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IMSUT Hospital

Department of AIDS Vaccine Development
エイズワクチン開発担当

Invited Professor
Tetsuro Matano, M.D., D.M.Sc.
Visiting Associate Professor Ai Kawana-Tachikawa, D.M.Sc.

教授（委嘱） 博士（医学）客員准教授 博士（医学）俣 野 哲 朗立川（川名） 愛

We are working on Microbiology and Immunology to elucidate the immune
mechanism for retroviral control in vivo. In particular, we are studying virus-hostimmune interaction and viral evolution using non-human primate models andhuman clinical samples derived from African and Asian countries as well as Japan.
Furthermore, we are developing vaccines eliciting antibody and/or cytotoxic T
lymphocyte responses targeting pathogens including HIV-1, HTLV-1, and SARSCoV-2.

1. Impaired protective role of HLA-B*57:01/58:01
in HIV-1 CRF01_AE infection: a cohort study inVietnam.
Tam Tran Thi Minh1, Yuta Hikichi2, Shoji Miki2, Yuriko Imanari2, Shigeru Kusagawa2, Midori Okazaki2, Thao Dang Thi Thu3, Teiichiro Shiino2, SaoriMatsuoka2, Hiroyuki Yamamoto2, Jun Ohashi4, William W. Hall5, Tetsuro Matano, Lan Anh Nguyen
Thi1, Ai Kawana-Tachikawa: 1Centre for Bio-Medical Research, National Institute of Hygiene and Epidemiology, Hanoi, Vietnam; 2AIDS ResearchCenter, National Institute of Infectious Diseases, Tokyo, Japan; 3Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan; 4Department of Biological Sciences,
Graduate School of Sciences, University of Tokyo,Tokyo, Japan; 5Center for Research in Infectious
Diseases, School of Medicine & Medical Science,
University College Dublin, Dublin, Ireland
Human Leukocyte Antigen HLA-B*57:01 andB*58:01 are considered anti-HIV-1 protective alleles.
HLA-B*57:01/58:01-restricted HIV-1 Gag TW10(TSTLQEQIGW, Gag residues 240-249) epitope-specific CD8+ T cell responses that frequently select for aGag escape mutation, T242N, with viral fitness costare crucial for HIV-1 control. Although this finding

has been observed in cohorts where HIV-1 subtype B
or C predominates, the protective impact of
HLA-B*57:01/58:01 has not been reported in Southeast
Asian countries where HIV-1 CRF01_AE is the major
circulating strain. In this study, the effect of
HLA-B*57:01/58:01 on CRF01_AE infection was investigated in a CRF01_AE-infected Vietnamese cohort (N= 280). HLA-B*57:01/58:01-positive individuals mostly had HIV-1 with T242N (62/63) but showed neither
a significant reduction in viral load nor increased
CD4 counts relative to B*57:01/58:01-negative participants. In vitro and in vivo analyses revealed a significant reduction in viral fitness of CRF01_AE withT242N. In silico analysis indicated reduced presentation of epitopes in the context of CRF01_AE comparedto subtype B or C in 10/16 HLA-B*57:01/58:01-restricted HIV-1 epitopes. These results indicate that the protective impact of HLA-B*57:01/58:01 on CRF01_AE
infection is impaired despite strong suppressive pressure by TW10-specific CD8+ T cells.
2.  Plasmacytoid dendritic cells stimulated withLactococcus lactis strain Plasma produce soluble factors to suppress SARS-CoV-2 replication.
Hiroshi Ishii2, Kenta Jounai6, Ryohei Tsuji6, Konomi
Ohshio6, Daiki Kaneda, Midori Okazaki2, Shigeyoshi

