Autophagy and Infections

Projects

The projects of the team focus on the role of autophagy during infections, mainly HIV-1 infection.

1. Autophagy and AIDS
In HIV-1-infected patients, CD4 T lymphocyte depletion is mainly due to apoptosis in bystander, uninfected CD4 T lymphocytes, since the degree of cell loss largely exceeds the number of infected cells. We demonstrated that autophagy is triggered during HIV-1 entry by the fusion of the viral and target cell membranes and that this mechanism is responsible for apoptosis of the bystander CD4 T cells. Autophagy is thus directly involved in HIV-1-induced immunodeficiency. The aim is now to study the pathways that are activated by the membrane fusion and that lead to autophagy. We also want to decipher the link between autophagy and apoptosis, a highly debated subject among the scientific community, which, during HIV-1 infection, plays an essential physiopathological role.

2. Autophagy: an antiviral mechanism counteracted by HIV-1 to favour its own replication
Autophagy can be a selective degradative mechanism by specifically targeting proteins or organelles through adaptor proteins. The team has shown very recently that autophagy is an anti-HIV-1 process by specifically degrading Tat, a viral protein essential for HIV-1 replication. To counteract this very powerful defence mechanism, several viral proteins, including Vif, can block autophagy. Results from a yeast two-hybrid screen indicate that all the HIV-1 proteins interact with several autophagy proteins (ATGs). We are now studying the role of Vpr in the regulation of autophagy.
  
              
Summary diagram of the projects 1 and 2

3. Autophagy and immune responses in dendritic cells during their infection by HIV-1
Autophagy and endocytosis pathways are important during HIV-1 entry into dendritic cells (DCs), with the formation of “immunoamphisomes” that regulate both the innate and adaptive immune responses. Several receptors, including DC-SIGN, could be involved in this process. The aim is now to elucidate the first steps of HIV-1 entry and the role of autophagy at this level. The impact of autophagy on the innate and adaptive immune responses and the relationship between HIV-1 and autophagy are also currently analysed in different DC subtypes. The ultimate goal is to reinforce the immune functions of the DCs during a viral infection by modulating autophagy.
 


4. Antiviral mechanisms in different DC subtypes
Very powerful restriction mechanisms have been set up by the cells to counteract the viral infections. Several DC subtypes cannot be infected by HIV-1 but the mechanisms involved are still unknown. We are investigating the restriction mechanisms that impede HIV-1 infection of several DC subtypes in comparison with those acting in monocyte-derived DCs using innovative high-throughput screening

2017

Vergne I, Lafont F, Espert L, Esclatine A, Biard-Piechaczyk M. Autophagy, ATG proteins and infectious diseases. Med Sci (Paris). 2017 Mar;33(3):312-318.

Gómez-Mora E, Robert-Hebmann V, García E, Massanella M, Clotet B, Cabrera C, Blanco J, Biard-Piechaczyk M. Brief Report: Impaired CD4 T-Cell Response to Autophagy in Treated HIV-1-Infected Individuals. J Acquir Immune Defic Syndr. 2017 Feb 1;74(2):201-205

 

2016

Klionsky DJ, Abdelmohsen, … Biard- Piechaczyk  M, … Espert L et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016 Apr;8(4):445-544.

Czubala MA, Finsterbusch K, Ivory MO, Mitchell JP, Ahmed Z, Shimauchi T, Karoo ROS, Coulman SA, Gateley C, Birchall JC, Blanchet FP, Piguet V. TGFβ Induces a SAMHD1-Independent Post-Entry Restriction to HIV-1 Infection of Human Epithelial Langerhans Cells. J Invest Dermatol. 2016 Oct;136(10):1981-1989.

Coulon PG, Richetta C, Rouers A, Blanchet FP, Urrutia A, Guerbois M, Piguet V, Theodorou I, Bet A, Schwartz O, Tangy F, Graff-Dubois S, Cardinaud S, Moris A. HIV-Infected Dendritic Cells Present Endogenous MHC Class II-Restricted Antigens to HIV-Specific CD4+ T Cells. J Immunol. 2016 Jul 15;197(2):517-32.

