CD8+ TCR Bias and Immunodominance in HIV-1 Infection.
Immunodominance describes a phenomenon whereby the immune system consistently targets only a fraction of the available Ag pool derived from a given pathogen. In the case of CD8(+) T cells, these constrained epitope-targeting patterns are linked to HLA class I expression and determine disease progression. Despite the biological importance of these predetermined response hierarchies, little is known about the factors that control immunodominance in vivo. In this study, we conducted an extensive analysis of CD8(+) T cell responses restricted by a single HLA class I molecule to evaluate the mechanisms that contribute to epitope-targeting frequency and antiviral efficacy in HIV-1 infection. A clear immunodominance hierarchy was observed across 20 epitopes restricted by HLA-B*42:01, which is highly prevalent in populations of African origin. Moreover, in line with previous studies, Gag-specific responses and targeting breadth were associated with lower viral load set-points. However, peptide-HLA-B*42:01 binding affinity and stability were not significantly linked with targeting frequencies. Instead, immunodominance correlated with epitope-specific usage of public TCRs, defined as amino acid residue-identical TRB sequences that occur in multiple individuals. Collectively, these results provide important insights into a potential link between shared TCR recruitment, immunodominance, and antiviral efficacy in a major human infection.
Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom; Department of International Health, Immunology, and Microbiology, University of Copenhagen, 2200-Copenhagen N, Denmark; KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban 4001, South Africa; henrik.kloverpris@k-rith.org.
Henrik N
HN
Kløverpris
Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom;
Reuben
R
McGregor
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
James E
JE
McLaren
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
Kristin
K
Ladell
Department of International Health, Immunology, and Microbiology, University of Copenhagen, 2200-Copenhagen N, Denmark;
Mikkel
M
Harndahl
Department of International Health, Immunology, and Microbiology, University of Copenhagen, 2200-Copenhagen N, Denmark;
Anette
A
Stryhn
Microsoft Research, eScience Group, Los Angeles, CA 90024;
Jonathan M
JM
Carlson
HIV Pathogenesis Program, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa;
Catherine
C
Koofhethile
Theoretical Biology Group, Utrecht University, 3584 CH Utrecht, the Netherlands;
Bram
B
Gerritsen
Theoretical Biology Group, Utrecht University, 3584 CH Utrecht, the Netherlands;
Can
C
Keşmir
Department of Sexual Health, Royal Berkshire Hospital, Reading RG1 5AN, United Kingdom;
Fabian
F
Chen
Department of Genitourinary Medicine, Northamptonshire Healthcare National Health Service Trust, Northampton General Hospital, Cliftonville, Northampton NN1 5BD, United Kingdom;
Lynn
L
Riddell
Department of Sexual Health, Wycombe Hospital, High Wycombe HP11 2TT, United Kingdom;
Graz
G
Luzzi
KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban 4001, South Africa;
Alasdair
A
Leslie
Ragon Institute of MGH, MIT, and Harvard, Boston, MA 02129; Howard Hughes Medical Institute, Chevy Chase, MD 20815; and.
Bruce D
BD
Walker
KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban 4001, South Africa; HIV Pathogenesis Program, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa; Max Planck Institute for Infection Biology, D-10117 Berlin, Germany.
Thumbi
T
Ndung'u
Department of International Health, Immunology, and Microbiology, University of Copenhagen, 2200-Copenhagen N, Denmark;
Søren
http://orcid.org/0000-0001-8363-1999
S
Buus
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
David A
DA
Price
Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom;
Philip J
PJ
Goulder
D000328:Adult; D000595:Amino Acid Sequence; D000915:Antibody Affinity / Q000276:immunology; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018076:DNA, Complementary / Q000235:genetics; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D015235:HLA-B Antigens / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D017422:Sequence Analysis, DNA; D019562:Viral Load; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology
D018076:DNA, Complementary; D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell; D054301:gag Gene Products, Human Immunodeficiency Virus