Escape in one of two cytotoxic T-lymphocyte epitopes bound by a high-frequency major histocompatibility complex class I molecule, Mamu-A*02: a paradigm for virus evolution and persistence?
It is now accepted that an effective vaccine against AIDS must include effective cytotoxic-T-lymphocyte (CTL) responses. The simian immunodeficiency virus (SIV)-infected rhesus macaque is the best available animal model for AIDS, but analysis of macaque CTL responses has hitherto focused mainly on epitopes bound by a single major histocompatibility complex (MHC) class I molecule, Mamu-A*01. The availability of Mamu-A*01-positive macaques for vaccine studies is therefore severely limited. Furthermore, it is becoming clear that different CTL responses are able to control immunodeficiency virus replication with varying success, making it a priority to identify and analyze CTL responses restricted by common MHC class I molecules other than Mamu-A*01. Here we describe two novel epitopes derived from SIV, one from Gag (Gag(71-79) GY9), and one from the Nef protein (Nef(159-167) YY9). Both epitopes are bound by the common macaque MHC class I molecule, Mamu-A*02. The sequences of these two eptiopes are consistent with the molecule's peptide-binding motif, which we have defined by elution of natural ligands from Mamu-A*02. Strikingly, we found evidence for the selection of escape variant viruses by CTL specific for Nef(159-167) YY9 in 6 of 6 Mamu-A*02-positive animals. In contrast, viral sequences encoding the Gag(71-79) GY9 epitope remained intact in each animal. This situation is reminiscent of Mamu-A*01-restricted CTL that recognize Tat(28-35) SL8, which reproducibly selects for escape variants during acute infection, and Gag(181-189) CM9, which does not. Differential selection by CTL may therefore be a paradigm of immunodeficiency virus infection.
Vogel
Thorsten U
TU
Wisconsin Regional Primate Research Center, University of Wisconsin, Madison, Wisconsin 53715, USA.
Friedrich
Thomas C
TC
O'Connor
David H
DH
Rehrauer
William
W
Dodds
Elizabeth J
EJ
Hickman
Heather
H
Hildebrand
William
W
Sidney
John
J
Sette
Alessandro
A
Hughes
Austin
A
Horton
Helen
H
Vielhuber
Kathy
K
Rudersdorf
Richard
R
De Souza
Ivna P
IP
Reynolds
Matthew R
MR
Allen
Todd M
TM
Wilson
Nancy
N
Watkins
David I
DI
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D019143:Evolution, Molecular; D015683:Gene Products, gag / Q000276:immunology; D015693:Gene Products, nef / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D016056:Immunodominant Epitopes; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000254:growth & development* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D015693:Gene Products, nef; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; C089390:Mamu-A 02 antigen