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Akatsuki Saito,
Masako Nomaguchi,
Ken Kono,
Yasumasa Iwatani,
Masaru Yokoyama,
Yasuhiro Yasutomi,
Hironori Sato,
Tatsuo Shioda,
Wataru Sugiura, Tetsuro Matano,
Akio Adachi,
Emi Nakayama,
Hirofumi Akari
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ABSTRACT: TRIM5α restricts human immunodeficiency virus type 1 (HIV-1) infection in cynomolgus monkey (CM) cells. We previously reported that a TRIMCyp allele expressing TRIM5-cyclophilin A fusion protein, was frequently found in CMs. Here we examined the influence of the TRIM5 gene variation on susceptibility of CMs to monkey-tropic HIV-1 derivative (HIV-1mt) and found that TRIMCyp homozygotes were highly susceptible to HIV-1mt not only in vitro but also in vivo. These results provide important insights into the inter-individual differences in susceptibility of macaques to HIV-1mt.
Journal of General Virology 03/2013; · 3.36 Impact Factor
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Naofumi Takahashi,
Takushi Nomura,
Yusuke Takahara,
Hiroyuki Yamamoto,
Teiichiro Shiino,
Akiko Takeda,
Makoto Inoue,
Akihiro Iida,
Hiroto Hara,
Tsugumine Shu,
Mamoru Hasegawa,
Hiromi Sakawaki,
Tomoyuki Miura,
Tatsuhiko Igarashi,
Yoshio Koyanagi,
Taeko K Naruse,
Akinori Kimura, Tetsuro Matano
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ABSTRACT: Several major histocompatibility complex class I (MHC-I) alleles are associated with lower viral loads and slower disease progression in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections. Immune-correlates analyses in these MHC-I-related HIV/SIV controllers would lead to elucidation of the mechanism for viral control. Viral control associated with some protective MHC-I alleles is attributed to CD8(+) T-cell responses targeting Gag epitopes. We have been trying to know the mechanism of SIV control in multiple groups of Burmese rhesus macaques sharing MHC-I genotypes at the haplotype level. Here, we found a protective MHC-I haplotype, 90-010-Id (D), which is not associated with dominant Gag-specific CD8(+) T-cell responses. Viral loads in five D(+) animals became significantly lower than those in our previous cohorts after 6 months. Most D(+) animals showed predominant Nef-specific but not Gag-specific CD8(+) T-cell responses after SIV challenge. Further analyses suggested two Nef-epitope-specific CD8(+) T-cell responses exerting strong suppressive pressure on SIV replication. Another set of five D(+) animals that received a prophylactic vaccine using a Gag-expressing Sendai virus vector showed significantly reduced viral loads compared to unvaccinated D(+) animals at 3 months, suggesting rapid SIV control by Gag-specific CD8(+) T-cell responses in addition to Nef-specific ones. These results present a pattern of SIV control with involvement of non-Gag antigen-specific CD8(+) T-cell responses.
PLoS ONE 01/2013; 8(1):e54300. · 4.09 Impact Factor
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Masako Nomaguchi,
Masaru Yokoyama,
Ken Kono,
Emi E Nakayama,
Tatsuo Shioda,
Akatsuki Saito,
Hirofumi Akari,
Yasuhiro Yasutomi, Tetsuro Matano,
Hironori Sato,
Akio Adachi
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ABSTRACT: HIV-1 is strictly adapted to humans, and cause disease-inducing persistent infection only in humans. We have generated a series of macaque-tropic HIV-1 (HIV-1mt) to establish non-human primate models for basic and clinical studies. HIV-1mt clones available to date grow poorly in macaque cells relative to SIVmac239. In this study, viral adaptive mutation in macaque cells, G114E in capsid (CA) helix 6 of HIV-1mt, that enhances viral replication was identified. Computer-assisted structural analysis predicted that another Q110D mutation in CA helix 6 would also increase viral growth potential. A new proviral construct MN4Rh-3 carrying CA-Q110D exhibited exquisitely enhanced growth property specifically in macaque cells. Susceptibility of MN4Rh-3 to macaque TRIM5α/TRIMCyp proteins was examined by their expression systems. HIV-1mt clones so far constructed already completely evaded TRIMCyp restriction, and further enhancement of TRIMCyp resistance by Q110D was not observed. In addition, Q110D did not contribute to evasion from TRIM5α restriction. However, the single-cycle infectivity of MN4Rh-3 in macaque cells was enhanced relative to the other HIV-1mt clones. Our results here indicate that CA-Q110D accelerates viral growth in macaque cells irrelevant to TRIM5 proteins restriction.
