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

Bridget S. Fisher, Richard R. Green, Rachel R. Brown, Matthew P. Wood, Tiffany Hensley-McBain, Cole Fisher, Jean Chang, Andrew D. Miller, William J. Bosche, Jeffrey D. Lifson, Maud Mavigner, Charlene J. Miller, Michael Gale, Guido Silvestri, Ann Chahroudi, Nichole R. Klatt, Donald L. Sodora

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18 Scopus citations


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.

Original languageEnglish (US)
Article numbere1006871
JournalPLoS pathogens
Issue number2
StatePublished - Feb 2018
Externally publishedYes

Bibliographical note

Funding Information:
This project was supported by funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health grant R21AI100782 (DLS) ( and funds from the National Institute of Dental and Craniofacial Research, National Institutes of Health grant R01DE023047 (DLS) ( Research was also supported in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, including 5K22AI098440 (NRK) and Contract No. HHSN272201300010C (MG), by the National Institutes of Health, Office of the Director P51OD010425 (MG), by the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E (JDL) (, and by the Office of the Director, National Institutes of Health under award number P51OD010425 (Washington National Primate Research Center) and P510D011132 (Yerkes National Primate Research Center). The content of this publication is solely the responsibility of the authors and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to acknowledge Dr. Alexis Kaushansky for helpful discussions, Nicholas Bense for technical support and Brian Johnson at the University of Washington Histology and Imaging Core for histology expertise and technical assistance.

Publisher Copyright:
© 2018 Fisher et al.


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