ORCID Profile
0000-0002-5810-8773
Current Organisation
Niigata University of Health and Welfare
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Publisher: American Society for Microbiology
Date: 15-10-2008
DOI: 10.1128/JVI.01103-08
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 in iduals.
Publisher: Cold Spring Harbor Laboratory
Date: 19-09-2017
DOI: 10.1101/190702
Abstract: Hematological abnormalities that include changes in bone marrow, such as in anemia and pancytopenia, are common among human immunodeficiency virus (HIV)-infected patients, particularly in the advanced stage of disease. This study aimed to provide better experimental evidence of such manifestations in animal models. NOD/SCID/JAK3 null (NOJ) mice were transplanted with human cord-derived CD34 + cells with or without transduction with a lentiviral vector expressing a promoter-targeting shRNA called PromA. At 16 weeks after transplantation, mice engrafted with CD34 + cells were infected with CCR5-tropic HIV-1 JRFL . At week 2 post infection, HIV replication was observed in peripheral blood mononuclear cells and splenocytes. In mice transplanted with unmanipulated CD34 + cells, viral replication was accompanied by a loss of peripheral/spleen CD4 + CCR5 + T cells. Interestingly, bone marrow CD34 + cells in HIV-infected mice were also depleted, but in a CXCR4-associated manner. Conversely, the lentiviral transfer of PromA in CD34 + cells prior to transplantation rendered the humanized NOJ mice resistant to HIV replication in CD4 + T cells, resulting in better preservation of peripheral/spleen CD4 + CCR5 + T cells and bone marrow CD34 + cells at two weeks after infection. These results implicate the importance of evaluating hematopoietic stem rogenitor cell pools in addition to peripheral CD4 + T-cell counts to assess the early stage of HIV infection. Moreover, stable gene transfer of PromA to hematopoietic stem cells not only limited HIV replication but also led to preservation of different subsets of hematopoietic cells, including bone marrow stem rogenitor cells.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-11-2010
Publisher: MDPI AG
Date: 08-02-2019
DOI: 10.20944/PREPRINTS201902.0079.V1
Abstract: Although current antiretroviral drug therapy can suppress human immunodeficiency virus (HIV) replication, a lifelong prescription is necessary to avoid viral rebound. The problem of persistent and ineradicable viral reservoirs in HIV-infected people continues to be a global threat. In addition, some HIV-infected patients do not experience sufficient T-cell immune restoration despite being aviremic during treatment, and this is likely due to altered hematopoietic potential. To achieve global eradication of HIV disease, a cure is needed. To this end, tremendous efforts have been made in the field of anti-HIV gene therapy. This review will discuss the concepts of HIV cure and relative viral attenuation and provide an overview of various gene therapy approaches aimed at a complete or functional HIV cure and protection of hematopoietic functions.
Publisher: American Society for Microbiology
Date: 27-02-2019
Abstract: Cytotoxic-T-lymphocyte (CTL) responses are important to control the replication of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). Accumulating evidence suggests that the ability of a few immunodominant T-cell populations to detect and kill HIV/SIV-infected cells is important in in iduals with a protective major histocompatibility complex class I (MHC-I) allele.
Publisher: American Society for Microbiology
Date: 15-02-2006
DOI: 10.1128/JVI.80.4.1949-1958.2006
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.
Publisher: Microbiology Society
Date: 02-2007
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 erse 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.
Publisher: MDPI AG
Date: 17-04-2022
DOI: 10.3390/V14040832
Abstract: Tissue and subcellular localization and its changes upon cell activation of virus-restricting APOBEC3 at protein levels are important to understanding physiological functions of this cytidine deaminase, but have not been thoroughly analyzed in vivo. To precisely follow the possible activation-induced changes in expression levels of APOBEC3 protein in different mouse tissues and cell populations, genome editing was utilized to establish knock-in mice that express APOBEC3 protein with an in-frame FLAG tag. Flow cytometry and immunohistochemical analyses were performed prior to and after an immunological stimulation. Cultured B cells expressed higher levels of APOBEC3 protein than T cells. All differentiation and activation stages of freshly prepared B cells expressed significant levels of APOBEC3 protein, but germinal center cells possessed the highest levels of APOBEC3 protein localized in their cytoplasm. Upon immunological stimulation with sheep red blood cells in vivo, germinal center cells with high levels of APOBEC3 protein expression increased in their number, but FLAG-specific fluorescence intensity in each cell did not change. T cells, even those in germinal centers, did not express significant levels of APOBEC3 protein. Thus, mouse APOBEC3 protein is expressed at distinctively high levels in germinal center B cells. Antigenic stimulation did not affect expression levels of cellular APOBEC3 protein despite increased numbers of germinal center cells.
