Consequences of cytotoxic T-lymphocyte escape: common escape mutations in simian immunodeficiency virus are poorly recognized in naive hosts.
Cytotoxic T lymphocytes (CTL) are associated with control of immunodeficiency virus infection but also select for variants that escape immune recognition. Declining frequencies of epitope-specific CTL frequencies have been correlated with viral escape in individual hosts. However, escape mutations may give rise to new epitopes that could be recognized by CTL expressing appropriate T-cell receptors and thus still be immunogenic when escape variants are passed to individuals expressing the appropriate major histocompatibility complex class I molecules. To determine whether peptide ligands that have been altered through escape can be immunogenic in new hosts, we challenged naïve, immunocompetent macaques with a molecularly cloned simian immunodeficiency virus (SIV) bearing common escape mutations in three immunodominant CTL epitopes. Responses to the altered peptides were barely detectable in fresh samples at any time after infection. Surprisingly, CTL specific for two of three escaped epitopes could be expanded by in vitro stimulation with synthetic peptides. Our results suggest that some escape variant epitopes evolving in infected individuals do not efficiently stimulate new populations of CTL, either in that individual or upon passage to new hosts. Nevertheless, escape variation may not completely abolish an epitope's immunogenicity. Moreover, since the mutant epitope sequences did not revert to wild type during the study period, it is possible that low-frequency CTL exerted enough selective pressure to preserve epitope mutations in viruses replicating in vivo.
Friedrich
Thomas C
TC
Wisconsin National Primate Research Center, 1220 Capitol Court, Madison, WI 53715, USA.
McDermott
Adrian B
AB
Reynolds
Matthew R
MR
Piaskowski
Shari
S
Fuenger
Sarah
S
De Souza
Ivna P
IP
Rudersdorf
Richard
R
Cullen
Candice
C
Yant
Levi J
LJ
Vojnov
Lara
L
Stephany
Jason
J
Martin
Sarah
S
O'Connor
David H
DH
Wilson
Nancy
N
Watkins
David I
DI
D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000235:genetics; D019143:Evolution, Molecular; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular; D016056:Immunodominant Epitopes / Q000235:genetics; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D009154:Mutation; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000276:immunology
D000956:Antigens, Viral; D015683:Gene Products, gag; D016056:Immunodominant Epitopes; C429284:NEF protein, SIV; D054334:Viral Regulatory and Accessory Proteins