DC-SIGN promotes exogenous MHC-I–restricted HIV-1 antigen presentation

Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2648-2654 ◽  
Author(s):  
Arnaud Moris ◽  
Cinzia Nobile ◽  
Florence Buseyne ◽  
Françoise Porrot ◽  
Jean-Pierre Abastado ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Cytotoxic T Lymphocytes ◽  
Viral Envelope ◽  
Class I Mhc ◽  
Mhc I ◽  
High Affinity ◽  
Histocompatibility Complex ◽  
Anti Hiv ◽  
Hiv 1

Abstract Dendritic cells (DCs) facilitate HIV-1 spread in the host by capturing virions and transferring them to permissive lymphocytes in lymphoid organs. Lectins such as DC-specific ICAM-grabbing non-integrin (DC-SIGN) are involved in HIV-1 uptake by DCs, through high-affinity binding to viral envelope glycoproteins. We examined the role of DC-SIGN on the fate of incoming virions and on major histocompatibility complex class I (MHC-I)–restricted HIV-1 antigen presentation. We show that DC-SIGN expression in B-cell lines dramatically enhances viral internalization. In these cells, and also in primary DCs, most of the captured virions are rapidly degraded, likely in a lysosomal compartment. In addition, a fraction of incoming viral material is processed by the proteasome, leading to activation of anti–HIV-specific cytotoxic T lymphocytes (CTLs) by DC-SIGN–expressing cells. In DCs, DC-SIGN is not the only receptor involved, and redundant pathways of virus capture leading to antigen presentation likely coexist. Altogether, our results highlight new aspects of DC-SIGN interactions with HIV-1. The lectin does not significantly protect captured virions against degradation and promotes MHC-I exogenous presentation of HIV-1 antigens.

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 Interaction of TAPBPR, a tapasin homolog, with MHC-I molecules promotes peptide editing

2016 ◽  
Vol 113 (8) ◽  
pp. E1006-E1015 ◽  
Author(s):  
Giora I. Morozov ◽  
Huaying Zhao ◽  
Michael G. Mage ◽  
Lisa F. Boyd ◽  
Jiansheng Jiang ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Class I Mhc ◽  
Mhc I ◽  
X Ray ◽  
X Ray Scattering ◽  
Histocompatibility Complex ◽  
Self Tolerance ◽  
Peptide Loading

Peptide loading of major histocompatibility complex class I (MHC-I) molecules is central to antigen presentation, self-tolerance, and CD8+ T-cell activation. TAP binding protein, related (TAPBPR), a widely expressed tapasin homolog, is not part of the classical MHC-I peptide-loading complex (PLC). Using recombinant MHC-I molecules, we show that TAPBPR binds HLA-A*02:01 and several other MHC-I molecules that are either peptide-free or loaded with low-affinity peptides. Fluorescence polarization experiments establish that TAPBPR augments peptide binding by MHC-I. The TAPBPR/MHC-I interaction is reversed by specific peptides, related to their affinity. Mutational and small-angle X-ray scattering (SAXS) studies confirm the structural similarities of TAPBPR with tapasin. These results support a role of TAPBPR in stabilizing peptide-receptive conformation(s) of MHC-I, permitting peptide editing.

scholarly journals Nef Obtained from Individuals with HIV-1 Vary in Their Ability to Antagonize SERINC3- and SERINC5-Mediated HIV-1 Restriction

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 423
Author(s):  
Zita Kruize ◽  
Ad C. van Nuenen ◽  
Stan W. van Wijk ◽  
Arginell F. Girigorie ◽  
Karel A. van Dort ◽  
...  
Keyword(s):  
Disease Progression ◽  
Class I Mhc ◽  
Mhc I ◽  
Surface Molecules ◽  
Histocompatibility Complex ◽  
Naturally Occurring ◽  
Multiple Amino Acid ◽  
The Impact ◽  
Increased Activity ◽  
Hiv 1