Microbes and Infection 10/2012; · 3.10 Impact Factor
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Kyoko Kurihara,
Yusuke Takahara,
Takushi Nomura,
Hiroshi Ishii,
Nami Iwamoto,
Naofumi Takahashi,
Makoto Inoue,
Akihiro Iida,
Hiroto Hara,
Tsugumine Shu,
Mamoru Hasegawa,
Chikaya Moriya, Tetsuro Matano
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ABSTRACT: Induction of durable cellular immune responses by vaccination is an important strategy for the control of persistent pathogen infection. Viral vectors are promising vaccine tools for eliciting antigen-specific T-cell responses. Repeated vaccination may contribute to durable memory T-cell induction, but anti-vector antibodies could be an obstacle to its efficacy. We previously developed a Sendai virus (SeV) vector vaccine and showed the potential of this vector for efficient T-cell induction in macaques. Here, we examined whether repeated SeV vector vaccination with short intervals can enhance antigen-specific CD8(+) T-cell responses. Four rhesus macaques possessing the MHC-I haplotype 90-120-Ia were immunized three times with intervals of three weeks. For the vaccination, we used replication-defective F-deleted SeV vectors inducing CD8(+) T-cell responses specific for simian immunodeficiency virus Gag(206-216) and Gag(241-249), which are dominant epitopes restricted by 90-120-Ia-derived MHC-I molecules. All four animals showed higher Gag(206-216)-specific and Gag(241-249)-specific CD8(+) T-cell responses after the third vaccination than those after the first vaccination, indicating enhancement of antigen-specific CD8(+) T-cell responses by the second/third SeV vector vaccination even with short intervals. These results suggest that repeated SeV vector vaccination can contribute to induction of efficient and durable T-cell responses.
Microbes and Infection 07/2012; · 3.10 Impact Factor
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ABSTRACT: T-cell immunoglobulin domain and mucin domain containing protein 1 (TIM1), also known as a cellular receptor for hepatitis A virus (HAVCR1) or a molecule induced by ischemic injury in the kidney (KIM1), is involved in the regulation of immune responses. We investigated a natural selection history of TIM1 by comparative sequencing analysis in 24 different primates. It was found that TIM1 had become a pseudogene in multiple lineages of the New World monkey. We also investigated T cell lines originated from four different New World monkey species and confirmed that TIM1 was not expressed at the mRNA level. On the other hand, there were ten amino acid sites in the Ig domain of TIM1 in the other primates, which were suggested to be under positive natural selection. In addition, mucin domain of TIM1 was highly polymorphic in the Old World monkeys, which might be under balanced selection. These data suggested that TIM1 underwent a lineage-specific evolutionary pathway in the primates.
Immunogenetics 06/2012; 64(9):669-78. · 2.93 Impact Factor
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Takushi Nomura,
Hiroyuki Yamamoto,
Teiichiro Shiino,
Naofumi Takahashi,
Taku Nakane,
Nami Iwamoto,
Hiroshi Ishii,
Tetsuo Tsukamoto,
Miki Kawada,
Saori Matsuoka,
Akiko Takeda,
Kazutaka Terahara,
Yasuko Tsunetsugu-Yokota,
Naoko Iwata-Yoshikawa,
Hideki Hasegawa,
Tetsutaro Sata,
Taeko K Naruse,
Akinori Kimura, Tetsuro Matano
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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 individual 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.
