Degenerate specificity of HTLV-1-specific CD8+ T cells during viral replication in patients with HTLV-1-associated myelopathy (HAM/TSP).
Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurologic disease caused by HTLV-1 infection, in which HTLV-1-infected CD4(+) T cells and HTLV-1-specific CD8(+) T cells may play a role in the disease pathogenesis. Patients with HAM/TSP have high proviral loads despite vigorous virus-specific CD8(+) T-cell responses; however, it is unknown whether the T cells are efficient in eliminating the virus in vivo. To define the dynamics of HTLV-1-specific CD8(+) T-cell responses, we investigated longitudinal alterations in HTLV-1 proviral load, amino acid changes in an immunodominant viral epitope, frequency of HTLV-1-specific T cells, and degeneracy of T-cell recognition in patients with HAM/TSP. We showed that the frequency and the degeneracy of the HTLV-1-specific CD8(+) T cells correlated well with proviral load in the longitudinal study. The proviral load was much higher in a patient with low degeneracy of HTLV-1-specific T cells compared to that in a patient with comparable frequency but higher degeneracy of the T cells. Furthermore, in a larger number of patients divided into 2 groups by the proviral load, those with high proviral load had lower degeneracy of T-cell recognition than those with low proviral load. Sequencing analysis revealed that epitope mutations were remarkably increased in a patient when the frequency and the degeneracy were at the lowest. These data suggest that HTLV-1-specific CD8(+) T cells with degenerate specificity are increased during viral replication and control the viral infection.
Kubota
Ryuji
R
Third Department of Internal Medicine, Center for Chronic Viral Diseases, Kagoshima University, Kagoshima, Japan. kubotar@m2.kufm.kagoshima-u.ac.jp
Furukawa
Yoshitaka
Y
Izumo
Shuji
S
Usuku
Koichiro
K
Osame
Mitsuhiro
M
D019943:Amino Acid Substitution; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D016356:Gene Products, tax / Q000235:genetics / Q000276:immunology; D016355:Genes, pX; D015789:HLA-A2 Antigen / Q000032:analysis; D015486:HTLV-I Antigens / Q000235:genetics / Q000276:immunology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D007564:Japan / Q000453:epidemiology; D008137:Longitudinal Studies; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D015493:Paraparesis, Tropical Spastic / Q000453:epidemiology / Q000276:immunology* / Q000821:virology; D010446:Peptide Fragments / Q000276:immunology; D011533:Proviruses / Q000235:genetics / Q000302:isolation & purification; D019562:Viral Load; D014779:Virus Replication
D004279:DNA, Viral; D016356:Gene Products, tax; D015789:HLA-A2 Antigen; D015486:HTLV-I Antigens; D016056:Immunodominant Epitopes; D010446:Peptide Fragments