Nef is a multifunctional viral protein that has the ability to downregulate cell surface molecules, including CD4 and major histocompatibility complex class I (MHC-I) and, as recently shown, also members of the serine incorporator family (SERINC). Here, we analyzed the impact of naturally occurring mutations in HIV-1 Nef on its ability to counteract SERINC restriction and the clinical course of infection. HIV-1 Nef sequences were obtained from 123 participants of the Amsterdam Cohort Studies and showed multiple amino acid variations and mutations. Most of the primary Nef proteins showed increased activity to counteract SERINC3 and SERINC5 as compared to NL4-3 Nef. Several mutations in Nef were associated with either an increased or decreased infectivity of Bal26-pseudotyped HIV-1 produced in the presence of SERINC3 or SERINC5. The 8R, 157N and R178G Nef mutations were shown to have an effect on disease progression. Survival analysis showed an accelerated disease progression of individuals infected with HIV-1 carrying arginine or asparagine at position 8 or 157 in Nef, respectively, or the R178G Nef mutation. Here, we observed that naturally occurring mutations in Nef affect the ability of Nef to counteract SERINC3- and SERINC5-mediated inhibition of viral infectivity. The majority of these Nef mutations had no significant effect on HIV-1 pathogenesis and only the 8R, 157N and R178G mutations were associated with disease course.

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 Nef-Induced CD4 and Major Histocompatibility Complex Class I (MHC-I) Down-Regulation Are Governed by Distinct Determinants: N-Terminal Alpha Helix and Proline Repeat of Nef Selectively Regulate MHC-I Trafficking

1999 ◽  
Vol 73 (3) ◽  
pp. 1964-1973 ◽  
Author(s):  
Aram Mangasarian ◽  
Vincent Piguet ◽  
Jen-Kuei Wang ◽  
Yen-Liang Chen ◽  
Didier Trono
Keyword(s):  
Major Histocompatibility Complex ◽  
Alpha Helix ◽  
Class I ◽  
Major Histocompatibility ◽  
Coated Pits ◽  
Down Regulation ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Hiv 1

ABSTRACT The Nef protein of primate lentiviruses triggers the accelerated endocytosis of CD4 and of class I major histocompatibility complex (MHC-I), thereby down-modulating the cell surface expression of these receptors. Nef acts as a connector between the CD4 cytoplasmic tail and intracellular sorting pathways both in the Golgi and at the plasma membrane, triggering the de novo formation of CD4-specific clathrin-coated pits (CCP). The downstream partners of Nef in this event are the adapter protein complex (AP) of CCP and possibly a subunit of the vacuolar ATPase. Whether Nef-induced MHC-I down-regulation stems from a similar mechanism is unknown. By comparing human immunodeficiency virus type 1 (HIV-1) Nef mutants for their ability to affect either CD4 or MHC-I expression, both in transient-transfection assays and in the context of HIV-1 infection, it was determined that Nef-induced CD4 and MHC-I down-regulation constitute genetically and functionally separate properties. Mutations affecting only CD4 regulation mapped to residues previously shown to mediate the binding of Nef to this receptor, such as W57 and L58, as well as to an AP-recruiting dileucine motif and to an acidic dipeptide in the C-terminal region of the protein. In contrast, mutation of residues in an alpha-helical region in the proximal portion of Nef and amino acid substitutions in a proline-based SH3 domain-binding motif selectively affected MHC-I down-modulation. Although both the N-terminal alpha-helix and the proline-rich region of Nef have been implicated in recruiting Src family protein kinases, the inhibitor herbimycin A did not block MHC-I down-regulation, suggesting that the latter process is not mediated through an activation of this family of tyrosine kinases.

scholarly journals Identification of Cryptic MHC I–restricted Epitopes Encoded by HIV-1 Alternative Reading Frames

