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PLoS Pathog. 2018 Feb 21;14(2):e1006871. doi: 10.1371/journal.ppat.1006871. eCollection 2018 Feb.

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

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Center for Infectious Disease Research, formally Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, Washington, United States of America.
Department of Pharmaceutics, Washington National Primate Research Center, University of Washington, Seattle, Washington, United States of America.
Cornell University College of Veterinary Medicine, Department of Biomedical Sciences, Section of Anatomic Pathology, Ithaca, New York, United States of America.
AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Emory Vaccine Research Center and, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America.
Emory University School of Medicine, Department of Pediatrics, Atlanta, Georgia, United States of America.


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.

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