Acute Liver Damage Associated with Innate Immune Activation in a Small Nonhuman Primate Model of Hepacivirus Infection

• Type of Material: Article
• Authors: Cordelia Manickam, Beth Israel Deaconess Medical Center; Premeela Rajakumar, Emory University; Lynn Wachtman, Harvard Medical School; Joshua A. Kramer, Harvard Medical School; Amanda J. Martinot, Beth Israel Deaconess Medical Center; Valerie Varner, Beth Israel Deaconess Medical Center; Luis D. Giavedoni, Texas Biomedical Research Institute; R. Keith Reeves, Beth Israel Deaconess Medical Center
• Language: English
• Date: 2016-10-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2016, American Society for Microbiology.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.01051-16
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 90
• Issue: 20
• Start Page: 9153
• End Page: 9162
• Grant/Funding Information: This work was supported by NIH grants R21 AI118468 and R21 AI101170 to R.K.R. and by NIH Office of Research Infrastructure Programs grants supporting the NEPRC (grant P51 OD011103) and SNPRC (grant P51 OD011133).
• Keywords: HCV INFECTION; Science & Technology; AGENT; VIRAL CLEARANCE; Virology; EXPRESSION; NATURAL-KILLER-CELLS; B INFECTION; HEPATITIS-C VIRUS; MARMOSET MODEL; Life Sciences & Biomedicine; DENDRITIC CELLS; CD8(+) T-CELLS
• Research Categories: Biology, Cell; Biology, Virology; Health Sciences, Immunology

Abstract

Despite its importance in shaping adaptive immune responses, viral clearance, and immune-based inflammation, tissue-specific innate immunity remains poorly characterized for hepatitis C virus (HCV) infection due to the lack of access to acutely infected tissues. In this study, we evaluated the impact of natural killer (NK) cells and myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells on control of virus replication and virus-induced pathology caused by another, more rapidly resolving hepacivirus, GB virus B (GBV-B), in infections of common marmosets. High plasma and liver viral loads and robust hepatitis characterized acute GBV-B infection, and while viremia was generally cleared by 2 to 3 months postinfection, hepatitis and liver fibrosis persisted after clearance. Coinciding with peak viral loads and liver pathology, the levels of NK cells, mDCs, and pDCs in the liver increased up to 3-fold. Although no obvious numerical changes in peripheral innate cells occurred, circulating NK cells exhibited increased perforin and Ki67 expression levels and increased surface expression of CXCR3. These data suggested that increased NK cell arming and proliferation as well as tissue trafficking may be associated with influx into the liver during acute infection. Indeed, NK cell frequencies in the liver positively correlated with plasma (R = 0.698; P = 0.015) and liver (R = 0.567; P = 0.057) viral loads. Finally, soluble factors associated with NK cells and DCs, including gamma interferon (IFN-γ) and RANTES, were increased in acute infection and also were associated with viral loads and hepatitis. Collectively, the findings showed that mobilization of local and circulating innate immune responses was linked to acute virus-induced hepatitis, and potentially to resolution of GBV-B infection, and our results may provide insight into similar mechanisms in HCV infection.