and Macrophage Function following SIV Infection of Rhesus Macaques

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Abstract Non-alcoholic fatty liver disease (NAFLD) contributes to morbidity and mortality in HIV-infected individuals. To evaluate liver immune changes during SIV infection of macaques, we obtained liver biopsies laparoscopically at 2, 6, and 16 weeks post-infection as well as at necropsy (32 weeks). SIV infection was associated with liver dysfunction that included elevated liver enzymes during acute infection, higher liver weight at necropsy, and histologic changes within the liver lobule (functional unit of the liver) including sinusoidal dilatation near central veins and portal expansion. The type-1 interferon (IFN-1) response (MX1 expression) increased over time post-SIV infection, initially being observed in macrophages (week 2) with a switch to a mixed hepatocyte/monocyte/macrophage response by 16–32 weeks. Over the course of SIV infection, macrophage frequencies also increased – both infiltrating (CD68+CD163+CD206-) and resident (CD68+CD163+CD206+) tissue macrophages – and these macrophages were found more near central veins over time. In contrast, CD68+CD163-CD206− trafficking myeloid cells/monocytes were detected predominantly in the periportal zone of the lobule and associated with elevated MX1 expression in that zone. Our findings identify pathologic changes within the livers of SIV infected macaques as early as 2 weeks post-infection, IFN-1 responses that are initially observed in liver macrophages, and an accumulation of macrophages associated with signs of inflammation by week 32. These studies offer quantitative and spatial insights to inform macrophage-targeted therapeutic approaches that may improve liver function during HIV infection. Supported by grants from NIH (R01AI134630)