2004 ◽  
Vol 199 (8) ◽  
pp. 1053-1063 ◽  
Author(s):  
Sylvain Cardinaud ◽  
Arnaud Moris ◽  
Michèle Février ◽  
Pierre-Simon Rohrlich ◽  
Laurence Weiss ◽  
...  
Keyword(s):  
Viral Proteins ◽  
Open Reading Frames ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Alternative Reading Frames ◽  
Anti Hiv ◽  
Alternative Reading ◽  
Reading Frames ◽  
Hiv 1

Human immunodeficiency virus (HIV) 1 major histocompatibility complex (MHC) I–restricted epitopes are widely believed to be derived from viral proteins encoded by primary open reading frames. However, the HIV-1 genome contains alternative reading frames (ARFs) potentially encoding small polypeptides. We have identified a panel of epitopes encoded by ARFs within the gag, pol, and env genes. The corresponding epitopic peptides were immunogenic in mice humanized for MHC-I molecules. In addition, cytotoxic T lymphocytes recognizing these epitopes were found in HIV-infected patients. These results reveal the existence of atypical mechanisms of HIV-1 epitope generation. They indicate that the repertoire of epitopes recognized by the cellular anti–HIV-1 immune response is broader than initially thought. This should be taken into account when designing vaccine strategies aimed at activating these responses.

scholarly journals Light control of the peptide-loading complex synchronizes antigen translocation and MHC I trafficking

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jamina Brunnberg ◽  
Valentina Herbring ◽  
Esteban Günther Castillo ◽  
Heike Krüger ◽  
Ralph Wieneke ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Antigen Processing ◽  
Adaptive Immune Response ◽  
Class I Mhc ◽  
Mhc I ◽  
Atp Binding Site ◽  
Histocompatibility Complex ◽  
Peptide Loading ◽  
Cellular Pathways ◽  
Cancerous Cells

AbstractAntigen presentation via major histocompatibility complex class I (MHC I) molecules is essential to mount an adaptive immune response against pathogens and cancerous cells. To this end, the transporter associated with antigen processing (TAP) delivers snippets of the cellular proteome, resulting from proteasomal degradation, into the ER lumen. After peptide loading and editing by the peptide-loading complex (PLC), stable peptide-MHC I complexes are released for cell surface presentation. Since the process of MHC I trafficking is poorly defined, we established an approach to control antigen presentation by introduction of a photo-caged amino acid in the catalytic ATP-binding site of TAP. By optical control, we initiate TAP-dependent antigen translocation, thus providing new insights into TAP function within the PLC and MHC I trafficking in living cells. Moreover, this versatile approach has the potential to be applied in the study of other cellular pathways controlled by P-loop ATP/GTPases.

Ligand Design for Specific MHC Class I Molecules on the Cell Surface

2020 ◽  
Author(s):  
Xizheng Sun ◽  
Reika Tokunaga ◽  
Yoko Nagai ◽  
Ryo Miyahara ◽  
Akihiro Kishimura ◽  
...  
Keyword(s):  
Cell Surface ◽  
Mhc Class I ◽  
Targeted Delivery ◽  
Peptide Ligands ◽  
Class I ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
High Binding Affinity ◽  
Mhc Class I Molecules

<p><a></a><a></a><a>We have validated that ligand peptides designed from antigen peptides could be used for targeting specific major histocompatibility complex class I (MHC-I)</a> molecules on cell surface. To design the ligand peptides, we used reported antigen peptides for each MHC-I molecule with high binding affinity. From the crystal structure of the peptide/MHC-I complexes, we determined a modifiable residue in the antigen peptides and replaced this residue with a lysine with an ε-amine group modified with functional molecules. The designed ligand peptides successfully bound to cells expressing the corresponding MHC-I molecules via exchange of peptides bound to the MHC-I. We demonstrated that the peptide ligands could be used to transport a protein or a liposome to cells expressing the corresponding MHC-I. The present strategy may be useful for targeted delivery to cells overexpressing MHC-I, which have been observed autoimmune diseases.</p>

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