Summary of the publications |
|
2023-2025 |
| Takayuki Chikata*, Kimiko Kuroki*, Nozomi Kuse*, Anna E Kliszczak, Wayne Paes, Nanami Tomioka, Robert Parker, Aure Aflalo, Tomohiro Akahoshi, Yu Zhang, Ryoya Yamashita, Ryuma Sakata, Hiroki Kusaka, Yosuke Watanabe, Annalisa Nicastri, Haruki Matsubara, Toyoyuki Ose, Shunsuke Kita, Shinichi Oka, Hiroyuki Gatanaga, Zhansong Lin, Nicola Ternette, Persephone Borrow, Katsumi Maenaka,, Masafumi Takiguchi, (*equal contribution), Molecular basis for selection and inhibition of HIV-1 escape virus by T cells and KIR2DL2+NK cells. Nat Commun. 16: 9796, 2025 |
| NK cells and CD8+ T cells both contribute to HIV-1 control. These cells not only suppress HIV-1 replication, but also select HIV-1 escape mutant viruses. Most viruses bearing T cell escape mutations are expected to remain susceptible to NK cell suppression, but their inhibition by NK cells is unclear. We investigated the role of HIV-1-specific CD8+ T cells and NK cells recognizing superimposed Pol peptides in selection and control of HIV-1 mutant virus. KIR2DL2+NK cells have an enhanced ability to recognize HIV-1-infected cells after selection of Pol mutant virus by PolIY11-specific HLA-C*12:02-restricted T cells. Mass spectrometry-based immunopeptidome profiling of HIV-1-infected cells and analysis of crystal structures of TCR- and KIR2DL2-HLA-C*12:02-peptide complexes demonstrate the molecular basis for selection and recognition of the escape mutant epitope by TCR and KIR2DL2. The present study elucidates the mechanism for selection and inhibition of an HIV-1 escape virus by T cells and NK cells. |
| Hung The Nguyen*, Takayuki Chikata*, Nozomi Kuse, Yu Zhang, Diep Thi Ngoc Pham, Nga Thi Do, Thanh Cong Nguyen, Ngoc Bich Lung, Hao Thi Minh Bui, Hiroyuki Gatanaga, Giang Van Tran, Binh Thanh Nguyen, Do Van Nguyen, Le Minh Giang, Shinichi Oka, and Masafumi Takiguchi (*equal contribution), HIV-1-specific CD8+ T cells with different abilities to recognize HIV-1-infected cells in HIV-1-exposed seronegative individuals. PNAS Nexus 4: pgaf336, 2025 |
| The presence of HIV-1-specific CD8+ T-cell responses in HIV-1-exposed seronegative (HESN) individuals has been reported, but the details of these T cells have yet to be analyzed. We investigated HIV-1-specific CD8+ T-cell responses to 281 17-mer overlapping HIV-1 peptides and six HLA-B*15:02-restricted HIV-1 subtype AE epitope peptides in 370 Vietnamese HESN men who have sex with men (MSM). Analysis of cultured T cells stimulated with these peptides using intracellular cytokine staining (ICS) assay demonstrated HIV-1-specific CD8+ T-cell responses in only eight of these HESN-MSM. HLA-restricted CD8+ T cells specific for five HIV-1 epitope peptides were identified in five of these individuals by ICS assay and/or assay using HLA multimers. CD8+ T cells specific for three HIV-1 peptides (GagHL9, PolSV9, and PolVF9) recognized HIV-1 subtype AE?infected cells, whereas those specific for two HIV-1 peptides did not recognize them. Among CD8+ T cells that can recognize HIV-1-infected cells, those specific for two epitopes, GagHL9 and PolSV9, were frequently elicited in HIV-1-infected individuals, whereas PolVF9-specific CD8+ T cells were not found in them. These results indicate that two types of HIV-1-specific CD8+ T cells were clearly detected in HESN-MSM; they include CD8+ T cells specific for the immunodominant or nonimmunodominant HIV-1 epitope peptide that is effectively presented in HIV-1-infected cells and those for the HIV-1 peptide that is very weakly or not presented by HLA class I in HIV-1-infected cells. The present study demonstrated the existence of different HIV-1-specific CD8+ T cells that can or cannot recognize HIV-1-infected cells before HIV-1 infection is established. |
| Hung The Nguyen, Takayuki Chikata, Yu Zhang, Giang Van Tran, Hiroyuki Gatanaga, Shinichi Oka, and Masafumi Takiguchi, Role of HLA-B*58:01-restricted CD8+ T cells in HIV-1 subtype AE infection. J Infect Dis. 231:175-185, 2025 |
| HLA-B*58:01 and HLA-B*57 are protective alleles against HIV-1 subtype B or C infection whereas these HLA alleles have not been reported as protective in HIV-1 subtype AE infection. Although HLA-B*58:01-restricted and HLA-B*57-restricted HIV-1-specific CD8+ T cells have been thoroughly analyzed in subtype B or C infection, they have only been partially analyzed in subtype AE infection. We identified six HLA-B*58:01-restricted subtype AE epitopes in Vietnamese individuals infected with subtype AE. HLA-B*58:01-restricted T-cell responses to Gag epitopes, which may control disease progression in HLA-B*58:01+ and HLA-B*57+ individuals infected with subtype B or C, were not protective in subtype AE infection. These findings suggest that the loss of HLA-B*58:01-restricted T cells specific for some Gag epitopes and/or their reduced ability may account for the lack of protective effects conferred by HLA-B*58:01 in subtype AE infection. |
| Nozomi Kuse, Osamu Noyori, Naofumi Takahashi, Yu Zhang, Shinya Suzu, and Masafumi Takiguchi, Recognition of HIV-1-infected fibrocytes lacking Nef-mediated HLA-B downregulation by HIV-1-specific T cells. J Virol. 98: e00791-24, 2024 |
| Fibrocytes were reported
to be host cells for HIV-1, but the immunological recognition of HIV-1-infected
fibrocytes has not been studied. Here, we investigated the recognition of
HIV-1-infected fibrocytes by HIV-1-specific CD8+ T cells. CD8+ T cells specific
for five HIV-1 epitopes (HLA-A*24:02-restricted, HLA-B*52:01-restricted,
and HLA-C*12:02-restricted epitopes) produced IFN-ƒÁ and expressed CD107a
after coculture with HIV-1-infected fibrocytes. HIV-1-infected fibrocytes
were effectively killed by HIV-1-specific CD8+ T cells. Although it is well
known that HIV-1 Nef-mediated downregulation of HLA-A and HLA-B critically
affects the T cell recognition of HIV-1-infected CD4+ T cells and HIV-1-infected
macrophages, Nef downregulated HLA-A, but not HLA-B, in HIV-1-infected fibrocytes.
