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

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.

scholarly journals HIV-1 Nef Interacts with LMP7 To Attenuate Immunoproteasome Formation and Major Histocompatibility Complex Class I Antigen Presentation

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Yang Yang ◽  
Weiyong Liu ◽  
Dan Hu ◽  
Rui Su ◽  
Man Ji ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Immune Responses ◽  
Major Histocompatibility Complex Class ◽  
Protein Degradation ◽  
Antigen Presentation ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Hiv 1

ABSTRACT The proteasome is a major protein degradation machinery with essential and diverse biological functions. Upon induction by cytokines, proteasome subunits β1, β2, and β5 are replaced by β1i/LMP2, β2i/MECL-1, and β5i/LMP7, resulting in the formation of an immunoproteasome (iProteasome). iProteasome-degraded products are loaded onto the major histocompatibility complex class I (MHC-I), regulating immune responses and inducing cytotoxic T lymphocytes (CTLs). Human immunodeficiency virus type 1 (HIV-1) is the causal agent of AIDS. HIV-1-specific CTLs represent a critical immune mechanism limiting viral replication. HIV-1 negative regulatory factor (Nef) counteracts host immunity, particularly the response involving MHC-I/CTL. This study identifies a distinct mechanism by which Nef facilitates immune evasion via suppressing the function of iProteasome and MHC-I. Nef interacts with LMP7 on the endoplasmic reticulum (ER), downregulating the incorporation of LMP7 into iProteasome and thereby attenuating its formation. Moreover, Nef represses the iProteasome function of protein degradation, MHC-I trafficking, and antigen presentation. IMPORTANCE The ubiquitin-proteasome system (UPS) is essential for the degradation of damaged proteins, which takes place in the proteasome. Upon activation by cytokines, the catalytic subunits of the proteasome are replaced by distinct isoforms resulting in the formation of an immunoproteasome (iProteasome). iProteasome generates peptides used by major histocompatibility complex class I (MHC-I) for antigen presentation and is essential for immune responses. HIV-1 is the causative agent of AIDS, and HIV-1-specific cytotoxic T lymphocytes (CTLs) provide immune responses limiting viral replication. This study identifies a distinct mechanism by which HIV-1 promotes immune evasion. The viral protein negative regulatory factor (Nef) interacts with a component of iProteasome, LMP7, attenuating iProteasome formation and protein degradation function, and thus repressing the MHC-I antigen presentation activity of MHC-I. Therefore, HIV-1 targets LMP7 to inhibit iProteasome activation, and LMP7 may be used as the target for the development of anti-HIV-1/AIDS therapy.

scholarly journals SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells

2015 ◽  
Vol 89 (14) ◽  
pp. 6994-7006 ◽  
Author(s):  
Diana Ayinde ◽  
Timothée Bruel ◽  
Sylvain Cardinaud ◽  
Françoise Porrot ◽  
Julia G. Prado ◽  
...  
Keyword(s):  
Immune Responses ◽  
Antigen Presentation ◽  
Cytotoxic T Lymphocytes ◽  
Viral Proteins ◽  
Productive Infection ◽  
Restriction Factors ◽  
Adaptive Immune Responses ◽  
Mhc I ◽  
Adaptive Immune ◽  
Hiv 1

