Abstract
Effective CD8 T cell responses are vital for the control of chronic viral infections. Many factors of the host immune response contribute to the maintenance of effector CD8 T cell responses versus CD8 T cell exhaustion during chronic infection. Specific MHC alleles and the degree of MHC heterogeneity are associated with enhanced CD8 T cell function and viral control during human chronic infection. However, it is currently unclear to what extent host genetics influences the establishment of chronic viral infection. In order to examine the impact of MHC heterogeneity versus non-MHC host genetics on the development of chronic viral infection, an F1 cross of B10.D2 x B6 (D2B6F1) and BALB.B x BALB/c (BCF1) mice were infected with the clone-13 (Cl-13) strain of lymphocytic choriomeningitis virus (LCMV). Following chronic Cl-13 infection both H-2bxd D2B6F1 and BCF1 mice demonstrated increased viral control compared to homozygous mice. Strikingly, H-2bxd D2B6F1 mice on a C57BL genetic background exhibited mortality following Cl-13 infection. CD8 T cell depletion prevented mortality in Cl-13-infected D2B6F1 mice indicating that mortality was CD8 T-cell-dependent. D2B6F1 mice maintained more CD8 T cell effector cytokine production and exhibited reduced expression of the T cell exhaustion marker PD-1. In addition, D2B6F1 mice also induced a larger Th1 response than BCF1 mice and Cl-13-induced mortality in D2B6F1 mice was also dependent on CD4 T-cell-mediated IFN-γ production. Thus, following a chronic viral infection, increased functionality of the CD8 T cell response allowed for more rapid viral clearance at the cost of enhanced immunopathology dependent on both MHC diversity and the genetic background of the host.
Highlights
Chronic viral infection such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) affect an estimated 185 million people worldwide
Host genetics contribute to CD8 T cell function data collection and analysis, decision to publish, or preparation of the manuscript
We sought to determine the impact of host genetics on the course of a chronic lymphocytic choriomeningitis virus (LCMV) Cl13 infection
Summary
Chronic viral infection such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) affect an estimated 185 million people worldwide. Expression of either heterozygous human leukocyte antigen (HLA) class I alleles or the specific HLA alleles HLA BÃ5701 and HLA BÃ2701 are associated with enhanced CD8 T cell responses and reduced viral loads during HIV infection [3, 5,6,7,8]. Clearance of HCV infection has been associated with the expression of heterozygous HLA alleles as well as with the expression of specific HLA alleles [2, 4] These host advantages driven by HLA expression patterns demonstrate the critical importance of the T cell response during chronic viral infection. CD8 T cell exhaustion is believed to occur in order to limit immunopathology to the host
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