These findings suggested that HIV-1-specific CD8+ T cells could recognize
HIV-1-infected fibrocytes more strongly than HIV-1-infected CD4+ T cells
or HIV-1-infected macrophages. HIV-1-infected fibrocytes were also recognized
by HIV-1-specific HLA-DR-restricted T cells, indicating that HIV-1-infected
fibrocytes can present HIV-1 epitopes to helper T cells. Collectively, these
findings suggest that fibrocytes have an important role as antigen-presenting
cells during HIV-1 infection. The present study demonstrates effective recognition
of HIV-1-infected fibrocytes by HIV-1-specific T cells and suggests possible
roles of fibrocytes in the induction and maintenance of HIV-1-specific T
cells.
Importance: Fibrocytes were identified as unique hematopoietic cells with the features of both macrophages and fibroblasts and were demonstrated to be host cells for HIV-1. However, T cell recognition of HIV-1-infected fibrocytes has not been studied. We investigated the recognition of HIV-1-infected fibrocytes by HIV-1-specific T cells. HIV-1-infected fibrocytes were effectively recognized and killed by CD8+ T cells specific for HIV-1 epitopes presented by HLA-A, HLA-B, or HLA-C and were recognized by HIV-1-specific HLA-DR-restricted CD4+ T cells. HIV-1 Nef-mediated downregulation of HLA-A and HLA-B was found in HIV-1-infected CD4+ T cells, whereas Nef did not downregulate HLA-B in HIV-1-infected fibrocytes. These results suggest that HIV-1-specific CD8+ T cells recognize HIV-1-infected fibrocytes more strongly than HIV-1-infected CD4+ T cells. The present study suggests the importance of fibrocytes in the induction and maintenance of HIV-1-specific T cells. |
| Nozomi Kuse, Hiroyuki Gatanaga, Yu Zhang, Takayuki Chikata, Shinichi Oka, and Masafumi Takiguchi, Epitope-dependent effect of long-term cART on maintenance and recovery of HIV-1-specific CD8+ T cells. J. Virol. 97: e01024-23, 2023 |
| HIV-1-specific CD8+ T cells are anticipated to become effector cells for curative treatment using the "shock and kill" approach in people living with HIV-1 (PLWH) under combined antiretroviral therapy (cART). Previous studies demonstrated that the frequency of HIV-1-specific CD8+ T cells is reduced under cART and their functional ability remains impaired. These studies analyzed T-cell responses to a small number of HIV-1 epitopes or overlapping HIV-1 peptides. Therefore, the features of CD8+ T cells specific for HIV-1 epitopes under cART remain only partially clarified. Here, we analyzed CD8+ T cells specific for 63 well-characterized epitopes in 90 PLWH. We demonstrated that CD8+ T cells specific for large numbers of HIV-1 epitopes were maintained in an epitope-dependent fashion under long-term cART and that long-term cART enhanced or restored the ability of HIV-1-specific T cells to proliferate in vitro. This study implies that some HIV-1-specific T cells would be useful as effector cells for curative treatment. |
| Takayuki Chikata, Hiroyuki Gatanaga, Hung The Nguyen, Daisuke Mizushima, Yu Zhang, Nozomi Kuse, Shinichi Oka, and Masafumi Takiguchi, HIV-1 protective epitope-specific CD8+ T cells in HIV-1-exposed seronegative individuals. iScience 26: 108089, 2023 |
| Although previous studies have reported HIV-1-specific T cell responses in HIV-1-exposed seronegative (HESN) individuals, there has been no detailed analysis of these T cells against HIV-1 infection. We investigated HIV-1-specific CD8+ T cell responses in 200 Japanese HESN men who have sex with men (MSM). T cell responses to 143 well-characterized HIV-1 epitope peptides were analyzed by intracellular cytokine staining assay consisting of 3-week cultures of PBMCs stimulated with peptides. HLA-B*51:01-restricted Pol TI8-specific and HLA-A?02:06-restricted Pol SV9-specific CD8+ T cells were identified in two and one individuals, respectively, whereas CD8+ T cells specific for other HLA-A*02:06-restricted or HLA-B*51:01 epitopes were not present in these individuals. These epitope-specific T cells recognized HIV-1-infected cells. Because these two epitopes were previously reported to be protective in HIV-1-infected individuals, these protective epitope-specific T cells might suppress HIV-1 replication in HESN-MSM individuals. The present study suggests the contribution of protective epitope-specific T cells to protection against HIV-1 infection. |