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Harada2, Daisuke Fujiwara6, Tetsuro Matano: 6Kirin Central Research Institute, Kirin Holdings, Co.,
Ltd., Japan
Innate immune responses are important in thecontrol of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. We have previously found a lactic acid bacteria species, Lactococcus lactis strain Plasma (LC-Plasma), which possesses
specific feature to activate plasmacytoid dendriticcells (pDCs) and thus may affect innate immune responses. In this study, we investigated the impact ofpDC activation by LC-Plasma on SARS-CoV-2 replication in vitro. Addition of the culture supernatant of
pDCs stimulated with LC-Plasma resulted in suppression of SARS-CoV-2 replication in Vero and Calu3 cells. We confirmed interferon-α (IFN-α) secretionin the supernatant of pDCs stimulated with LC-Plasma and induction of IFN-stimulated genes in cells
treated with the pDC supernatant. Anti-IFN-α antibody impaired the suppression of SARS-CoV-2 replication by the supernatant of LC-Plasma-stimulated
pDCs, suggesting that IFN-α plays an important rolein the SARS-CoV-2 suppression. These results indicate the potential of LC-Plasma to induce inhibitory
responses against SARS-CoV-2 replication throughpDC stimulation with IFN-α secretion.
3.  HTLV-1 proliferation after CD8+ cell depletionby monoclonal anti-CD8 antibody administration in latently HTLV-1-infected cynomolgus
macaques.
Midori Nakamura-Hoshi2, Takushi Nomura3,Masako Nishizawa2, Trang Thi Thu Hau2, Hiroyuki
Yamamoto2, Midori Okazaki2, Hiroshi Ishii2, Kenzo
Yonemitsu7, Yuriko Suzaki7, Yasushi Ami7, Tetsuro
Matano: 7Management Department of Biosafety,Laboratory Animal, and Pathogen Bank, National
Institute of Infectious Diseases, Tokyo, JapanHTLV-1 induces chronic asymptomatic latent infection with substantial proviral load but without significant viral replication in vivo. Cumulative studies
have indicated involvement of CD8+ cells including
virus-specific CD8+ T cells in the control of HTLV-1
replication. However, whether HTLV-1 expression
from latently infected cells in vivo occurs in the absence of CD8+ cells remains unclear. In this study, we
examined the impact of CD8+ cell depletion by monoclonal anti-CD8 antibody administration on proviralload in HTLV-1-infected cynomolgus macaques. Fivecynomolgus macaques were infected with HTLV-1 byinoculation with HTLV-1-producing cells. Administration of monoclonal anti-CD8 antibody in the chronic phase resulted in complete depletion of peripheral
CD8+ T cells for approximately two months. All fivemacaques showed an increase in proviral load following CD8+ cell depletion, which peaked just before thereappearance of peripheral CD8+ T cells. Tax-specificCD8+ T cell responses were detected in these recovered CD8+ T cells. Importantly, anti-HTLV-1 antibodies also increased after CD8+ cell depletion, indicating HTLV-1 antigen expression. These results provide
evidence indicating that HTLV-1 can proliferate fromthe latent phase in the absence of CD8+ cells and suggest that CD8+ cells are responsible for the control ofHTLV-1 replication.
4. Breadth and durability of SARS-CoV-2 specific
T cell responses following long-term recovery
from COVID-19.
Dang Thi Thu Thao3, Alitzel Anzurez2, Kaori Nakayama-Hosoya2, Shoji Miki2, Kazuo Yamashita8,
Mark de Souza2, Tetsuro Matano, Ai Kawana-Tachikawa: 8KOTAI Biotechnologies, Inc., JapanT cell immunity is crucial for long-term immunological memory, but the profile of SARS-CoV-2-specific memory T cells in individuals who recoveredfrom COVID-19 (COVID-19-convalescent individuals) is not sufficiently assessed. In this study, thebreadth and magnitude of SARS-CoV-2-specific T cell
responses were determined in COVID-19-convalescent individuals in Japan. Memory T cells against
SARS-CoV-2 were detected in all convalescent individuals, and those with more severe disease exhibiteda broader T cell response relative to cases with mild
symptoms. Comprehensive screening of T cell responses at the peptide level was conducted for spike(S) and nucleocapsid (N) proteins, and regions frequently targeted by T cells were identified. Multiple
regions in S and N proteins were targeted by memory
T cells, with median numbers of target regions of 13and 4, respectively. A maximum of 47 regions wererecognized by memory T cells for an individual.
These data indicate that SARS-CoV-2-convalescentindividuals maintain a substantial breadth of memory T cells for at least several months following infection. Broader SARS-CoV-2-specific CD4+ T cell responses, relative to CD8+ T cell responses, wereobserved for the S but not the N protein, suggestingthat antigen presentation is different between viralproteins. The binding affinity of predicted CD8+ Tcell epitopes to HLA class I molecules in these regions
was preserved for the Delta variant and at 94 to 96%
for SARS-CoV-2 Omicron subvariants, suggestingthat the amino acid changes in these variants do nothave a major impact on antigen presentation to SARSCoV-2-specific CD8+ T cells.

