| 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, 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 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/Jak3(-/-)
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 (CD27(low)CD28(-)CD45RA(+/-)CCR7(-) and CD27(-)CD28(-)CD45RA(+/-)CCR7(-),
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. |
| Takuya Naruto*, Hiroyuki
Gatanaga*, George Nelson, Keiko Sakai, Mary Carrington,
Shinichi Oka*, and Masafumi Takiguchi* (*Equal contribution),
HLA class I-mediated control of HIV-1 in the Japanese population, in which
the protective HLA-B*57 and HLA-B*27 alleles are absent. J. Virol. 86:10870-10872,
2012 |
| We investigated the effect of HLA class
I alleles on clinical parameters for HIV-1 disease progression in the Japanese
population, where two strongly protective alleles, HLA-B*57 and HLA-B*27,
are virtually nonexistent. HLA-B alleles showed a dominant role, primarily
through HLA-B*67:01 and the HLA-B*52:01-C*12:02 haplotype. Neither a rare-allele
nor a heterozygote advantage was found, suggesting that the effect of HLA
alleles in the Japanese population is either different from those observed
in Africans and Caucasians or undetectable due to limited power. |
| Masao Hashimoto, Tomohiro
Akahoshi, Hayato Murakoshi, Naoki Ishizuka, Shinichi
Oka, and Masafumi Takiguchi, CTL recognition of HIV-1-infected
cells via cross-recognition of multiple overlapping peptides from a single
11-mer Pol sequence. Eur. J. Immunol. 42:2621-2631, 2012 |
| It is known that overlapping HIV-1 peptides
of different lengths can be presented by a given HLA class I molecule. However,
the role of those peptides in CD8(+) T cells recognition of HIV-1-infected
cells remains unclear. Here we investigated the recognition of overlapping
8-mer to 11-mer peptides of Pol 155-165 by HLA-B*54:01-restricted CD8(+)
T cells. The analysis of ex vivo T cells using ELISPOT and tetramer binding
assays showed that there were different patterns of CD8(+) T-cell responses
to these peptides among chronically HIV-1-infected HLA-B*54:01(+) individuals,
though the response to the 9-mer peptide was the strongest among them. CD8(+)
T-cell clones with TCRs specific for the 9-mer, 10-mer, and/or 11-mer peptides
effectively killed HIV-1-infected cells. Together, these results suggest
that the 9-mer and 10-mer peptides could be predominantly presented by HLA-B*54:01,
though it remains possible that the 11-mer peptide was also presented by
this HLA allele. The present study demonstrates effective CD8(+) T-cell
recognition of HIV-1-infected cells via presentation of multiple overlapping
HIV-1 peptides and cross-recognition by the CD8(+) T cells. |
| Hiroshi Takata, Takuya
Naruto, and Masafumi Takiguchi, Functional heterogeneity
of human effector CD8+ T cells. Blood. 119:1390-8, 2012 |
| Effector CD8(+) T cells are believed to be terminally differentiated
cells having cytotoxic activity and the ability to produce effector cytokines
such as INF-γ and TNF-α. We investigated the difference between CXCR1(+)
and CXCR1(-) subsets of human effector CD27(-)CD28(-)CD8(+) T cells. Both
subsets similarly expressed cytolytic molecules and exerted substantial
cytolytic activity, whereas only the CXCR1(-) subset had IL-2 productivity
and self-proliferative activity and was more resistant to cell death than
the CXCR1(+) subset. These differences were explained by the specific up-regulation
of CAMK4, SPRY2, and IL-7R in the CXCR1(-) subset and that of pro-apoptotic
DAPK1 in the CXCR1(+) subset. The IL-2 producers were more frequently found
in the IL-7R(+) subset of the CXCR1(-) effector CD8(+) T cells than in the
IL-7R(-) subset. IL-7/IL-7R signaling promoted cell survival only in the
CXCR1(-) subset. The present study has highlighted a novel subset of effector
CD8(+) T cells producing IL-2 and suggests the importance of this subset
in the homeostasis of effector CD8(+) T cells. |
| Tomohiro Akahoshi, Takayuki
Chikata, Yoshiko Tamura, Hiroyuki Gatanaga, Shinichi
Oka, and Masafumi Takiguchi, Selection and accumulation
of an HIV-1 escape mutant by three types of HIV-1-specific CTLs recognizing
wild-type and/or escape mutant epitopes. J. Virol. 86:1971-1981, 2012 |
| It is known that cytotoxic T lymphocytes (CTLs) recognizing
HIV-1 escape mutants are elicited in HIV-1-infected individuals,but their
role in the control of HIV-1 replication remains unclear. We investigated
the antiviral ability of CTLs recognizing the HLA-A24:02-restricted Gag28
-36 (KYKLKHIVW) epitope and/or its escape mutant (KYRLKHIVW) elicited in
the early and chronic phases of the infection. Wild-type (WT)-epitope-specific
CTLs, as well as cross-reactive CTLs recognizing both WT and K30R (3R) epitopes,
which were predominantly elicited at early and/or chronic phases in HLA-A24:02
individuals infected with the WT virus, suppressed the replication of the
WT virus but failed to suppress that of the 3R virus, indicating that the
3R virus was selected by these 2 types of CTLs. On the other hand, cross-reactive
and 3R-specific CTLs, which were elicited in those infected with the 3R
virus, did not suppress the replication of either WT or 3R virus, indicating
that these CTLs did not contribute to the control of 3R virus replication.
High accumulation of the 3R mutation was found in a Japanese population
recently recruited. The selection and accumulation of this 3R mutation resulted
from the antiviral ability of these Gag28-specific CTLs and high prevalence
of HLA-A24:02 in a Japanese population. The present study highlighted the
mechanisms for the roles of cross-reactive and mutant-epitope-specific CTLs,
as well as high accumulation of escape mutants, in an HIV-1-infected population.
|