Laboratories and Institutions   Center for AIDS Research, Kumamoto University
Program Description > International Collaborative Research Grant for Young Investigators > Publications of awardees

Masao Hashimoto
(Takiguchi Project Lab, Center for AIDS Research, Kumamoto University)
FY2010-2011 awardee
【FY2008-2009 awardee of International Collaborative Research Development Grant for Young Investigators 】
International collaborator Victor Appay  (INSERM, France)

Kristin Ladell*, Masao Hashimoto*, Maria Candela Iglesias*, Pascal G. Wilmann*, James E. McLaren, Stephanie Gras, Takayuki Chikata, Nozomi Kuse, Solene Fastenackels, Emma Gostick, John S. Bridgeman, Vanessa Venturi, Zaina Ait Arkoub, Henri Agut, David J. van Bockel, Jorge R. Almeida, Daniel C. Douek, Laurence Meyer, Alain Venet, Masafumi Takiguchi**, Jamie Rossjohn1**, David A. Price** and Victor Appay** (*,** Equal contribution), A molecular basis for the control of pre-immune escape variants by HIV-specific CD8+ T-cells. Immunity. 38:425-436, 2013

The capacity of the immune system to adapt to rapidly evolving viruses is a primary feature of effective immunity, yet its molecular basis is unclear. Here, we investigated protective HIV-1-specific CD8+ T cell responses directed against the immunodominant p24 Gag-derived epitope KK10 (KRWIILGLNK263-272) presented by human leukocyte antigen (HLA)-B∗2705. We found that cross-reactive CD8+ T cell clonotypes were mobilized to counter the rapid emergence of HIV-1 variants that can directly affect T cell receptor (TCR) recognition. These newly recruited clonotypes expressed TCRs that engaged wild-type and mutant KK10 antigens with similar affinities and almost identical docking modes, thereby accounting for their antiviral efficacy in HLA-B∗2705+ individuals. A protective CD8+ T cell repertoire therefore encompasses the capacity to control TCR-accessible mutations, ultimately driving the development of more complex viral escape variants that disrupt antigen presentation.




Madoka Koyanagi
(Takiguchi Project Lab, Center for AIDS Research, Kumamoto University)
FY2010-2012 awardee
【FY2009 awardee of International Collaborative Research Development Grant for Young Investigators 】
International collaborator Philip Goulder  (University of Oxford, UK)

Philippa C. Matthews*, Madoka Koyanagi*, Henrik N. Kloverpris*, Mikkel Harndahl, Anette Stryhn, Tomohiro Akahoshi, Hiroyuki Gatanaga, Shinichi Oka, Claudia Juarez Molina, Humberto Valenzuela Ponce, Santiago Avila Rios, David Cole, Jonathan Carlson, Rebecca P. Payne, Anthony Ogwu, Alfred Bere, Thumbi Ndung’u, Kamini Gounder, Fabian Chen, Lynn Riddell, Graz Luzzi, Roger Shapiro, Christian Brander, Bruce Walker, Andrew K Sewell, Gustavo Reyes Teran, David Heckerman, Eric Hunter, Soren Buus, Masafumi Takiguchi, and Philip J. R. Goulder (*Equal contribution), Differential clade-specific HLA-B*3501 association with HIV-1 disease outcome is linked to immunogenicity of a single Gag epitope. J. Virol. 86:12643-12654, 2012

The strongest genetic influence on immune control in HIV-1 infection is the HLA class I genotype. Rapid disease progression in B-clade infection has been linked to HLA-B*35 expression, in particular to the less common HLA-B*3502 and HLA-B*3503 subtypes but also to the most prevalent subtype, HLA-B*3501. In these studies we first demonstrated that whereas HLA-B*3501 is associated with a high viral set point in two further B-clade-infected cohorts, in Japan and Mexico, this association does not hold in two large C-clade-infected African cohorts. We tested the hypothesis that clade-specific differences in HLA associations with disease outcomes may be related to distinct targeting of critical CD8(+) T-cell epitopes. We observed that only one epitope was significantly targeted differentially, namely, the Gag-specific epitope NPPIPVGDIY (NY10, Gag positions 253 to 262) (P = 2 × 10(-5)). In common with two other HLA-B*3501-restricted epitopes, in Gag and Nef, that were not targeted differentially, a response toward NY10 was associated with a significantly lower viral set point. Nonimmunogenicity of NY10 in B-clade-infected subjects derives from the Gag-D260E polymorphism present in ∼90% of B-clade sequences, which critically reduces recognition of the Gag NY10 epitope. These data suggest that in spite of any inherent HLA-linked T-cell receptor repertoire differences that may exist, maximizing the breadth of the Gag-specific CD8(+) T-cell response, by the addition of even a single epitope, may be of overriding importance in achieving immune control of HIV infection. This distinction is of direct relevance to development of vaccines designed to optimize the anti-HIV CD8(+) T-cell response in all individuals, irrespective of HLA type.



Yoshinori Sato
(Takiguchi Project Lab, Center for AIDS Research, Kumamoto University)
FY2011-2012 awardee
【FY2010 awardee of International Collaborative Research Development Grant for Young Investigators 】

International collaborator

Tomas Hanke  (University of Oxford, UK)


Yoshinori Sato, Sayaka Nagata, and Masafumi Takiguchi, Effective elicitation of human effector CD8+ T cells in HLA-B*51:01 transgenic humanized mice after infection with HIV-1. PLoS ONE. PLoS ONE 7: e42776, 2012

Humanized mice are expected to be useful as small animal models for in vivo studies on the pathogenesis of infectious diseases. However, it is well known that human CD8+ T cells cannot differentiate into effector cells in immunodeficient mice transplanted with only human CD34+ hematopoietic stem cells (HSCs), because human T cells are not educated by HLA in the mouse thymus. We here established HLA-B*51:01 transgenic humanized mice by transplanting human CD34+ HSCs into HLA-B*51:01 transgenic NOD/SCID/Jak32/2 mice (hNOK/B51Tg mice) and investigated whether human effector CD8+ T cells would be elicited in the mice or in those infected with HIV-1 NL4-3. There were no differences in the frequency of late effector memory and effector subsets (CD27lowCD282CD45RA+/2CCR72 and CD272CD282CD45RA+/2CCR72, respectively)
among human CD8+ T cells and in that of human CD8+ T cells expressing CX3CR1 and/or CXCR1 between hNOK/B51Tg and hNOK mice. In contrast, the frequency of late effector memory and effector CD8+ T cell subsets and of those expressing
CX3CR1 and/or CXCR1 was significantly higher in HIV-1-infected hNOK/B51Tg mice than in uninfected ones, whereas there was no difference in that of these subsets between HIV-1-infected and uninfected hNOK mice. These results suggest that
hNOK/B51Tg mice had CD8+ T cells that were capable of differentiating into effector T cells after viral antigen stimulation and had a greater ability to elicit effector CD8+ T cells than hNOK ones.




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