Histamine increases the level of IFNγ produced by HIV-1 specific CTLs and this production depends on total IgE level

The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression.

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Different Abilities of Escape Mutant-Specific Cytotoxic T Cells To Suppress Replication of Escape Mutant and Wild-Type Human Immunodeficiency Virus Type 1 in New Hosts

Journal of Virology ◽

10.1128/jvi.01452-07 ◽

2007 ◽

Vol 82 (1) ◽

pp. 138-147 ◽

Cited By ~ 28

Author(s):

Mamoru Fujiwara ◽

Junko Tanuma ◽

Hirokazu Koizumi ◽

Yuka Kawashima ◽

Kazutaka Honda ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Escape Mutant ◽

Wild Type ◽

Specific Ctls ◽

Immunodeficiency Virus ◽

New Hosts ◽

Hiv 1 ◽

Hla Molecules

ABSTRACT There is much evidence that in human immunodeficiency virus type 1 (HIV-1)-infected individuals, strong cytotoxic T lymphocyte (CTL)-mediated immune pressure results in the selection of HIV-1 mutants that have escaped from wild-type-specific CTLs. If escape mutant-specific CTLs are not elicited in new hosts sharing donor HLA molecules, the transmission of these mutants results in the accumulation of escape mutants in the population. However, whether escape mutant-specific CTLs are definitively not elicited in new hosts sharing donor HLA molecules still remains unclear. A previous study showed that a Y-to-F substitution at the second position (2F) of the Nef138-10 epitope is significantly detected in HLA-A*2402+ hemophilic donors. Presently, we confirmed that this 2F mutant was an escape mutant by demonstrating strong and weak abilities of Nef138-10-specific CTL clones to suppress replication of the wild-type and 2F mutant viruses, respectively. We demonstrated the existence of the 2F-specific CTLs in three new hosts who had been primarily infected with the 2F mutant. The 2F-specific CTL clones suppressed the replication of both wild-type and mutant viruses. However, the abilities of these clones to suppress replication of the 2F virus were much weaker than those of wild-type-specific and the 2F-specific ones to suppress replication of the wild-type virus. These findings indicate that the 2F mutant is conserved in HIV-1-infected donors having HLA-A*2402, because the 2F-specific CTLs failed to completely suppress the 2F mutant replication and effectively prevented viral reversion in new hosts carrying HLA-A*2402.

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Selection of HLA-B57-associated Gag A146P mutant by HLA-B∗48:01-restricted Gag140-147-specific CTLs in chronically HIV-1-infected Japanese

Microbes and Infection ◽

10.1016/j.micinf.2011.03.009 ◽

2011 ◽

Vol 13 (8-9) ◽

pp. 766-770 ◽

Cited By ~ 1

Author(s):

Takuya Naruto ◽

Hayato Murakoshi ◽

Takayuki Chikata ◽

Madoka Koyanagi ◽

Yuka Kawashima ◽

...

Keyword(s):

Specific Ctls ◽

Hiv 1 ◽

Selection Of

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An Efficient and Versatile Mammalian Viral Vector System for Major Histocompatibility Complex Class I/Peptide Complexes

Journal of Virology ◽

10.1128/jvi.76.23.11982-11988.2002 ◽

2002 ◽

Vol 76 (23) ◽

pp. 11982-11988 ◽

Cited By ~ 14

Author(s):

Ai Kawana-Tachikawa ◽

Mariko Tomizawa ◽

Jun-ichi Nunoya ◽

Tatsuo Shioda ◽

Atsushi Kato ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Immune Responses ◽

Mhc Class I ◽

Class I ◽

Vector System ◽

Specific Ctls ◽

Histocompatibility Complex ◽

Peptide Complexes ◽

Hiv 1 ◽

Made In

ABSTRACT We report a Sendai virus (SeV) vector system for expression of major histocompatibility complex (MHC) class I/peptide complexes. We cloned the extracellular domain of a human MHC class I heavy chain, HLA-A*2402, and human β-2 microglobulin (β2m) fused with HLA-A*2402-restricted human immunodeficiency virus type 1 (HIV-1) cytotoxic T-lymphocyte (CTL) epitopes (e-β2m) in separate SeV vectors. When we coinfected nonhuman mammalian cells with the SeVs, naturally folded human MHC class I/peptide complexes were secreted in the culture supernatants. Biotin binding peptide sequences on the C terminus of the heavy chain were used to tetramerize the complexes. These tetramers made in the SeV system recognized specific CD8-positive T cells in peripheral blood mononuclear cells of HIV-1-positive patients with a specificity and sensitivity similar to those of MHC class I tetramers made in an Escherichia coli system. Solo infection of e-β2m/SeV produced soluble e-β2m in the culture supernatant, and cells pulsed with the soluble protein were recognized by specific CTLs. Furthermore, when cells were infected with e-β2m/SeV, these cells were recognized by the specific CTLs more efficiently than the protein pulse per se. SeV is nonpathogenic for humans, can transduce foreign genes into nondividing cells, and may be useful for immunotherapy to enhance antigen-specific immune responses. Our system can be used not only to detect but also to stimulate antigen-specific cellular immune responses.

