Minor viral and host genetic polymorphisms can dramatically impact the biologic outcome of an epitope-specific CD8 T-cell response.
Human immunodeficiency virus-1 subtypes A and C differ in the highly conserved Gag-TL9 epitope at a single amino acid position. Similarly, the TL9 presenting human leukocyte antigen (HLA) class I molecules B42 and B81 differ only at 6 amino acid positions. Here, we addressed the influence of such minor viral and host genetic variation on the TL9-specific CD8 T-cell response. The clonotypic characteristics of CD8 T-cell populations elicited by subtype A or subtype C were distinct, and these responses differed substantially with respect to the recognition and selection of TL9 variants. Irrespective of the presenting HLA class I molecule, CD8 T-cell responses elicited by subtype C exhibited largely comparable TL9 variant cross-recognition properties, expressed T-cell receptors that used almost exclusively the TRBV 12-3 gene, and selected for predictable patterns of viral variation within TL9. In contrast, subtype A elicited TL9-specific CD8 T-cell populations with completely different, more diverse TCRBV genes and did not select for viral variants. Moreover, TL9 variant cross-recognition properties were extensive in B81(+) subjects but limited in B42(+) subjects. Thus, minor viral and host genetic polymorphisms can dramatically alter the immunologic and virologic outcome of an epitope-specific CD8 T-cell response.
Geldmacher
Christof
C
Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA. geldmacher@lrz.uni-muenchen.de
Metzler
Ian S
IS
Tovanabutra
Sodsai
S
Asher
Tedi E
TE
Gostick
Emma
E
Ambrozak
David R
DR
Petrovas
Constantinos
C
Schuetz
Alexandra
A
Ngwenyama
Njabulo
N
Kijak
Gustavo
G
Maboko
Leonard
L
Hoelscher
Michael
M
McCutchan
Francine
F
Price
David A
DA
Douek
Daniel C
DC
Koup
Richard A
RA
D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D011110:Polymorphism, Genetic / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
D004279:DNA, Viral; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins