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 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 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 Endotoxemia Is Associated with Altered Innate and Adaptive Immune Responses in Untreated HIV-1 Infected Individuals

PLoS ONE ◽  
2011 ◽  
Vol 6 (6) ◽  
pp. e21275 ◽  
Author(s):  
Anne Roslev Bukh ◽  
Jesper Melchjorsen ◽  
Rasmus Offersen ◽  
Jens Magnus Bernth Jensen ◽  
Lars Toft ◽  
...  
Keyword(s):  
Immune Responses ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Hiv 1

scholarly journals Host Genetic and Viral Determinants of HIV-1 RNA Set Point among HIV-1 Seroconverters from Sub-Saharan Africa

2014 ◽  
Vol 89 (4) ◽  
pp. 2104-2111 ◽  
Author(s):  
Romel D. Mackelprang ◽  
Mary Carrington ◽  
Katherine K. Thomas ◽  
James P. Hughes ◽  
Jared M. Baeten ◽  
...  
Keyword(s):  
Immune Responses ◽  
Human Leukocyte ◽  
Sub Saharan Africa ◽  
Host Responses ◽  
Adaptive Immune Responses ◽  
Hla Alleles ◽  
Set Point ◽  
Transmission Potential ◽  
Adaptive Immune ◽  
Hiv 1

ABSTRACTWe quantified the collective impact of source partner HIV-1 RNA levels, human leukocyte antigen (HLA) alleles, and innate responses through Toll-like receptor (TLR) alleles on the HIV-1 set point. Data came from HIV-1 seroconverters in African HIV-1 serodiscordant couple cohorts. Linear regression was used to determine associations with set point andR2to estimate variation explained by covariates. The strongest predictors of set point were HLA alleles (B*53:01, B*14:01, and B*27:03) and plasma HIV-1 levels of the transmitting partner, which explained 13% and 10% of variation in set point, respectively. HLA-A concordance between partners and TLR polymorphisms (TLR2rs3804100 andTLR7rs179012) also were associated with set point, explaining 6% and 5% of the variation, respectively. Overall, these factors and genital factors of the transmitter (i.e., male circumcision, bacterial vaginosis, and use of acyclovir) explained 46% of variation in set point. We found that both innate and adaptive immune responses, together with plasma HIV-1 levels of the transmitting partner, explain almost half of the variation in viral load set point.IMPORTANCEAfter HIV-1 infection, uncontrolled virus replication leads to a rapid increase in HIV-1 concentrations. Once host immune responses develop, however, HIV-1 levels reach a peak and subsequently decline until they reach a stable level that may persist for years. This stable HIV-1 set point represents an equilibrium between the virus and host responses and is predictive of later disease progression and transmission potential. Understanding how host and virus factors interact to determine HIV-1 set point may elucidate novel mechanisms or biological pathways for treating HIV-1 infection. We identified host and virus factors that predict HIV-1 set point in people who recently acquired HIV-1, finding that both innate and adaptive immune responses, along with factors that likely influence HIV-1 virulence and inoculum, explain ∼46% of the variation in HIV-1 set point.

scholarly journals Dendritic Cells and Their Multiple Roles during Malaria Infection

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Kelly N. S. Amorim ◽  
Daniele C. G. Chagas ◽  
Fernando B. Sulczewski ◽  
Silvia B. Boscardin
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Antigen Presentation ◽  
Causative Agent ◽  
Malaria Infection ◽  
Multiple Roles ◽  
Key Factors ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

Dendritic cells (DCs) play a central role in the initiation of adaptive immune responses, efficiently presenting antigens to T cells. This ability relies on the presence of numerous surface and intracellular receptors capable of sensing microbial components as well as inflammation and on a very efficient machinery for antigen presentation. In this way, DCs sense the presence of a myriad of pathogens, includingPlasmodiumspp., the causative agent of malaria. Despite many efforts to control this infection, malaria is still responsible for high rates of morbidity and mortality. Different groups have shown that DCs act duringPlasmodiuminfection, and data suggest that the phenotypically distinct DCs subsets are key factors in the regulation of immunity during infection. In this review, we will discuss the importance of DCs for the induction of immunity against the different stages ofPlasmodium, the outcomes of DCs activation, and also what is currently known aboutPlasmodiumcomponents that trigger such activation.

scholarly journals Innate and Adaptive Immune Responses Both Contribute to Pathological CD4 T Cell Activation in HIV-1 Infected Ugandans