Journal of Virology 04/2012; 86(12):6481-90. · 5.40 Impact Factor
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ABSTRACT: Highly active antiretroviral therapy (HAART) of HIV-infected people results in viral control. When HAART is interrupted, however, HIV-infected individuals lose viral control and show reappearance of plasma viremia. Thus, they need to continue HAART almost forever for prevention of AIDS progression. Cytotoxic T lymphocyte (CTL) responses play an important role in viral suppression but are mostly reduced during HAART. There have been many attempts to develop therapeutic vaccines inducing CTL responses during HAART toward better control, although none of them has yet shown sufficient efficacy.
Nippon rinsho. Japanese journal of clinical medicine 04/2012; 70(4):676-80.
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ABSTRACT: An understanding of host cell factors that affect viral replication contributes to elucidation of the mechanism for determination of viral tropism. Cyclophilin A (CypA), a peptidyl-prolyl cis-trans isomerase (PPIase), is a host factor essential for efficient replication of human immunodeficiency virus type 1 (HIV-1) in human cells. However, the role of cyclophilins in simian immunodeficiency virus (SIV) replication has not been determined. In the present study, we examined the effect of cyclosporine A (CsA), a PPIase inhibitor, on SIV replication.
SIV replication in human CEM-SS T cells was not inhibited but rather enhanced by treatment with CsA, which inhibited HIV-1 replication. CsA treatment of target human cells enhanced an early step of SIV replication. CypA overexpression enhanced the early phase of HIV-1 but not SIV replication, while CypA knock-down resulted in suppression of HIV-1 but not SIV replication in CEM-SS cells, partially explaining different sensitivities of HIV-1 and SIV replication to CsA treatment. In contrast, CsA treatment inhibited SIV replication in macaque T cells; CsA treatment of either virus producer or target cells resulted in suppression of SIV replication. SIV infection was enhanced by CypA overexpression in macaque target cells.
CsA treatment enhanced SIV replication in human T cells but abrogated SIV replication in macaque T cells, implying a host cell species-specific effect of CsA on SIV replication. Further analyses indicated a positive effect of CypA on SIV infection into macaque but not into human T cells. These results suggest possible contribution of CypA to the determination of SIV tropism.
Retrovirology 01/2012; 9:3. · 6.47 Impact Factor
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ABSTRACT: Virus-specific cytotoxic T lymphocytes (CTLs) are major effectors in acquired immune responses against viral infection. Virus-specific CTLs recognize specific viral peptides presented by major histocompatibility complex class-I (MHC-I) on the surface of virus-infected target cells via their T cell receptor (TCR) and eliminate target cells by both direct and indirect mechanisms. In human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections, host immune responses fail to contain the virus and allow persistent viral replication, leading to AIDS progression. CTL responses exert strong suppressive pressure on HIV/SIV replication and cumulative studies have indicated association of HLA/MHC-I genotypes with rapid or slow AIDS progression.
Frontiers in microbiology. 01/2012; 3:234.
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Hiroshi Ishii,
Miki Kawada,
Tetsuo Tsukamoto,
Hiroyuki Yamamoto,
Saori Matsuoka,
Teiichiro Shiino,
Akiko Takeda,
Makoto Inoue,
Akihiro Iida,
Hiroto Hara,
Tsugumine Shu,
Mamoru Hasegawa,
Taeko K Naruse,
Akinori Kimura,
Masafumi Takiguchi, Tetsuro Matano
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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 individual 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.