ABSTRACTMonocyte-derived dendritic cells (MDDC) stimulate CD8+cytotoxic T lymphocytes (CTL) by presenting endogenous and exogenous viral peptides via major histocompatibility complex class I (MHC-I) molecules. MDDC are poorly susceptible to HIV-1, in part due to the presence of SAMHD1, a cellular enzyme that depletes intracellular deoxynucleoside triphosphates (dNTPs) and degrades viral RNA. Vpx, an HIV-2/SIVsm protein absent from HIV-1, antagonizes SAMHD1 by inducing its degradation. The impact of SAMHD1 on the adaptive cellular immune response remains poorly characterized. Here, we asked whether SAMHD1 modulates MHC-I-restricted HIV-1 antigen presentation. Untreated MDDC or MDDC pretreated with Vpx were exposed to HIV-1, and antigen presentation was examined by monitoring the activation of an HIV-1 Gag-specific CTL clone. SAMHD1 depletion strongly enhanced productive infection of MDDC as well as endogenous HIV-1 antigen presentation. Time-lapse microscopy analysis demonstrated that in the absence of SAMHD1, the CTL rapidly killed infected MDDC. We also report that various transmitted/founder (T/F) HIV-1 strains poorly infected MDDC and, as a consequence, did not stimulate CTL. Vesicular stomatitis virus glycoprotein (VSV-G) pseudotyping of T/F alleviated a block in viral entry and induced antigen presentation only in the absence of SAMHD1. Furthermore, by using another CTL clone that mostly recognizes incoming HIV-1 antigens, we demonstrate that SAMHD1 does not influence exogenous viral antigen presentation. Altogether, our results demonstrate that the antiviral activity of SAMHD1 impacts antigen presentation by DC, highlighting the link that exists between restriction factors and adaptive immune responses.IMPORTANCEUpon viral infection, DC may present antigens derived from incoming viral material in the absence of productive infection of DC or from newly synthesized viral proteins. In the case of HIV, productive infection of DC is blocked at an early postentry step. This is due to the presence of SAMHD1, a cellular enzyme that depletes intracellular levels of dNTPs and inhibits viral reverse transcription. We show that the depletion of SAMHD1 in DCs strongly stimulates the presentation of viral antigens derived from newly produced viral proteins, leading to the activation of HIV-1-specific cytotoxic T lymphocytes (CTL). We further show in real time that the enhanced activation of CTL leads to killing of infected DCs. Our results indicate that the antiviral activity of SAMHD1 not only impacts HIV replication but also impacts antigen presentation by DC. They highlight the link that exists between restriction factors and adaptive immune responses.

scholarly journals Structure of HIV-2 Nef reveals unique features distinct from HIV-1 involved in immune regulation

2019 ◽  
Author(s):  
Kengo Hirao ◽  
Sophie Andrews ◽  
Kimiko Kuroki ◽  
Hiroki Kusaka ◽  
Takashi Tadokoro ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Immune Regulation ◽  
Titration Calorimetry ◽  
Viral Control ◽  
Mhc I ◽  
Infected People ◽  
Sorting Motif ◽  
Α Helix ◽  
Hiv 1

SummaryThe HIV accessory protein Nef plays a major role in establishing and maintaining infection, particularly through immune evasion. Many HIV-2 infected people experience long-term viral control and survival, resembling HIV-1 elite control. HIV-2 Nef has overlapping but also distinct functions from HIV-1 Nef. Here we report the crystal structure of HIV-2 Nef core. The dileucine sorting motif forms a helix bound to neighboring molecules, and moreover, isothermal titration calorimetry demonstrated that the CD3 endocytosis motif can directly bind to HIV-2 Nef, ensuring AP-2 mediated endocytosis for CD3. The highly-conserved C-terminal region forms a α-helix, absent from HIV-1. We further determined the structure of SIV Nef harboring this region, demonstrating similar C-terminal α-helix, which may contribute to AP-1 binding for MHC-I downregulation. These results provide new insights into the distinct pathogenesis of HIV-2 infection.

scholarly journals Inhibition of lipid antigen presentation in dendritic cells by HIV-1 Vpu interference with CD1d recycling from endosomal compartments

Blood ◽  
2010 ◽  
Vol 116 (11) ◽  
pp. 1876-1884 ◽  
Author(s):  
Markus Moll ◽  
Sofia K. Andersson ◽  
Anna Smed-Sörensen ◽  
Johan K. Sandberg
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Antigen Presentation ◽  
Nkt Cells ◽  
Cellular Immune Responses ◽  
Antigen Presentation Pathway ◽  
Early Endosomes ◽  
Presentation Pathway ◽  
Cellular Immune ◽  
Hiv 1

