HLA class I binding of HBZ determines outcome in HTLV-1 infection.
CD8(+) T cells can exert both protective and harmful effects on the virus-infected host. However, there is no systematic method to identify the attributes of a protective CD8(+) T cell response. Here, we combine theory and experiment to identify and quantify the contribution of all HLA class I alleles to host protection against infection with a given pathogen. In 432 HTLV-1-infected individuals we show that individuals with HLA class I alleles that strongly bind the HTLV-1 protein HBZ had a lower proviral load and were more likely to be asymptomatic. We also show that in general, across all HTLV-1 proteins, CD8(+) T cell effectiveness is strongly determined by protein specificity and produce a ranked list of the proteins targeted by the most effective CD8(+) T cell response through to the least effective CD8(+) T cell response. We conclude that CD8(+) T cells play an important role in the control of HTLV-1 and that CD8(+) cells specific to HBZ, not the immunodominant protein Tax, are the most effective. We suggest that HBZ plays a central role in HTLV-1 persistence. This approach is applicable to all pathogens, even where data are sparse, to identify simultaneously the HLA Class I alleles and the epitopes responsible for a protective CD8(+) T cell response.
Macnamara
Aidan
A
Department of Immunology, Faculty of Medicine, Imperial College, London, United Kingdom.
Rowan
Aileen
A
Hilburn
Silva
S
Kadolsky
Ulrich
U
Fujiwara
Hiroshi
H
Suemori
Koichiro
K
Yasukawa
Masaki
M
Taylor
Graham
G
Bangham
Charles R M
CR
Asquith
Becca
B
D000483:Alleles; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016022:Case-Control Studies; D015331:Cohort Studies; D000939:Epitopes / Q000276:immunology; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism; D005805:Genes, MHC Class I / Q000502:physiology*; D015490:HTLV-I Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D012191:Retroviridae Proteins; D012984:Software; D013602:T-Lymphocytes, Cytotoxic; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D050976:Basic-Leucine Zipper Transcription Factors; D000939:Epitopes; D016356:Gene Products, tax; C479751:HBZ protein, human T-cell leukemia virus type I; D010446:Peptide Fragments; D012191:Retroviridae Proteins; D014764:Viral Proteins