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Strong Human Immunodeficiency Virus (HIV)-Specific Cytotoxic T-Lymphocyte Activity in Sydney Blood Bank Cohort Patients Infected with nef-Defective HIV Type 1

Journal of Virology ◽

10.1128/jvi.73.1.436-443.1999 ◽

1999 ◽

Vol 73 (1) ◽

pp. 436-443 ◽

Cited By ~ 74

Author(s):

Wayne B. Dyer ◽

Graham S. Ogg ◽

Marie-Ange Demoitie ◽

Xia Jin ◽

Andrew F. Geczy ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Lymphocyte ◽

Blood Bank ◽

Specific Ctls ◽

Sydney Blood Bank Cohort ◽

Immunodeficiency Virus ◽

Hiv Type 1 ◽

Hiv 1 ◽

Ctl Responses

ABSTRACT Proposals for the use of live attenuated human immunodeficiency virus (HIV) type 1 (HIV-1) as a vaccine candidate in humans have been based on the protection afforded by attenuated simian immunodeficiency virus in the macaque model. Although it is not yet known if this strategy could succeed in humans, a study of the Sydney Blood Bank Cohort (SBBC), infected with an attenuated HIV-1 quasispecies with natural nef and nef/long terminal repeat deletions for up to 17 years, could provide insights into the long-term immunological consequences of living with an attenuated HIV-1 infection. In this study, HIV-specific cytoxic T-lymphocyte (CTL) responses in an SBBC donor and six recipients were examined over a 3-year period with enzyme-linked immunospot, tetrameric complex binding, direct CTL lysis, and CTL precursor level techniques. Strong HIV-specific CTL responses were detected in four of seven patients, including one patient with an undetectable viral load. Two of seven patients had weak CTL responses, and in one recipient, no HIV-specific CTLs were detected. High levels of circulating effector and memory HIV-specific CTLs can be maintained for prolonged periods in these patients despite very low viral loads.

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Biphasic CD8+T-Cell Defense in Simian Immunodeficiency Virus Control by Acute-Phase Passive Neutralizing Antibody Immunization

Journal of Virology ◽

10.1128/jvi.00557-16 ◽

2016 ◽

Vol 90 (14) ◽

pp. 6276-6290 ◽

Cited By ~ 14

Author(s):

Sumire Iseda ◽

Naofumi Takahashi ◽

Hugo Poplimont ◽

Takushi Nomura ◽

Sayuri Seki ◽

...

Keyword(s):

Immune Responses ◽

Simian Immunodeficiency Virus ◽

Acute Phase ◽

Passive Immunization ◽

Virus Control ◽

Specific Ctls ◽

Immunodeficiency Virus ◽

Ctl Escape ◽

Hiv 1 ◽

Ctl Responses

ABSTRACTIdentifying human immunodeficiency virus type 1 (HIV-1) control mechanisms by neutralizing antibodies (NAbs) is critical for anti-HIV-1 strategies. Recentin vivostudies on animals infected with simian immunodeficiency virus (SIV) and related viruses have shown the efficacy of postinfection NAb passive immunization for viremia reduction, and one suggested mechanism is its occurrence through modulation of cellular immune responses. Here, we describe SIV control in macaques showing biphasic CD8+cytotoxic T lymphocyte (CTL) responses following acute-phase NAb passive immunization. Analysis of four SIVmac239-infected rhesus macaque pairs matched with major histocompatibility complex class I haplotypes found that counterparts receiving day 7 anti-SIV polyclonal NAb infusion all suppressed viremia for up to 2 years without accumulating viral CTL escape mutations. In the first phase of primary viremia control attainment, CD8+cells had high capacities to suppress SIVs carrying CTL escape mutations. Conversely, in the second, sustained phase of SIV control, CTL responses converged on a pattern of immunodominant CTL preservation. During this sustained phase of viral control, SIV epitope-specific CTLs showed retention of phosphorylated extracellular signal-related kinase (ERK)hi/phosphorylated AMP-activated protein kinase (AMPK)losubpopulations, implying their correlation with SIV control. The results suggest that virus-specific CTLs functionally boosted by acute-phase NAbs may drive robust AIDS virus control.IMPORTANCEIn early HIV infection, NAb responses are lacking and CTL responses are insufficient, which leads to viral persistence. Hence, it is important to identify immune responses that can successfully control such HIV replication. Here, we show that monkeys receiving NAb passive immunization in early SIV infection strictly control viral replication for years. Passive infusion of NAbs with CTL cross-priming capacity resulted in induction of functionally boosted early CTL responses showing enhanced suppression of CTL escape mutant virus replication. Accordingly, the NAb-infused animals did not show accumulation of viral CTL escape mutations during sustained SIV control, and immunodominant CTL responses were preserved. This early functional augmentation of CTLs by NAbs provides key insights into the design of lasting and viral escape mutation-free protective immunity against HIV-1 infection.