AbstractDendritic cells (DCs) play an important role in viral infections both as initiators of immunity and as viral targets. Interaction between DCs and the innate-like CD1d-restricted natural killer T (NKT) cells results in the mutual activation of both cells and the subsequent initiation of cellular immune responses. Here, we show that HIV-1 inhibits the surface expression of CD1d in productively infected DCs and identify this as a novel activity of the HIV-1 vpu gene product. Interestingly, the viral protein U (Vpu) does not enhance constitutive CD1d endocytosis or induce rapid CD1d degradation. Instead, the Vpu protein interacts with CD1d and suppresses its recycling from endosomal compartments to the cell surface by retaining CD1d in early endosomes. This interference with the CD1d antigen presentation pathway strongly inhibits the ability of infected DCs to activate CD1d-restricted NKT cells. Given that the interaction with CD1d-expressing DCs is central to the ability of NKT cells to regulate immunity, these data suggest that interference with the CD1d antigen presentation pathway represents an HIV-1 strategy to evade innate cellular immune responses and imply a role for the innate-like CD1d-restricted NKT cells in the host defense against HIV-1.

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

2002 ◽  
Vol 76 (23) ◽  
pp. 11982-11988 ◽  
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.

scholarly journals Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation

2021 ◽  
Vol 12 ◽  
Author(s):  
Karthik Dhatchinamoorthy ◽  
Jeff D. Colbert ◽  
Kenneth L. Rock
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Antigen Presentation ◽  
Cd8 T Cells ◽  
Class I ◽  
Immune Control ◽  
Class I Mhc ◽  
Mhc I ◽  
Mhc Class I Antigen ◽  
Underlying Mechanisms

Major histocompatibility class I (MHC I) molecules bind peptides derived from a cell's expressed genes and then transport and display this antigenic information on the cell surface. This allows CD8 T cells to identify pathological cells that are synthesizing abnormal proteins, such as cancers that are expressing mutated proteins. In order for many cancers to arise and progress, they need to evolve mechanisms to avoid elimination by CD8 T cells. MHC I molecules are not essential for cell survival and therefore one mechanism by which cancers can evade immune control is by losing MHC I antigen presentation machinery (APM). Not only will this impair the ability of natural immune responses to control cancers, but also frustrate immunotherapies that work by re-invigorating anti-tumor CD8 T cells, such as checkpoint blockade. Here we review the evidence that loss of MHC I antigen presentation is a frequent occurrence in many cancers. We discuss new insights into some common underlying mechanisms through which some cancers inactivate the MHC I pathway and consider some possible strategies to overcome this limitation in ways that could restore immune control of tumors and improve immunotherapy.

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

2016 ◽  
Vol 90 (14) ◽  
pp. 6276-6290 ◽  
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.

scholarly journals Unexpected Diversity of Cellular Immune Responses against Nef and Vif in HIV-1-Infected Patients Who Spontaneously Control Viral Replication

PLoS ONE ◽  
2010 ◽  
Vol 5 (7) ◽  
pp. e11436 ◽  
Author(s):  
Leandro F. Tarosso ◽  
Mariana M. Sauer ◽  
Sabri Sanabani ◽  
Maria Teresa Giret ◽  
Helena I. Tomiyama ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Replication ◽  
Cellular Immune Responses ◽  
Cellular Immune ◽  
Hiv 1

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

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4832-4838 ◽  
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.

scholarly journals Correction: Unexpected Diversity of Cellular Immune Responses against Nef and Vif in HIV-1-Infected Patients Who Spontaneously Control Viral Replication

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
Author(s):  
Leandro F. Tarosso ◽  
Mariana M. Sauer ◽  
Sabri Sanabani ◽  
Maria Teresa Giret ◽  
Helena I. Tomiyama ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Replication ◽  
Cellular Immune Responses ◽  
Cellular Immune ◽  
Hiv 1
Sign in / Sign up

Export Citation Format

Share Document