Summary of the publications
Hiroko Tomiyama, Shinichi Oka, Graham S. Ogg, Setsuko Ida, Andrew J. McMichael and Masafumi Takiguchi, Expansion of HIV-1-specific CD28-CD45RA-CD8+ T cells in chronically HIV-1 infected individuals. AIDS. 14:2049-2051, 2000.
There is growing evidence that cytotoxic T lymphocytes (CTL) play an important role in protection against HIV-1 infection and the suppression of HIV-1 replication in infected hosts. Analysis of CD8 T cells in HIV-1-infected individuals is therefore expected to contribute to the clarification of AIDS immunopathogenesis. Many phenotype analyses of CD8 T cells from HIV-1-infected individuals have been performed. The number of CD28-CD8+ T cells increases early in primary infection and further during the progression towards AIDS. It has been suggested that CD28-CD8+ T cells are involved in the control of virus replication [6?8]. A recent study [9] indirectly showed expansion of the CD28- phenotype in HIV-1-specific CD8 T cells. All the above studies imply that CD28-CD8+ T cells are cytotoxic effector cells.
Hiroko Tomiyama, Naoyuki Yamada, Hiroki Komatsu, Kazuo Hirayama and Masafumi Takiguchi, A single CTL clone can recognize a naturally processed HIV-1 epitope presented by two different HLA class I molecules. Eur. J. Immunol. 30:2521-2530, 2000.
Although it is known that a single peptide can be recognized by CTL restricted to two MHC class I alleles, there is no direct evidence for presentation of a single peptide by two MHC class I molecules. Furthermore, it is unclear whether such peptides are presented to the same T cell or to different T cells. Our previous study suggested that CTL recognition of the human immunodeficiency virus-1 (HIV-1) Pol HIV-B35-SF2-24 epitope (IPLTEEAEL) occurs via both HLA-B35 and HLA-B51 restriction. Here we provide the first direct evidence that a single CTL clone can recognize this peptide presented by both HLA-B35 and HLA-B51. Furthermore, we directly purified this peptide eluted from both HLA-B*3501 and HLA-B*5101 molecules isolated from target cells infected with HIV-1 recombinant vaccinia virus. These results demonstrate that HIV-B35-SF2-24 is a naturally processed peptide which is presented by both HLA-B*3501 and HLA-B*5101. TCR analysis of one CTL clone suggested that it is a single clone. B*3501-SF2-24-tetrameric complexes inhibited both HLA-B*3501- and HLA-B*5101-restricted recognition of this clone, suggesting that the TCR of this clone cross-recognize the structure of both HLA class I-peptide complexes.
Yuki Ikeda-Moore, Hiroko Tomiyama, Kiyoshi Miwa, Shinichi Oka, Aikichi Iwamoto, Yutaro Kaneko, and Masafumi Takiguchi, Identification and characterization of multiple HLA-A24-restricted HIV-1 CTL epitopes: Strong epitopes are derived from V regions of HIV-1. J. Immunol. 159:6242-6252, 1997. [Abstract]
HIV-1-specific CTL has a crucial role in the elimination of the virus. However, a restricted number of common HLA class I alleles has been studied for their presentation of HIV-1 CTL epitopes. We have attempted to identify HIV-1 CTL epitopes presented by HLA-A*2402 using reverse immunogenetics. Fifty-three HLA-A*2402-binding HIV-1 peptides were used to induce specific CTL in PBL of four HIV-1-infected individuals carrying HLA-A24. Twelve peptides were strongly suggested to be HLA- A*2402-restricted HIV-1 CTL epitopes because these peptides induced the specific CTL that killed both the target cells pulsed with the specific peptides and those infected with the vaccinia HIV-1 recombinant virus in at least one HIV-1-infected individual. Of these epitopes, 11 were confirmed by the generation of the specific CTL clones. Six were the Env epitopes while three, one, and one were derived from Gag, Pol, and Nef proteins, respectively. Analysis of 12 HIV-1-infected individuals using these peptides showed that 5 derived from the Env protein and one from the Nef protein were strong epitopes. These strong epitopes were derived from the diverse region of HIV-1 while weak epitopes were conserved in the HIV-1 clade B strain. Analysis of CTL recognition of mutations in these strong epitopes suggested that the mutations in the Env epitopes may critically influence CTL recognition in vivo.
Hiroko Tomiyama, Kiyoshi Miwa, Hajime Shiga, Yuki Ikeda-Moore, Shinichi Oka, Aikichi Iwamoto, Yutaro Kaneko and Masafumi Takiguchi, Evidence of presentation of multiple HIV-1 cytotoxic T lymphocyte epitopes by HLA-B*3501 molecules that are associated with the accelerated progression of AIDS. J. Immunol. 158:5026-5034, 1997. [Abstract]
We recently showed HLA-B35-restricted CTL activity for 10 HIV-1 epitopes in PBL from two HIV-1-infected individuals. In the present study, we established CTL clones specific for nine of these HIV-1 epitopes to confirm these HLA-B35-restricted epitopes. The specific CTL clones effectively killed the HLA-B*3501-positive target cells infected with the HIV-1 vaccinia recombinant virus. These results confirmed that nine HIV-1 CTL epitopes are presented by HLA-B*3501 molecules. The CTL activity specific for four Pol and two Nef epitopes was induced in the peptide-stimulated PBL from three or more of seven HIV-1-infected individuals, indicating that these six are common epitopes. Eight were considered strong epitopes because the specific CTL activity was detected in the cultured PBL that was once stimulated with peptides. Thus, the present study excluded the possibility that the disability of the presentation of HIV-1 epitopes by HLA-B35 molecules is associated with the accelerated progression of AIDS in HLA-B35-positive individuals. Analysis of mutated epitopes found in an HIV-1 type B strain using the CTL clones revealed that most mutated epitopes partially or markedly affect the recognition of CTL clones. Of 19 mutations that affected recognition of the CTL clones, 7 reduced peptide-HLA-B*3501 binding, while 12 affected TCR recognition. These results indicate that natural mutations of HLA-B35-restricted HIV-1 CTL epitopes affect the recognition of CTL by mechanisms that reduce both peptide binding and TCR recognition.