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HIV-1–specific CTLs effectively suppress replication of HIV-1 in HIV-1–infected macrophages

Blood ◽

10.1182/blood-2006-07-037481 ◽

2007 ◽

Vol 109 (11) ◽

pp. 4832-4838 ◽

Cited By ~ 31

Author(s):

Mamoru Fujiwara ◽

Masafumi Takiguchi

Keyword(s):

T Cells ◽

Antigen Presentation ◽

Cd4 T Cells ◽

Hla Class I ◽

The Other ◽

Class I ◽

Cytolytic T Lymphocytes ◽

Down Regulation ◽

Specific Ctls ◽

Hiv 1

AbstractBoth CD4+ T cells and macrophages are major reservoirs of HIV-1. Previous study showed that HIV-1–specific cytolytic T lymphocytes (CTLs) hardly recognize HIV-1–infected CD4+ T cells because of Nef-mediated HLA class I down-regulation, suggesting that HIV-1 escapes from HIV-1–specific CTLs and continues to replicate in HIV-1–infected donors. On the other hand, the CTL recognition of HIV-1–infected macrophages and the effect of Nef-mediated HLA class I down-regulation on this recognition still remain unclear. We show a strong HIV-1 antigen presentation by HIV-1–infected macrophages. HIV-1–specific CTLs had strong abilities to suppress HIV-1R5 virus replication in HIV-1–infected macrophages and to kill HIV-1R5–infected macrophages. Nef-mediated HLA class I down-regulation minimally influenced the recognition of HIV-1–infected macrophages by HIV-1–specific CTLs. In addition, HIV-1–infected macrophages had a stronger ability to stimulate the proliferation of HIV-1–specific CTLs than HIV-1–infected CD4+ T cells. Thus, the effect of Nef-mediated HLA class I down-regulation was less critical with respect to the recognition by HIV-1–specific CTLs of HIV-infected macrophages than that of HIV-1–infected CD4+ T cells. These findings support the idea that the strong HIV-1 antigen presentation by HIV-1–infected macrophages is one of the mechanisms mediating effective induction of HIV-1–specific CTLs in the acute and early chronic phases of HIV-1 infection.

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Altering Effects of Antigenic Variations in HIV-1 on Antiviral Effectiveness of HIV-Specific CTLs

The Journal of Immunology ◽

10.4049/jimmunol.178.9.5513 ◽

2007 ◽

Vol 178 (9) ◽

pp. 5513-5523 ◽

Cited By ~ 29

Author(s):

Takamasa Ueno ◽

Yuka Idegami ◽

Chihiro Motozono ◽

Shinichi Oka ◽

Masafumi Takiguchi

Keyword(s):

Specific Ctls ◽

Hiv 1

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HIV-1 Nef interacts with LMP7 to attenuate immunoproteasome formation and MHC-I antigen presentation

10.1101/697946 ◽

2019 ◽

Author(s):

Yang Yang ◽

Weiyong Liu ◽

Dan Hu ◽

Rui Su ◽

Man Ji ◽

...

Keyword(s):

Immune Responses ◽

Viral Replication ◽

Protein Degradation ◽

Antigen Presentation ◽

Immune Evasion ◽

Mhc I ◽

Specific Ctls ◽

Distinct Mechanism ◽

Hiv 1 ◽

Presentation Activity

AbstractProteasome is major protein degradation machinery and plays essential roles in diverse biological functions. Upon cytokine inductions, proteasome subunits β1, β2, and β5 are replaced by β1i/LMP2, β2i/MECL-1, and β5i/LMP7, leading to the formation of immunoproteasome. Immunoproteasome-degraded products are loaded onto the major histocompatibility complex class I (MHC-I) to regulate immune responses and induce cytotoxic-T-lymphocytes (CTLs). Human immunodeficiency virus type 1 (HIV-1) is the causal agent of acquired immunodeficiency syndrome (AIDS). HIV-1-specific CTLs represent critical immune responses to limit viral replication. HIV-1 negative regulatory factor (Nef) counteracts host immunity, especially the MHC-I/CTL. This study reveals a distinct mechanism by which Nef facilitates immune evasion through attenuating the functions of immunoproteasome and MHC-I. Nef interacts with LMP7 on the endoplasmic reticulum (ER) to down-regulate the incorporation of LMP7 into immunoproteasome, and thereby attenuating immunoproteasome formation. Moreover, Nef represses immunoproteasome protein degradation function, MHC-I trafficking, and antigen presentation activity.ImportanceUbiquitin-proteasome system (UPS) is essential for degradation of damaged proteins, which takes place in proteasome. Upon cytokine inductions, proteasome catalytic activities are replaced by distinct isoforms resulting in formation of immunoproteasome. Immunoproteasome generates peptides for MHC-I antigen presentation and plays important roles in immune responses. HIV-1 is the agent of AIDS, and HIV-1-specific CTLs represent immune responses to limit viral replication. This study reveals a distinct mechanism by which HIV-1 promotes immune evasion. Viral protein Nef interacts with immunoproteasome component LMP7 to attenuate immunoproteasome formation and protein degradation function, and repress MHC-I antigen presentation activity. Therefore, HIV-1 targets LMP7 to inhibit immunoproteasome activation and LMP7 may be used as a target for the development of anti-HIV-1/AIDS therapy.

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