Abstract
Cytotoxic T lymphocytes (CTLs) represent key immune effectors of the host response against chronic viruses, due to their cytotoxic response to virus-infected cells. In response to this selection pressure, viruses may accumulate escape mutations that evade CTL-mediated control. To study the emergence of CTL escape mutations, we employed the murine chronic infection model of lymphocytic choriomeningitis virus (LCMV). We developed an amplicon-based next-generation sequencing pipeline to detect low frequency mutations in the viral genome and identified non-synonymous mutations in the immunodominant LCMV CTL epitope, GP33-41, in infected wildtype mice. Infected Rag2-deficient mice lacking CTLs did not contain such viral mutations. By using transgenic mice with T cell receptors specific to GP33-41, we characterized the emergence of viral mutations in this epitope under varying selection pressure. We investigated the two most abundant viral mutations by employing reverse genetically engineered viral mutants encoding the respective mutations. These experiments provided evidence that these mutations prevent activation and expansion of epitope-specific CD8 T cells. Our findings on the mutational dynamics of CTL escape mutations in a widely-studied viral infection model contributes to our understanding of how chronic viruses interact with their host and evade the immune response. This may guide the development of future treatments and vaccines against chronic infections.
Highlights
The action of cytotoxic T lymphocytes (CTLs) is a key means by which the immune system controls viral infections [1, 2]
We analyzed seven infected C57BL/6J Rag2-/- mice from two independent experiments and did not find any such mutation in the GP33-41 epitope (Figure 1A). These observations suggest that the viral mutations found in infected WT mice, at relatively low frequencies, may have escaped the CTL response against the GP33-41 epitope
CTLs are important to control chronic viral infections such as lymphocytic choriomeningitis virus (LCMV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV), which may evade this immune pressure by the selection of mutations in CTL epitopes [8, 9, 20, 22, 41,42,43,44]
Summary
The action of cytotoxic T lymphocytes (CTLs) is a key means by which the immune system controls viral infections [1, 2]. Binding of the TCR to the viral peptide-MHCI complex, together with sufficient costimulatory signals from receptor/ligand interactions and cytokines, results in proliferation and migration of the CTLs to the site of infection [2]. CTLs initiate targeted cell death, by apoptosis, of infected cells through the secretion of perforin and granzymes and/or binding of Fas ligand to Fas receptors on the infected cell [6, 7]. Due to their cytotoxic nature, CTL activity constitutes a direct antiviral selection pressure and is considered essential to control viral infections [8]
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.
