Acquired Immunodeficiency Syndrome: Takeda A

Yamamoto T, Iwamoto N, Yamamoto H, Tsukamoto T, Kuwano T, Takeda A, Kawada M, Tsunetsugu-Yokota Y, Matano T. · Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan. · J Virol. · Pubmed #19297503 No free full text.

Abstract: Rapid depletion of memory CD4(+) T cells and delayed induction of neutralizing antibody (NAb) responses are characteristics of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections. Although it was speculated that postinfection NAb induction could have only a limited suppressive effect on primary HIV replication, a recent study has shown that a single passive NAb immunization of rhesus macaques 1 week after SIV challenge can result in reduction of viral loads at the set point, indicating a possible contribution of postinfection NAb responses to virus control. However, the mechanism accounting for this NAb-triggered SIV control has remained unclear. Here, we report rapid induction of virus-specific polyfunctional T-cell responses after the passive NAb immunization postinfection. Analysis of SIV Gag-specific responses of gamma interferon, tumor necrosis factor alpha, interleukin-2, macrophage inflammatory protein 1beta, and CD107a revealed that the polyfunctionality of Gag-specific CD4(+) T cells, as defined by the multiplicity of these responses, was markedly elevated in the acute phase in NAb-immunized animals. In the chronic phase, despite the absence of detectable NAbs, virus control was maintained, accompanied by polyfunctional Gag-specific T-cell responses. These results implicate virus-specific polyfunctional CD4(+) T-cell responses in this NAb-triggered virus control, suggesting possible synergism between NAbs and T cells for control of HIV/SIV replication.

Kawada M, Tsukamoto T, Yamamoto H, Iwamoto N, Kurihara K, Takeda A, Moriya C, Takeuchi H, Akari H, Matano T. · International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. · J Virol. · Pubmed #18667518 links to  free full text

Abstract: Gag-specific cytotoxic T lymphocytes (CTLs) exert strong suppressive pressure on human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. However, it has remained unclear whether they can actually contain primary viral replication. Recent trials of prophylactic vaccines inducing virus-specific T-cell responses have indicated their potential to confer resistance against primary SIV replication in rhesus macaques, while the immunological determinant for this vaccine-based viral control has not been elucidated thus far. Here we present evidence implicating Gag-specific CTLs as responsible for the vaccine-based primary SIV control. Prophylactic vaccination using a Gag-expressing Sendai virus vector resulted in containment of SIVmac239 challenge in all rhesus macaques possessing the major histocompatibility complex (MHC) haplotype 90-120-Ia. In contrast, 90-120-Ia-positive vaccinees failed to contain SIVs carrying multiple gag CTL escape mutations that had been selected, at the cost of viral fitness, in SIVmac239-infected 90-120-Ia-positive macaques. These results show that Gag-specific CTL responses do play a crucial role in the control of wild-type SIVmac239 replication in vaccinees. This study implies the possibility of Gag-specific CTL-based primary HIV containment by prophylactic vaccination, although it also suggests that CTL-based AIDS vaccine efficacy may be abrogated in viral transmission between MHC-matched individuals.

Seki S, Kawada M, Takeda A, Igarashi H, Sata T, Matano T. · International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. · J Virol. · Pubmed #18337572 links to  free full text

Abstract: Cytotoxic T-lymphocyte (CTL) responses frequently select for immunodeficiency virus mutations that result in escape from CTL recognition with viral fitness costs. The replication in vivo of such viruses carrying not single but multiple escape mutations in the absence of the CTL pressure has remained undetermined. Here, we have examined the replication of simian immunodeficiency virus (SIV) with five gag mutations selected in a macaque possessing the major histocompatibility complex haplotype 90-120-Ia after its transmission into 90-120-Ia-negative macaques. Our results showed that even such a "crippled" SIV infection can result in persistent viral replication, multiple reversions, and AIDS progression.

Moriya C, Igarashi H, Takeda A, Tsukamoto T, Kawada M, Yamamoto H, Inoue M, Iida A, Shu T, Hasegawa M, Nagai Y, Matano T. · International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. · Microbes Infect. · Pubmed #18316225 No free full text.