Journal of Virology 11/2011; 86(2):738-45. · 5.40 Impact Factor
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Chikaya Moriya,
Satoshi Horiba,
Kyoko Kurihara,
Takeo Kamada,
Yusuke Takahara,
Makoto Inoue,
Akihiro Iida,
Hiroto Hara,
Tsugumine Shu,
Mamoru Hasegawa, Tetsuro Matano
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ABSTRACT: Viral vectors are promising vaccine tools for eliciting potent cellular immune responses. Pre-existing anti-vector antibodies, however, can be an obstacle to their clinical use in humans. We previously developed a Sendai virus (SeV) vector vaccine and showed the potential of this vector for efficient CD8(+) T-cell induction in macaques. Here, we investigated the immunogenicity of SeV vector vaccination in the presence of anti-SeV antibodies. We compared antigen-specific CD8(+) T-cell responses after intranasal or intramuscular immunization with a lower dose (one-tenth of that in our previous studies) of SeV vector expressing simian immunodeficiency virus Gag antigen (SeV-Gag) between naive and pre-SeV-infected cynomolgus macaques. Intranasal SeV-Gag immunization efficiently elicited Gag-specific CD8(+) T-cell responses not only in naive but also in pre-SeV-infected animals. In contrast, intramuscular SeV-Gag immunization induced Gag-specific CD8(+) T-cell responses efficiently in naive but not in pre-SeV-infected animals. These results indicate that both intranasal and intramuscular SeV administrations are equivalently immunogenic in the absence of anti-SeV antibodies, whereas intranasal SeV vaccination is more immunogenic than intramuscular in the presence of anti-SeV antibodies. It is inferred from a recent report investigating the prevalence of anti-SeV antibodies in humans that SeV-specific neutralizing titers in more than 70% of people are no more than those at the SeV-Gag vaccination in pre-SeV-infected macaques in the present study. Taken together, this study implies the potential of intranasal SeV vector vaccination to induce CD8(+) T-cell responses even in humans, suggesting a rationale for proceeding to a vaccine clinical trial using this vector.
Vaccine 09/2011; 29(47):8557-63. · 3.77 Impact Factor
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Midori Nakamura,
Yusuke Takahara,
Hiroshi Ishii,
Hiromi Sakawaki,
Mariko Horiike,
Tomoyuki Miura,
Tatsuhiko Igarashi,
Taeko K Naruse,
Akinori Kimura, Tetsuro Matano,
Saori Matsuoka
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ABSTRACT: Major histocompatibility complex class I (MHC-I)-restricted CD8(+) cytotoxic T lymphocyte (CTL) responses are crucial for the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. In particular, Gag-specific CTL responses have been shown to exert strong suppressive pressure on HIV/SIV replication. Additionally, association of Vif-specific CTL frequencies with in vitro anti-SIV efficacy has been suggested recently. Host MHC-I genotypes could affect the immunodominance patterns of these potent CTL responses. Here, Gag- and Vif-specific CTL responses during primary SIVmac239 infection were examined in three groups of Burmese rhesus macaques, each group having a different MHC-I haplotype. The first group of four macaques, which possessed the MHC-I haplotype 90-010-Ie, did not show Gag- or Vif-specific CTL responses. However, Nef-specific CTL responses were elicited, suggesting that primary SIV infection does not induce predominant CTL responses specific for Gag/Vif epitopes restricted by 90-010-Ie-derived MHC-I molecules. In contrast, Gag- and Vif-specific CTL responses were induced in the second group of two 89-075-Iw-positive animals and the third group of two 91-010-Is-positive animals. Considering the potential of prophylactic vaccination to affect CTL immunodominance post-viral exposure, these groups of macaques would be useful for evaluation of vaccine antigen-specific CTL efficacy against SIV infection.
Microbiology and Immunology 09/2011; 55(11):768-73. · 1.30 Impact Factor
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ABSTRACT: Development of an effective AIDS vaccine is considered essential for control of HIV pandemic. Previous failures in clinical vaccine trials have indicated the importance of virological and immunological basic studies for elucidation of the mechanism of HIV control. This review describes current progress in prophylactic AIDS vaccine development.
Nippon rinsho. Japanese journal of clinical medicine 09/2011; 69(9):1622-7.
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ABSTRACT: Cynomolgus macaques are widely used as a primate model for human diseases associated with an immunological process. Because there are individual differences in immune responsiveness, which are controlled by the polymorphic nature of the major histocompatibility (MHC) locus, it is important to reveal the diversity of MHC in the model animal. In this study, we analyzed 26 cynomolgus macaques from five families for MHC class I genes. We identified 32 Mafa-A, 46 Mafa-B, 6 Mafa-I, and 3 Mafa-AG alleles in which 14, 20, 3, and 3 alleles were novel. There were 23 MHC class I haplotypes and each haplotype was composed of one to three Mafa-A alleles and one to five Mafa-B alleles. Family studies revealed that there were two haplotypes which contained two Mafa-A1 alleles. These observations demonstrated further the complexity of MHC class I locus in the Old World monkey.