PLoS ONE ◽  
2011 ◽  
Vol 6 (4) ◽  
pp. e18779 ◽  
Author(s):  
Michael A. Eller ◽  
Kim G. Blom ◽  
Veronica D. Gonzalez ◽  
Leigh Anne Eller ◽  
Prossy Naluyima ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Hiv 1

scholarly journals Restriction by SAMHD1 Limits cGAS/STING-Dependent Innate and Adaptive Immune Responses to HIV-1

Cell Reports ◽  
2016 ◽  
Vol 16 (6) ◽  
pp. 1492-1501 ◽  
Author(s):  
Jonathan Maelfait ◽  
Anne Bridgeman ◽  
Adel Benlahrech ◽  
Chiara Cursi ◽  
Jan Rehwinkel
Keyword(s):  
Immune Responses ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Hiv 1

scholarly journals Transcriptome Analysis Shows That IFN-I Treatment and Concurrent SAV3 Infection Enriches MHC-I Antigen Processing and Presentation Pathways in Atlantic Salmon-Derived Macrophage/Dendritic Cells

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 464 ◽  
Author(s):  
Cheng Xu ◽  
Øystein Evensen ◽  
Hetron Mweemba Munang’andu
Keyword(s):  
Atlantic Salmon ◽  
Immune Responses ◽  
Transcriptome Analysis ◽  
Antigen Processing ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Mhc I ◽  
Mhc Ii ◽  
Adaptive Immune ◽  
Antigen Processing And Presentation

Type I interferons (IFNs) have been shown to play an important role in shaping adaptive immune responses in addition to their antiviral properties in immune cells. To gain insight into the impact of IFN-I-induced pathways involved in early adaptive immune responses, i.e., antigen-presenting pathways, in an Atlantic salmon-derived (Salmo salar L.) macrophage cell line (TO-cells), we used a comparative de novo transcriptome analysis where cells were treated with IFN-I or kept untreated and concurrently infected with salmonid alphavirus subtype 3 (SAV3). We found that concurrent treatment of TO-cells with IFN-I and SAV3 infection (SAV3/IFN+) significantly enriched the major histocompatibility complex class I (MHC-I) pathway unlike the non-IFN-I treated TO-cells (SAV3/IFN−) that had lower expression levels of MHC-I pathway-related genes. Genes such as the proteasomal activator (PA28) and β-2 microglobulin (β2M) were only differentially expressed in the SAV3/IFN+ cells and not in the SAV3/IFN− cells. MHC-I pathway genes like heat shock protein 90 (Hsp90), transporter of antigen associated proteins (TAPs) and tapasin had higher expression levels in the SAV3/IFN+ cells than in the SAV3/IFN− cells. There were no MHC-II pathway-related genes upregulated in SAV3/IFN+-treated cells, and cathepsin S linked to the degradation of endosomal antigens in the MHC-II pathway was downregulated in the SAV3/IFN− cells. Overall, our findings show that concurrent IFN-I treatment of TO-cells and SAV3 infection enriched gene expression linked to the MHC-I antigen presentation pathway. Data presented indicate a role of type I IFNs in strengthening antigen processing and presentation that may facilitate activation particularly of CD8+ T-cell responses following SAV3 infection, while SAV3 infection alone downplayed MHC-II pathways.

Antigen presentation and adaptive immune responses in skin

2019 ◽  
Vol 31 (7) ◽  
pp. 423-429 ◽  
Author(s):  
Tetsuya Honda ◽  
Gyohei Egawa ◽  
Kenji Kabashima
Keyword(s):  
Immune Responses ◽  
Antigen Presentation ◽  
Immune Cells ◽  
Adaptive Immune Response ◽  
Short Review ◽  
Contact Hypersensitivity ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Draining Lymph Nodes

Abstract For the induction of adequate cutaneous immune responses, the antigen presentation and recognition that occur in both the skin and skin-draining lymph nodes are essential. In each process of cutaneous immune responses, several distinct subsets of immune cells, including dendritic cells and T cells, are involved, and they elicit their respective functions in a harmonious manner. For example, in the elicitation phase of cutaneous acquired immunity, immune cells form a specific lymphoid structure named inducible skin-associated lymphoid tissue (iSALT) to facilitate efficient antigen presentation in situ. In this short review, we will overview the mechanisms of how antigens are presented and how cutaneous adaptive immune responses are conducted in the skin, especially focusing on contact hypersensitivity, a prototypic adaptive immune response in the skin.

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