Publisher: Frontiers Media SA
Date: 21-02-2020
Publisher: Cold Spring Harbor Laboratory
Date: 25-05-2017
DOI: 10.1101/142075
Abstract: Human immunodeficiency virus (HIV) causes damage, directly or indirectly, to the whole hematopoietic system including CD34 + hematopoietic stem rogenitor cells (HSPC). CXCR4-tropic strains of HIV-1 may be potent to affect the function of CD34 + CXCR4 + progenitor cells either by infecting the cells or by modifying the dynamics of more differentiated hematopoietic cells. However, CD34 + cells are known for the resistance to HIV-1 infection in vitro, restricting the detailed analysis of the impact of HIV upon HSPC. Here the authors report a use of RetroNectin, a recombinant fibronectin fragment used for gene transfer with lentiviral vectors, to overcome the limitation.
Publisher: Wiley
Date: 02-07-2010
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.VACCINE.2008.09.074
Abstract: Viral vectors are promising vaccine tools for eliciting antigen-specific T-cell responses. We previously showed the potential of recombinant Sendai virus (SeV) vectors to induce virus-specific T-cell responses in macaque AIDS models. Here, we have evaluated the immunogenicity of replication-competent V-knocked-out and replication-defective F-deleted SeV vectors in macaques. Intranasal replication-competent and replication-defective SeV immunizations both elicited robust systemic antigen-specific T-cell responses, whereas the responses induced by the former were more durable than those by the latter. However, even the latter-induced T-cell responses remained detectable in a local, retropharyngeal lymph node two months after the immunization. These findings are useful for establishment of a vaccine protocol using SeV vectors.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-05-2008
Publisher: Springer Science and Business Media LLC
Date: 10-2009
Publisher: American Society for Microbiology
Date: 15-09-2009
DOI: 10.1128/JVI.01120-09
Abstract: Despite many efforts to develop AIDS vaccines eliciting virus-specific T-cell responses, whether induction of these memory T cells by vaccination before human immunodeficiency virus (HIV) exposure can actually contribute to effective T-cell responses postinfection remains unclear. In particular, induction of HIV-specific memory CD4 + T cells may increase the target cell pool for HIV infection because the virus preferentially infects HIV-specific CD4 + T cells. However, virus-specific CD4 + helper T-cell responses are thought to be important for functional CD8 + cytotoxic-T-lymphocyte (CTL) induction in HIV infection, and it has remained unknown whether HIV-specific memory CD8 + T cells induced by vaccination without HIV-specific CD4 + T-cell help can exert effective responses after virus exposure. Here we show the impact of CD8 + T-cell memory induction without virus-specific CD4 + T-cell help on the control of a simian immunodeficiency virus (SIV) challenge in rhesus macaques. We developed a prophylactic vaccine by using a Sendai virus (SeV) vector expressing a single SIV Gag 241-249 CTL epitope fused with enhanced green fluorescent protein (EGFP). Vaccination resulted in induction of SeV-EGFP-specific CD4 + T-cell and Gag 241-249 -specific CD8 + T-cell responses. After a SIV challenge, the vaccinees showed dominant Gag 241-249 -specific CD8 + T-cell responses with higher effector memory frequencies in the acute phase and exhibited significantly reduced viral loads. These results demonstrate that virus-specific memory CD8 + T cells induced by vaccination without virus-specific CD4 + T-cell help could indeed facilitate SIV control after virus exposure, indicating the benefit of prophylactic vaccination eliciting virus-specific CTL memory with non-virus-specific CD4 + T-cell responses for HIV control.