Immunogenetics 09/2011; 64(2):131-41. · 2.93 Impact Factor
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Yusuke Takahara,
Saori Matsuoka,
Tetsuya Kuwano,
Tetsuo Tsukamoto,
Hiroyuki Yamamoto,
Hiroshi Ishii,
Tadashi Nakasone,
Akiko Takeda,
Makoto Inoue,
Akihiro Iida,
Hiroto Hara,
Tsugumine Shu,
Mamoru Hasegawa,
Hiromi Sakawaki,
Mariko Horiike,
Tomoyuki Miura,
Tatsuhiko Igarashi,
Taeko K Naruse,
Akinori Kimura, Tetsuro Matano
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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.
Biochemical and Biophysical Research Communications 05/2011; 408(4):615-9. · 2.48 Impact Factor
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ABSTRACT: Natural-killer group 2 member D (NKG2D) is an activating receptor that plays an important role in the immune response mediated by NK cells, γδ(+) T cells, and CD8(+) T cells. In humans, MHC class I chain-related genes and UL-16 binding protein (ULBP)/retinoic acid early transcript 1 (REAT1) gene family encode ligands for NKG2D. The rhesus and crab-eating macaques, which belong to the Old World monkeys, are widely used as non-human primate models in medical researches on the immunological process. In the present study, we investigated the polymorphisms of ULBP4/RAET1E, a member of the ULBP/RAET1 family, and found 25 and 14 alleles from the rhesus and crab-eating macaques, respectively, of which diversities were far more extended than in humans. A phylogenetic study suggested that the allelic diversification of ULBP4/RAET1E predated the divergence of rhesus and crab-eating macaques.
Immunogenetics 05/2011; 63(8):501-9. · 2.93 Impact Factor
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ABSTRACT: Cytotoxic T lymphocyte (CTL) responses exert a suppressive effect on HIV and simian immunodeficiency virus (SIV) replication. Under the CTL pressure, viral CTL escape mutations are frequently selected with viral fitness costs. Viruses with such CTL escape mutations often need additional viral genome mutations for recovery of viral fitness. Persistent HIV/SIV infection sometimes shows replacement of a CTL escape mutation with an alternative escape mutation toward higher viral fitness. Thus, multiple viral genome changes under CTL pressure are observed in the chronic phase of HIV/SIV infection. HIV/SIV transmission to HLA/MHC-mismatched hosts drives further viral genome changes including additional CTL escape mutations and reversions under different CTL pressure. Understanding of viral structure/function and host CTL responses would contribute to prediction of HIV evolution and control of HIV prevalence.
Frontiers in microbiology. 01/2011; 2:267.
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ABSTRACT: In our prior study on a prophylactic T-cell-based vaccine, some vaccinated macaques controlled a simian immunodeficiency virus (SIV) challenge. These animals allowed viremia in the acute phase but showed persistent viral control after the setpoint. Here, we examined the breadth of postchallenge virus-specific cellular immune responses in these SIV controllers.
We previously reported that in a group of Burmese rhesus macaques possessing the MHC haplotype 90-120-Ia, immunization with a Gag-expressing vaccine results in nonsterile control of a challenge with SIVmac239 but not a mutant SIV carrying multiple cytotoxic T lymphocyte (CTL) escape gag mutations. In the present study, we investigated whether broader cellular immune responses effective against the mutant SIV replication are induced after challenge in those vaccinees that maintained wild-type SIVmac239 control.
We analyzed cellular immune responses in these SIV controllers (n = 8).