Abstract: A current promising AIDS vaccine strategy is to elicit CD8(+) cytotoxic T lymphocyte (CTL) responses that broadly recognize highly-diversified HIVs. In our previous vaccine trial eliciting simian immunodeficiency virus (SIV) mac239 Gag-specific CTL responses, a group of Burmese rhesus macaques possessing a major histocompatibility complex haplotype 90-120-Ia have shown vaccine-based viral control against a homologous SIVmac239 challenge. Vaccine-induced Gag(206-216) epitope-specific CTL responses exerted strong selective pressure on the virus in this control. Here, we have evaluated in vivo efficacy of vaccine-induced Gag(206-216)-specific CTL responses in two 90-120-Ia-positive macaques against challenge with a heterologous SIVsmE543-3 that has the same Gag(206-216) epitope sequence with SIVmac239. Despite efficient Gag(206-216)-specific CTL induction by vaccination, both vaccinees failed to control SIVsmE543-3 replication and neither of them showed mutations within the Gag(206-216) epitope. Further analysis indicated that Gag(206-216)-specific CTLs failed to show responses against SIVsmE543-3 infection due to a change from aspartate to glutamate at Gag residue 205 immediately preceding the amino terminus of Gag(206-216) epitope. Our results suggest that even vaccine-induced CTL efficacy can be abrogated by a single amino acid change in viral epitope flanking region, underlining the influence of viral epitope flanking sequences on CTL-based AIDS vaccine efficacy.

Tsukamoto T, Yuasa M, Yamamoto H, Kawada M, Takeda A, Igarashi H, Matano T. · International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. · J Virol. · Pubmed #17728225 links to  free full text

Abstract: Recent recombinant viral vector-based AIDS vaccine trials inducing cellular immune responses have shown control of CXCR4-tropic simian-human immunodeficiency virus (SHIV) replication but difficulty in containment of pathogenic CCR5-tropic simian immunodeficiency virus (SIV) in rhesus macaques. In contrast, controlled infection of live attenuated SIV/SHIV can confer the ability to contain SIV superchallenge in macaques. The specific immune responses responsible for this control may be induced by live virus infection but not consistently by viral vector vaccination, although those responses have not been determined. Here, we have examined in vitro anti-SIV efficacy of CD8+ cells in rhesus macaques that showed prophylactic viral vector vaccine-based control of CXCR4-tropic SHIV89.6PD replication. Analysis of the effect of CD8+ cells obtained at several time points from these macaques on CCR5-tropic SIVmac239 replication in vitro revealed that CD8+ cells in the chronic phase after SHIV challenge suppressed SIV replication more efficiently than those before challenge. SIVmac239 superchallenge of two of these macaques at 3 or 4 years post-SHIV challenge was contained, and the following anti-CD8 antibody administration resulted in transient CD8+ T-cell depletion and appearance of plasma SIVmac239 viremia in both of them. Our results indicate that CD8+ cells acquired the ability to efficiently suppress SIV replication by controlled SHIV infection, suggesting the contribution of CD8+ cell responses induced by controlled live virus infection to containment of HIV/SIV superinfection.

Kawada M, Tsukamoto T, Yamamoto H, Takeda A, Igarashi H, Watkins DI, Matano T. · International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. · J Virol. · Pubmed #17344296 links to  free full text

Abstract: Induction of virus-specific CD8(+) cytotoxic T-lymphocyte (CTL) responses is a promising strategy for AIDS vaccine development. However, it has remained unclear if or how long-term viral containment and disease control are attainable by CTL-based nonsterile protection. Here, we present three rhesus macaques that successfully maintained Env-independent vaccine-based control of simian immunodeficiency virus (SIV) mac239 replication without disease progression for more than 3 years. SIV-specific neutralizing antibody induction was inefficient in these controllers. Vaccine-induced Gag-specific CTLs were crucial for the chronic as well as the primary viral control in one of them, whereas those Gag-specific CTL responses became undetectable and CTLs specific for SIV antigens other than Gag, instead, became predominant in the chronic phase in the other two controllers. A transient CD8(+) cell depletion experiment 3 years postinfection resulted in transient reappearance of plasma viremia in these two animals, suggesting involvement of the SIV non-Gag-specific CTLs in the chronic SIV control. This sustained, neutralizing antibody-independent viral control was accompanied with preservation of central memory CD4(+) T cells in the chronic phase. Our results suggest that prophylactic CTL vaccine-based nonsterile protection can result in long-term viral containment by adapted CTL responses for AIDS prevention.

Yamamoto H, Kawada M, Tsukamoto T, Takeda A, Igarashi H, Miyazawa M, Naruse T, Yasunami M, Kimura A, Matano T. · International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Tokyo 108-8639, Japan. · J Gen Virol. · Pubmed #17251584 links to  free full text

