Protection Against CTL Escape and Clinical Disease in a Murine Model of Virus Persistence

Abstract

CTL escape mutations have been identified in several chronic infections, including mice infected with mouse hepatitis virus strain JHM. One outstanding question in understanding CTL escape is whether a CD8 T cell response to two or more immunodominant CTL epitopes would prevent CTL escape. Although CTL escape at multiple epitopes seems intuitively unlikely, CTL escape at multiple CD8 T cell epitopes has been documented in some chronically infected individual animals. To resolve this apparent contradiction, we engineered a recombinant variant of JHM that expressed the well-characterized gp33 epitope of lymphocytic choriomeningitis virus, an epitope with high functional avidity. The results show that the presence of a host response to this second epitope protected mice against CTL escape at the immunodominant JHM-specific CD8 T cell epitope, the persistence of infectious virus, and the development of clinical disease.

Pathogenic Potential of Borna Disease Virus Lacking the Immunodominant CD8 T-Cell Epitope

“…Similar results were later obtained with influenza A virus in T-cell receptor-transgenic mice (33). Virus variants with mutations affecting CD8 T-cell epitopes were reported to accumulate in monkeys infected with simian immunodeficiency virus (SIV) (6,28) and in mice infected with mouse hepatitis virus (17,26,27). Mutation of CD8 T-cell epitopes can lead to increased virus titers in immune animals (6,28) and may thus contribute to morbidity and mortality resulting from virus infection.…”

Consequences of Immunodominant Epitope Deletion for Minor Influenza Virus-Specific CD8+-T-Cell Responses

“…Individuals with subclinical human immunodeficiency virus (HIV) infection may suddenly show evidence of increased viral load following the emergence of mutants that no longer express a key peptide recognized by controlling CD8 ϩ T cells (13,14). Evidence of T-cell-induced in vivo variation is also found experimentally with a model of chronic neurological disease caused by mouse hepatitis virus (21). However, even the small RNA viruses generally express a spectrum of immunogenic peptides that can be presented in the context of one or another of the four or more different major histocompatibility complex class I (MHCI) glycoproteins expressed in any healthy person or MHC heterozygous mouse (4,17,38).…”

Protective Capacity of Memory CD8+ T Cells Is Dictated by Antigen Exposure History and Nature of the Infection

“…Virulent Listeria monocytogenes expressing gp33 (LM-gp33) (Kaech and Ahmed, 2001) was grown and injected i.v. Recombinant MHV expressing gp33 (Kim and Perlman, 2003) was kindly provided by Dr. Stanley Perlman, and was given intranasally. All animal experiments followed approved Institutional Animal Care and Use Committee protocols.…”