These controllers elicited CTL responses directed against SIV non-Gag antigens as well as Gag in the chronic phase. Postvaccinated, prechallenge CD8(+) cells obtained from these animals suppressed wild-type SIV replication in vitro, but mostly had no suppressive effect on the mutant SIV replication, whereas CD8(+) cells in the chronic phase after challenge showed efficient antimutant SIV efficacy. The levels of in-vitro antimutant SIV efficacy of CD8(+) cells correlated with Vif-specific CD8(+) T-cell frequencies. Plasma viremia was kept undetectable even after the mutant SIV superchallenge in the chronic phase.
These results suggest that vaccine-based wild-type SIV controllers can acquire CD8(+) cells with the potential to suppress replication of SIV variants carrying CTL escape mutations.
AIDS (London, England) 11/2010; 24(18):2777-87. · 4.91 Impact Factor
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Akatsuki Saito,
Masako Nomaguchi,
Sayuki Iijima,
Ayumu Kuroishi,
Tomoyuki Yoshida,
Young-Jung Lee,
Toshiyuki Hayakawa,
Ken Kono,
Emi E Nakayama,
Tatsuo Shioda,
Yasuhiro Yasutomi,
Akio Adachi, Tetsuro Matano,
Hirofumi Akari
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ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) hardly replicates in Old World monkeys. Recently, a mutant HIV-1 clone, NL-DT5R, in which a small part of gag and the entire vif gene are replaced with SIVmac239-derived ones, was shown to be able to replicate in pigtail monkeys but not in rhesus monkeys (RM). In the present study, we found that a modified monkey-tropic HIV-1 (HIV-1mt), MN4-5S, acquired the ability to replicate efficiently in cynomolgus monkeys as compared with the NL-DT5R, while neither NL-DT5R nor MN4-5S replicated in RM cells. These results suggest that multiple determinants may be involved in the restriction of HIV-1 replication in macaques, depending on the species of macaques. The new HIV-1mt clone will be useful for studying molecular mechanisms by which anti-viral host factors regulate HIV-1 replication in macaques.
Microbes and Infection 10/2010; 13(1):58-64. · 3.10 Impact Factor
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ABSTRACT: The Gag capsid (CA) is one of the most conserved proteins in highly-diversified human and simian immunodeficiency viruses (HIV and SIV). Understanding the limitations imposed on amino acid sequences in CA could provide valuable information for vaccine immunogen design or anti-HIV drug development. Here, by comparing two pathogenic SIV strains, SIVmac239 and SIVsmE543-3, we found critical amino acid residues for functional interaction between the N-terminal and the C-terminal domains in CA.
We first examined the impact of Gag residue 205, aspartate (Gag205D) in SIVmac239 and glutamate (Gag205E) in SIVsmE543-3, on viral replication; due to this difference, Gag206-216 (IINEEAADWDL) epitope-specific cytotoxic T lymphocytes (CTLs) were previously shown to respond to SIVmac239 but not SIVsmE543-3 infection. A mutant SIVmac239, SIVmac239Gag205E, whose Gag205D is replaced with Gag205E showed lower replicative ability. Interestingly, however, SIVmac239Gag205E passaged in macaque T cell culture often resulted in selection of an additional mutation at Gag residue 340, a change from SIVmac239 valine (Gag340V) to SIVsmE543-3 methionine (Gag340M), with recovery of viral fitness. Structural modeling analysis suggested possible intermolecular interaction between the Gag205 residue in the N-terminal domain and Gag340 in the C-terminal in CA hexamers. The Gag205D-to-Gag205E substitution in SIVmac239 resulted in loss of in vitro core stability, which was recovered by additional Gag340V-to-Gag340M substitution. Finally, selection of Gag205E plus Gag340M mutations, but not Gag205E alone was observed in a chronically SIVmac239-infected rhesus macaque eliciting Gag206-216-specific CTL responses.
These results present in vitro and in vivo evidence implicating the interaction between Gag residues 205 in CA NTD and 340 in CA CTD in SIV replication. Thus, this study indicates a structural constraint for functional interaction between SIV CA NTD and CTD, providing insight into immunogen design to limit viral escape options.
Retrovirology 10/2010; 7:90. · 6.47 Impact Factor