Abstract: The X4-tropic simian/human immunodeficiency virus (SHIV) 89.6P (or 89.6PD) causes rapid CD4(+) T-cell depletion leading to an acute crash of the host immune system, whereas pathogenic R5-tropic simian immunodeficiency virus (SIV) infection, like HIV-1 infection in humans, results in chronic disease progression in macaques. Recent pre-clinical vaccine trials inducing cytotoxic T lymphocyte (CTL) responses have succeeded in controlling replication of the former but shown difficulty in control of the latter. Analysis of the immune responses involved in consistent control of SHIV would contribute to elucidation of the mechanism for consistent control of SIV replication. This study followed up rhesus macaques that showed vaccine-based control of primary SHIV89.6PD replication and found that all of these controllers maintained viraemia control for more than 2 years. SHIV89.6PD control was observed in vaccinees of diverse major histocompatibility complex (MHC) haplotypes and was maintained without rapid selection of CTL escape mutations, a sign of particular CTL pressure. Despite the vaccine regimen not targeting Env, all of the SHIV controllers showed efficient elicitation of de novo neutralizing antibodies by 6 weeks post-challenge. These results contrast with our previous observation of particular MHC-associated control of SIV replication without involvement of neutralizing antibodies and suggest that vaccine-based control of SHIV89.6PD replication can be stably maintained in the presence of multiple functional immune effectors.

Kawada M, Igarashi H, Takeda A, Tsukamoto T, Yamamoto H, Dohki S, Takiguchi M, Matano T. · Department of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. · J Virol. · Pubmed #16439550 links to  free full text

Abstract: Cytotoxic T-lymphocyte (CTL) responses are crucial for the control of immunodeficiency virus replication. Possible involvement of a dominant single epitope-specific CTL in control of viral replication has recently been indicated in preclinical AIDS vaccine trials, but it has remained unclear if multiple epitope-specific CTLs can be involved in the vaccine-based control. Here, by following up five rhesus macaques that showed vaccine-based control of primary replication of a simian immunodeficiency virus, SIVmac239, we present evidence indicating involvement of multiple epitope-specific CTL responses in this control. Three macaques maintained control for more than 2 years without additional mutations in the provirus. However, in the other two that shared a major histocompatibility complex haplotype, viral mutations were accumulated in a similar order, leading to viral evasion from three epitope-specific CTL responses with viral fitness costs. Accumulation of these multiple escape mutations resulted in the reappearance of plasma viremia around week 60 after challenge. Our results implicate multiple epitope-specific CTL responses in control of immunodeficiency virus replication and furthermore suggest that sequential accumulation of multiple CTL escape mutations, if allowed, can result in viral evasion from this control.

Kobayashi M, Igarashi H, Takeda A, Kato M, Matano T. · Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Japan. · J Virol. · Pubmed #16103206 links to  free full text

Abstract: Vaccine-based control of the replication of a simian immunodeficiency virus (SIV), SIVmac239, in macaques has recently been shown. In the process of the control, a mutant virus escaping from epitope-specific cytotoxic-T-lymphocyte (CTL) responses was rapidly selected and contained. In this study, we show that the wild-type virus appeared and became predominant in the absence of the epitope-specific CTL after inoculation of naive macaques with a molecular clone DNA of the CTL escape mutant SIV. This is the first report describing reversion in vivo from an inoculated, molecular proviral DNA clone of immunodeficiency virus with a CTL escape mutation.

Kato M, Igarashi H, Takeda A, Sasaki Y, Nakamura H, Kano M, Sata T, Iida A, Hasegawa M, Horie S, Higashihara E, Nagai Y, Matano T. · Department of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. · Vaccine. · Pubmed #15837216 No free full text.

Abstract: Recent prophylactic vaccine trials inducing virus-specific CD8+ T-cell responses have shown control of primary infections of a pathogenic simian-human immunodeficiency virus (SHIV) in macaques. In the chronic phase, therapeutic immunization replenishing virus-specific CD8+ T-cells is likely to contribute to sustained control of virus replication. In this study, we have administered a recombinant Sendai virus (SeV) vector into five rhesus macaques that had received prophylactic vaccinations and had controlled SHIV replication for more than 1 year after challenge. Our results indicate that virus-specific CD8+ T-cell responses can be expanded and broadened by therapeutic immunization with SeV vectors in the chronic phase after prophylactic vaccine-based control of primary immunodeficiency virus infections.

Kato M, Igarashi H, Takeda A, Horie S, Higashihara E, Matano T. · Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. · Jpn J Infect Dis. · Pubmed #15507782 links to  free full text

Abstract: Virus-specific CD8+ cytotoxic T lymphocyte (CTL) responses play an important role in the control of immunodeficiency virus infections. Therapeutic immunization with antigen-pulsed dendritic cells (DC) may be a promising strategy for stimulating CTL. However, decreases in DC number and function have been suggested in the host persistently infected with the virus, and this may constitute an obstacle to DC-based immunotherapy in the chronic phase. In this study, we show that virus-specific CTL responses were augmented by therapeutic immunization with inactivated virus-pulsed autologous DC in rhesus macaques that had maintained prophylactic vaccine-based control of virus replication for more than 3 years after simian or simian-human immunodeficiency virus challenge. Our results indicate the potential of DC in the chronic phase for efficiently stimulating CTL in vivo, suggesting the feasibility of therapeutic DC immunization for replenishing virus-specific CTL responses in the chronic phase after the prophylactic vaccine-based control of primary immunodeficiency virus infection.

