SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells
| Autor: | Arnaud Moris, Françoise Porrot, Julia G. Prado, Timothée Bruel, Sylvain Cardinaud, Diana Ayinde, Olivier Schwartz |
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| Přispěvatelé: | Virus et Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche sur le Vaccin (VRI), PRES Université Paris-Est-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), IrsiCaixa (Institut de Recerca de la Sida), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), D.A. was supported by a postdoctoral fellowship from ANRS and the FP7 HIT Hidden HIV program. The work was supported by grants from the ANRS, SIDACTION, AREVA Foundation, the Labex IBEID program, the FP7 program, HIT Hidden HIV (Health-F3-2012-305762), and Institut Pasteur, as well as by the Vaccine Research Institute, Investissements d'Avenir program (ANR-10-LABX-77).We thank the Programme EVA Centre for AIDS Reagents and the NIH AIDS Reagent Program for the gifts of reagents., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), European Project: 305762,HEALTH,FP7-HEALTH-2012-INNOVATION-1,HIT HIDDEN HIV(2012), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'Immunologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2015 |
| Předmět: |
HIV Antigens
[SDV]Life Sciences [q-bio] Immunology Antigen presentation Cellular Response to Infection MESH: Monomeric GTP-Binding Proteins CD8-Positive T-Lymphocytes Major histocompatibility complex Microbiology SAM Domain and HD Domain-Containing Protein 1 03 medical and health sciences 0302 clinical medicine Antigen Viral entry Virology Humans Cytotoxic T cell Cells Cultured Monomeric GTP-Binding Proteins 030304 developmental biology Antigen Presentation [SDV.GEN]Life Sciences [q-bio]/Genetics 0303 health sciences MESH: Humans biology MESH: Antigen Presentation Dendritic Cells MESH: HIV Antigens/immunology 3. Good health CTL [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology MESH: CD8-Positive T-Lymphocytes/immunology MESH: T-Lymphocytes Cytotoxic/immunology Insect Science HIV-1 Pseudotyping biology.protein [SDV.IMM]Life Sciences [q-bio]/Immunology MESH: HIV-1/immunology T-Lymphocytes Cytotoxic MESH: Cells Cultured MESH: Dendritic Cells/immunology 030215 immunology SAMHD1 |
| Zdroj: | Journal of Virology Journal of Virology, 2015, 89 (14), pp.6994-7006. ⟨10.1128/JVI.00069-15⟩ Journal of Virology, American Society for Microbiology, 2015, 89 (14), pp.6994-7006. ⟨10.1128/JVI.00069-15⟩ |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.00069-15 |
| Popis: | Monocyte-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. IMPORTANCE Upon 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. |
| Databáze: | OpenAIRE |
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