Publisher: Wiley
Date: 06-01-2020
DOI: 10.1111/JMP.12460
Abstract: We characterized Japanese macaque (Macaca fuscata) hematopoietic cells using flow cytometry and identified 28 cross-reactive anti-human antibody clones. Furthermore, productive infection of peripheral T lymphocytes with simian immunodeficiency virus (SIV) in vitro was confirmed by intracellular SIV p27 staining. This study could facilitate using Japanese macaques as models for human hematological and immunological disorders and infectious diseases.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.BBRC.2011.04.071
Abstract: Cytotoxic T lymphocyte (CTL) responses are crucial for the control of human and simian immunodeficiency virus (HIV and SIV) replication. A promising AIDS vaccine strategy is to induce CTL memory resulting in more effective CTL responses post-viral exposure compared to those in natural HIV infections. We previously developed a CTL-inducing vaccine and showed SIV control in some vaccinated rhesus macaques. These vaccine-based SIV controllers elicited vaccine antigen-specific CTL responses dominantly in the acute phase post-challenge. Here, we examined CTL responses post-challenge in those vaccinated animals that failed to control SIV replication. Unvaccinated rhesus macaques possessing the major histocompatibility complex class I haplotype 90-088-Ij dominantly elicited SIV non-Gag antigen-specific CTL responses after SIV challenge, while those induced with Gag-specific CTL memory by prophylactic vaccination failed to control SIV replication with dominant Gag-specific CTL responses in the acute phase, indicating dominant induction of vaccine antigen-specific CTL responses post-challenge even in non-controllers. Further analysis suggested that prophylactic vaccination results in dominant induction of vaccine antigen-specific CTL responses post-viral exposure but delays SIV non-vaccine antigen-specific CTL responses. These results imply a significant influence of prophylactic vaccination on CTL immunodominance post-viral exposure, providing insights into antigen design in development of a CTL-inducing AIDS vaccine.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-11-2019
Publisher: Cold Spring Harbor Laboratory
Date: 26-05-2019
DOI: 10.1101/142539
Abstract: HIV-1 causes the loss of CD4 + T cells via depletion or impairment of their production. The latter involves infection of thymocytes, but the involvement of other cells including haematopoietic CD34 + cells remains unclear even though HIV-positive patients frequently manifest myelosuppression. This study utilised the OP9-DL1 coculture system, which supports in vitro T-lineage differentiation of human haematopoietic stem rogenitor cells. Cord-derived CD34 + cells were infected with CXCR4-tropic HIV-1 NL4-3 and cocultured. HIV-infected cocultures exhibited sustained viral replication for 5 weeks, as well as reduced CD4 + T-cell growth at weeks 3–5. It was further revealed that CD34 + CD7 + CXCR4 + cells can be quickly depleted as early as in 1 week after infection of the subset, and this was accompanied by the emergence of CD34 + CD7 + CD4 + cells. These results indicate that CXCR4-tropic HIV-1 strains may disrupt CD34 + CD7 + lymphoid progenitor cell pools, presumably leading to impaired T-cell production potential.
Publisher: American Society for Microbiology
Date: 11-2007
DOI: 10.1128/JVI.01475-07
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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2022
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.JVIROMET.2017.08.003
Abstract: Human immunodeficiency virus (HIV) causes damage, directly or indirectly, to the whole hematopoietic system, including CD34
Publisher: MDPI AG
Date: 11-03-2019
DOI: 10.3390/PHARMACEUTICS11030114
Abstract: Although current antiretroviral drug therapy can suppress the replication of human immunodeficiency virus (HIV), a lifelong prescription is necessary to avoid viral rebound. The problem of persistent and ineradicable viral reservoirs in HIV-infected people continues to be a global threat. In addition, some HIV-infected patients do not experience sufficient T-cell immune restoration despite being aviremic during treatment. This is likely due to altered hematopoietic potential. To achieve the global eradication of HIV disease, a cure is needed. To this end, tremendous efforts have been made in the field of anti-HIV gene therapy. This review will discuss the concepts of HIV cure and relative viral attenuation and provide an overview of various gene therapy approaches aimed at a complete or functional HIV cure and protection of hematopoietic functions.
Publisher: Frontiers Media SA
Date: 29-01-2017
Publisher: American Society for Microbiology
Date: 15-06-2012
DOI: 10.1128/JVI.07077-11
Abstract: Nonhuman primate AIDS models are essential for the analysis of AIDS pathogenesis and the evaluation of vaccine efficacy. Multiple studies on human immunodeficiency virus and simian immunodeficiency virus (SIV) infection have indicated the association of major histocompatibility complex class I (MHC-I) genotypes with rapid or slow AIDS progression. The accumulation of macaque groups that share not only a single MHC-I allele but also an MHC-I haplotype consisting of multiple polymorphic MHC-I loci would greatly contribute to the progress of AIDS research. Here, we investigated SIVmac239 infections in four groups of Burmese rhesus macaques sharing in idual MHC-I haplotypes, referred to as A, E, B, and J. Out of 20 macaques belonging to A + ( n = 6), E + ( n = 6), B + ( n = 4), and J + ( n = 4) groups, 18 showed persistent viremia. Fifteen of them developed AIDS in 0.5 to 4 years, with the remaining three at 1 or 2 years under observation. A + animals, including two controllers, showed slower disease progression, whereas J + animals exhibited rapid progression. E + and B + animals showed intermediate plasma viral loads and survival periods. Gag-specific CD8 + T-cell responses were efficiently induced in A + animals, while Nef-specific CD8 + T-cell responses were in A + , E + , and B + animals. Multiple comparisons among these groups revealed significant differences in survival periods, peripheral CD4 + T-cell decline, and SIV-specific CD4 + T-cell polyfunctionality in the chronic phase. This study indicates the association of MHC-I haplotypes with AIDS progression and presents an AIDS model facilitating the analysis of virus-host immune interaction.