Caucheteux SM, Mitchell JP, Ivory MO, Hirosue S, Hakobyan S, Dolton G, Ladell K, Miners K, Price DA, Kan-Mitchell J, Sewell AK, Nestle F, Moris A, Karoo RO, Birchall JC, Swartz MA, Hubbel JA, Blanchet FP, Piguet V. Polypropylene Sulfide Nanoparticle p24 Vaccine Promotes Dendritic Cell-Mediated Specific Immune Responses against HIV-1. J Invest Dermatol. 2016 Jun;136(6):1172-81.

 

2015

Borel S., Robert-Hebmann V., Alfaisal J., Jain A., Faure M., Espert L., Chaloin L., Paillart J. C., Johansen T., Biard-Piechaczyk M. HIV-1 Vif interacts with LC3 and inhibits autophagy. AIDS. 29:275–286.

Sagnier S., Daussy C.F., Beaumelle B., Borel S., Robert-Hebmann V., Faure M., Blanchet F.P., Biard-Piechaczyk M., Espert L.. Autophagy restricts HIV-1 infection by selectively degrading Tat in CD4 T lymphocytes. Journal of Virology. 89(1):615-25. Article online in Global Medical Discovery (https://globalmedicaldiscovery.com/)

Papin L., Daussy CF., Alfaisal J., Espert L., Blanchet FP., Blanco J., Biard-Piechaczyk M. Autophagy and HIV infection. Encyclopedia of AIDS.

María-Soledad V., de Armas-Rillo L., Barroso-González J., Ziglio S., Batisse J., Dubois N., Marrero-Hernández S., Borel S., García-Expósito L., Biard-Piechaczyk M., Paillart JC., Valenzuela-Fernández A. The HDAC6/APOBEC3G complex regulates HIV-1 infectiveness by inducing Vif autophagic degradation. Retrovirology. 12 :53.

Espert L., Beaumelle B., Vergne I. Autophagy in Mycobacterium tuberculosis and HIV infections. Microbiology. Front Cell Infect Microbiol. 2;5:49.

Blanchet F.P.. Inflammasome and HIV. Encyclopedia of AIDS.

Daussy CF, Beaumelle B, Espert L. Autophagy restricts HIV-1 infection. Oncotarget. 2015 Aug 28;6(25):20752-3.

 

2014

Loukil A., Zonca M., Rebouissou C., Baldin V., Coux O., Biard-Piechaczyk M., Blanchard JM., Peter M. High resolution live cell imaging reveals novel cyclin A2 degradation foci involving autophagy. J Cell Sci. 127:2145-2150.

Alfaisal J., Daussy C.F., Blanchet F.P., Espert L., Salinas S., Biard-Piechaczyk M. To eat or not to eat: the intricate relationship between autophagy and HIV-1. Current Topics in Virology. 12:23-51.

Morgan AH., Hammond VJ., Sakoh-Nakatogawa M., Ohsumi Y., Thomas CP., Blanchet F., Piguet V., Kiselyov K., O'Donnell VB.. A novel role for 12/15-lipoxygenase in regulating autophagy. Redox Biol. 4C:40-47.

Fielding CA., Aicheler R., Stanton RJ., Wang EC., Han S., Seirafian S., Davies J., McSharry BP., Weekes MP., Antrobus PR., Prod'homme V., Blanchet FP., Sugrue D., Cuff S., Roberts D., Davison AJ., Lehner PJ., Wilkinson GW., Tomasec P. Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation. 2014. PLoS Pathog. 10:e1004058.

 

2013

Kaur I., Puri M., Ahmed Z., Blanchet F.P., Mangeat B., Piguet V. Inhibition of HIV-1 replication by balsamin, a ribosome inactivating protein of Momordica balsamina. PLoS One. 8:e73780.

Espert L. and Biard-Piechaczyk M. Induction of Autophagy in HIV-1-Uninfected Cells: Role of Fusogenic Activity of gp41. Book chapter, Elsevier Publishing Company. Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, and Infection. Volume 2 - Role in General Diseases. Editor : M Hayat.

Blanchet FP, Stalder R, Czubala M, Lehmann M, Rio L, Mangeat B, Piguet V. TLR-4 engagement of dendritic cells confers a BST-2/tetherin-mediated restriction of HIV-1 infection to CD4+ T cells across the virological synapse. Retrovirology. 2013 Jan 11;10:6. doi: 10.1186

 

2012

Klionsky DJ., … Biard-Piechaczyk M…. Espert L…(alphabetical order). Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy. Autophagy 8:4, 1–100.