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Publications
1.		Minh, T.T.T., Hikichi, Y., Miki, S., Imanari, Y., Kusagawa, S., Okazaki, M., Thu, T.D.T., Shiino, T.,Matsuoka, S., Yamamoto, H., Ohashi, J., Hall,W.W., Matano, T., Thi, L.A.N., and KawanaTachikawa, A. Impaired protective role of
HLA-B*57:01/58:01 in HIV-1 CRF01_AE infection:a cohort study in Vietnam. Int. J. Infect. Dis. 128:2031, 2023.
2.		Kashima, Y., Mizutani, T., Nakayama-Hosoya, K.,Moriyama, S., Matsumura, T., Yoshimura, Y., Sasaki, H., Horiuchi, H., Miyata, N., Miyazaki, K., Tachikawa, N., Takahashi, Y., Suzuki, T., Sugano, S.,Matano, T., Kawana-Tachikawa, A., and Yutaka
Suzuki, Y. Multimodal single-cell analyses of peripheral blood mononuclear cells of COVID-19 patients in Japan. Sci. Rep. 13:1935, 2023.
3.		Ishii, H., Jounai, K., Tsuji, R., Ohshio, K., Kaneda,
D., Okazaki, M., Harada, S., Fujiwara, D., and Matano, T. Plasmacytoid dendritic cells stimulatedwith Lactococcus lactis strain Plasma produce soluble factors to suppress SARS-CoV-2 replication.
Biochem. Biophys. Res. Commun. 662:26-30, 2023.
4.		Otani, M., Shiino, T., Hachiya, A., Gatanaga, H.,Watanabe, D., Minami, R., Nishizawa, M., Teshima, T., Yoshida, S., Ito, T., Hayashida, T., Koga, M.,
Nagashima, M., Sadamasu, K., Kondo, M., Kato,S., Uno, S., Taniguchi, T., Igari, H., Samukawa, S.,Nakajima, H., Yoshino, Y., Horiba, M., Moro, H.,
Watanabe, T., Imahashi, M., Yokomaku, Y., Mori,H., Fujii, T., Takada, K., Nakamura, A., Nakamura,H., Tateyama, M., Matsushita, S., Yoshimura, K.,
Sugiura, W., Matano, T., Kikuchi, T., and Japanese
Drug Resistance HIV-1 Surveillance Network. As-sociation of demographics, HCV co-infection,
HIV-1 subtypes and genetic clustering with late
HIV diagnosis: a retrospective analysis from theJapanese Drug Resistance HIV-1 Surveillance Network. J. Int. AIDS Soc., 26:e26086, 2023.
5.		Abana, C.Z., Kushitor, D.K., Asigbee, T.W., Parbie,P.K., Ishikawa, K., Kiyono, H., Mizutani, T., Siaw,
S., Ofori, S.B., Addo-Tetebo, G., Ansong, M.R.D.,
Williams, M., Morton, S., Danquah, G., Matano, T.,
Ampofo, W.K., and Bonney, E.Y. Community
based multi-disease health screening as an opportunity for early detection of HIV cases and linking
them to care. BMC Public Health 23:1051, 2023.
6.		Nakamura-Hoshi, M., Nomura, T., Nishizawa, M.,
Hau, T.T.T., Yamamoto, H., Okazaki, M., Ishii, H.,
Yonemitsu, K., Suzaki, Y., Ami, Y., and Matano, T.
HTLV-1 Proliferation after CD8+ cell depletion bymonoclonal anti-CD8 antibody administration inlatently HTLV-1-infected cynomolgus macaques.
Microbiol Spectr. 11: e0151823, 2023.
7.		Thao, D.T.T., Anzurez, A., Nakayama-Hosoya, K.,
Miki, S., Yamashita, K., de Souza, M., Matano, T.,
and Kawana-Tachikawa, A. Breadth and durability of SARS-CoV-2 specific T cell responses following long-term recovery from COVID-19. Microbiol. Spectr. 11:e0214323, 2023.
8.		Yoshida, T., Kasuya, Y., Yamamoto, H., Kawai, G.,Hanaki, K., Matano, T., and Masuda, T. HIV-1
RNAs whose transcription initiate from the third
deoxyguanosine of GGG-tract in the 5’ long terminal repeat serve as a dominant genome for efficient provirus DNA formation. J. Virol., in press.