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.MICINF.2007.12.002
Abstract: A current promising AIDS vaccine strategy is to elicit CD8(+) cytotoxic T lymphocyte (CTL) responses that broadly recognize highly- ersified 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.
Publisher: American Society for Microbiology
Date: 06-2009
DOI: 10.1128/JVI.00145-09
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 1β, 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.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.MEHY.2016.06.024
Abstract: Although antiretroviral therapy has made human immunodeficiency virus (HIV) infection a controllable disease, it is still unclear how viral replication persists in untreated patients and causes CD4(+) T-cell depletion leading to acquired immunodeficiency syndrome (AIDS) in several years. Theorists tried to explain it with the ersity threshold theory in which accumulated mutations in the HIV genome make the virus so erse that the immune system will no longer be able to recognize all the variants and fail to control the viraemia. Although the theory could apply to a number of cases, macaque AIDS models using simian immunodeficiency virus (SIV) have shown that failed viral control at the set point is not always associated with T-cell escape mutations. Moreover, even monkeys without a protective major histocompatibility complex (MHC) allele can contain replication of a super infected SIV following immunization with a live-attenuated SIV vaccine, while those animals are not capable of fighting primary SIV infection. Here we propose a recursion-based virus-specific naive CD4(+) T-cell depletion hypothesis through thinking on what may happen in in iduals experiencing primary immunodeficiency virus infection. This could explain the mechanism for impairment of virus-specific immune response in the course of HIV infection.
Publisher: Elsevier BV
Date: 2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-11-2018
Publisher: American Society for Microbiology
Date: 15-01-2012
DOI: 10.1128/JVI.06226-11
Abstract: Cytotoxic T lymphocyte (CTL) responses play a central role in viral suppression in human immunodeficiency virus (HIV) infections. Prophylactic vaccination resulting in effective CTL responses after viral exposure would contribute to HIV control. It is important to know how CTL memory induction by vaccination affects postexposure CTL responses. We previously showed vaccine-based control of a simian immunodeficiency virus (SIV) challenge in a group of Burmese rhesus macaques sharing a major histocompatibility complex class I haplotype. Gag 206-216 and Gag 241-249 epitope-specific CTL responses were responsible for this control. In the present study, we show the impact of in idual epitope-specific CTL induction by prophylactic vaccination on postexposure CTL responses. In the acute phase after SIV challenge, dominant Gag 206-216 -specific CTL responses with delayed, naive-derived Gag 241-249 -specific CTL induction were observed in Gag 206-216 epitope-vaccinated animals with prophylactic induction of single Gag 206-216 epitope-specific CTL memory, and vice versa in Gag 241-249 epitope-vaccinated animals with single Gag 241-249 epitope-specific CTL induction. Animals with Gag 206-216 -specific CTL induction by vaccination selected for a Gag 206-216 -specific CTL escape mutation by week 5 and showed significantly less decline of plasma viral loads from week 3 to week 5 than in Gag 241-249 epitope-vaccinated animals without escape mutations. Our results present evidence indicating significant influence of prophylactic vaccination on postexposure CTL immunodominance and cooperation of vaccine antigen-specific and non-vaccine antigen-specific CTL responses, which affects virus control. These findings provide great insights into antigen design for CTL-inducing AIDS vaccines.
Publisher: American Society for Microbiology
Date: 15-05-2007
DOI: 10.1128/JVI.02881-06
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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-10-2023
Publisher: Frontiers Media SA
Date: 2021
Location: France
Location: Japan
Location: No location found
Start Date: 2015
End Date: 2017
Funder: Primate Research Institute, Kyoto University
View Funded ActivityStart Date: 2019
End Date: 2022
Funder: Japan Society for the Promotion of Science
View Funded ActivityStart Date: 2019
End Date: 2022
Funder: Kindai University
View Funded ActivityStart Date: 2016
End Date: 2016
Funder: Astellas Foundation for Research on Metabolic Disorders
View Funded ActivityStart Date: 2021
End Date: 2021
Funder: Mochida Memorial Foundation for Medical and Pharmaceutical Research
View Funded ActivityStart Date: 2021
End Date: 2022
Funder: Children's Cancer Association of Japan
View Funded Activity