Lun WH, Takeda A, Nakamura H, Kano M, Mori K, Sata T, Nagai Y, Matano T. · AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. · J Gen Virol. · Pubmed #15218180 links to  free full text

Abstract: Virus-specific cellular immune responses play an important role in the control of immunodeficiency virus replication. However, preclinical trials of vaccines that induce virus-specific cellular immune responses have failed to contain simian immunodeficiency virus (SIV) replication in macaques. A defective provirus DNA vaccine system that efficiently induces virus-specific CD8(+) T-cell responses has previously been developed. The vaccinated macaques showed reduced viral loads, but failed to contain SIVmac239 replication. In this study, macaques that showed partial control of SIV replication were followed up to see if or how they lost this control in the chronic phase. Two of them showed increased viral loads about 4 or 8 months after challenge and finally developed AIDS. Analysis of SIV-specific T-cell levels by detection of SIV-specific gamma interferon (IFN-gamma) production revealed that these two macaques maintained SIV-specific CD8(+) T cells, even after loss of control, but lost SIV-specific CD4(+) T cells when plasma viral loads increased. The remaining macaque kept viral loads at low levels and maintained SIV-specific CD4(+) T cells, as well as CD8(+) T cells, for more than 3 years. Additional analysis using macaques vaccinated with a Gag-expressing Sendai virus vector also found loss of viraemia control, with loss of SIV-specific CD4(+) T cells in the chronic phase of SIV infection. Thus, SIV-specific CD4(+) T cells that were able to produce IFN-gamma in response to SIV antigens were preserved by the vaccine-based partial control of primary SIV replication, but were lost with abrogation of control in the chronic phase.

Matano T, Kobayashi M, Igarashi H, Takeda A, Nakamura H, Kano M, Sugimoto C, Mori K, Iida A, Hirata T, Hasegawa M, Yuasa T, Miyazawa M, Takahashi Y, Yasunami M, Kimura A, O'Connor DH, Watkins DI, Nagai Y. · Department of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. · J Exp Med. · Pubmed #15210746 links to  free full text

Abstract: Recently, encouraging AIDS vaccine trials in macaques have implicated cytotoxic T lymphocytes (CTLs) in the control of the simian human immunodeficiency virus SHIV89.6P that induces acute CD4(+) T cell depletion. However, none of these vaccine regimens have been successful in the containment of replication of the pathogenic simian immunodeficiency viruses (SIVs) that induce chronic disease progression. Indeed, it has remained unclear if vaccine-induced CTL can control SIV replication. Here, we show evidence suggesting that vaccine-induced CTLs control SIVmac239 replication in rhesus macaques. Eight macaques vaccinated with DNA-prime/Gag-expressing Sendai virus vector boost were challenged intravenously with SIVmac239. Five of the vaccinees controlled viral replication and had undetectable plasma viremia after 5 wk of infection. CTLs from all of these five macaques rapidly selected for escape mutations in Gag, indicating that vaccine-induced CTLs successfully contained replication of the challenge virus. Interestingly, analysis of the escape variant selected in three vaccinees that share a major histocompatibility complex class I haplotype revealed that the escape variant virus was at a replicative disadvantage compared with SIVmac239. These findings suggested that the vaccine-induced CTLs had "crippled" the challenge virus. Our results indicate that vaccine induction of highly effective CTLs can result in the containment of replication of a highly pathogenic immunodeficiency virus.

Takeda A, Igarashi H, Nakamura H, Kano M, Iida A, Hirata T, Hasegawa M, Nagai Y, Matano T. · Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. · J Virol. · Pubmed #12915583 links to  free full text

Abstract: We previously demonstrated the excellent protective efficacy of DNA priming followed by Gag-expressing Sendai virus (SeV) boosting (DNA prime/SeV-Gag boost vaccine) against a pathogenic simian-human immunodeficiency virus (SHIV89.6PD) infection in macaques. Here we show that we established a practical, safer AIDS vaccine protocol, a single DNA priming followed by a single booster with a recently developed replication-defective F deletion SeV-expressing Gag, and show its protective efficacy against SHIV89.6PD infections.

Matano T, Kano M, Takeda A, Nakamura H, Nomura N, Furuta Y, Shioda T, Nagai Y. · Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Japan. · AIDS. · Pubmed #12799562 No free full text.

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Takeda A, Nakamura H, Matano T. · AIDS Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan. · Jpn J Infect Dis. · Pubmed #11135708 links to  free full text

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Kano M, Matano T, Nakamura H, Takeda A, Kato A, Ariyoshi K, Mori K, Sata T, Nagai Y. · No affiliation provided · AIDS. · Pubmed #10894297 No free full text.

This publication has no abstract.