Eekels J.M., Sagnier S., Geerts D., Jeeninga R .E., Biard-Piechaczyk M., Berkhout B. Inhibition of HIV-1 replication with stable RNAi-mediated knockdown of autophagy factors. Virol. J. 9:69. “Highly accessed”

Biard-Piechaczyk M., Espert L., Borel S., De Bettignies G., Coux O. HIV-1, Ubiquitin and Ubiquitin-like proteins: the dialectic interactions of a virus with a sophisticated network of post-translational modifications. Biol. Cell. 104, 1–24

Borel S., Espert L., Biard-Piechaczyk M.. Macroautophagy regulation during HIV-1 infection of CD4+ T cells and macrophages. Front. Immunol. 3:97.

 

2011

Sagnier S., Biard-Piechaczyk M., Espert L. Autophagie. Chapitre de livre : Ubiquitine/Ubiquitine-like/protéasome publié aux éditions Lavoisier.

Sitbon M., Biard-Piechaczyk M., Robert V., Briant L., Köhler S., Labesse G., Devaux C.. Montpellier Infectious Diseases (MID): 1st Annual Meeting. Infect Genet Evol. 11(7):1493-8.

Pombo-Grégoire I., Borel S., Richetta C., Meyniel L., Pradezynski F., Diaz O., Deloire A., Le Breton M., Azocar O., Mangeot P.E., Navratil V., Joubert P.E., Flacher M., Vidalain P.O., André P., Lotteau V., Biard-Piechaczyk M., Rabourdin-Combe C., Faure M. IRGM is a common target of RNA viruses that subvert the autophagy network. PLoS Pathog. 7(12): e1002422

Blanchet, F., Moris, A., Mitchell, J.P., and Piguet, V. A look at HIV journey: from dendritic cells to infection spread in CD4(+) T cells. Current opinion in HIV and AIDS 6, 391-397.

Lehmann, M., Rocha, S., Mangeat, B., Blanchet, F., Uji, I.H., Hofkens, J., and Piguet, V. (2011). Quantitative multicolor super-resolution microscopy reveals tetherin HIV-1 interaction. PLoS pathogens 7, e1002456.

Nikolic, D.S., Lehmann, M., Felts, R., Garcia, E., Blanchet, F.P., Subramaniam, S., and Piguet, V. HIV-1 activates Cdc42 and induces membrane extensions in immature dendritic cells to facilitate cell-to-cell virus propagation. Blood 118, 4841-4852.

 

2010

Blanchet, F.P., Moris, A., Nikolic, D.S., Lehmann, M., Cardinaud, S., Stalder, R., Garcia, E., Dinkins, C., Leuba, F., Wu, L., et al. Human immunodeficiency virus-1 inhibition of immunoamphisomes in dendritic cells impairs early innate and adaptive immune responses. Immunity 32, 654-669.

Blanchet, F.P., and Piguet, V. Immunoamphisomes in dendritic cells amplify TLR signaling and enhance exogenous antigen presentation on MHC-II. Autophagy 6, 816-818.

Stalder, R., Blanchet, F., Mangeat, B., and Piguet, V. Arsenic modulates APOBEC3G-mediated restriction to HIV-1 infection in myeloid dendritic cells. Journal of leukocyte biology 88, 1251-1258.

Local :

  • L. CHALOIN, IRIM, UMR9004 CNRS/UM, Montpellier.
  • B. BEAUMELLE et JM. MESNARD, IRIM, UMR9004 CNRS/UM, Montpellier.
  • C. GOUJON – IRIM, UMR9004 CNRS/UM, Montpellier
  • M. BENKIRANE, IGH, CNRS UPR1142, Montpellier
  • S. NISOLE, IRIM, UMR9004 CNRS/UM, Montpellier.
  • P. VAN de PERRE, U1058 INSERM/UM, Montpellier

National :

  • CODOGNO, INEM, Paris
  • FAURE, CIRI, Lyon
  • N. MAZURE, Unice, Nice
  • A. MORIS, CIMI, Paris
  • I. VERGNE, IPBS, Toulouse
  • D. FENARD, Genethon, Evry

International :

  • J. BLANCO, IrsiCaixa Foundation, Barcelona, Spain
  • A. FERNANDEZ-VALENZUELA, University of La Laguna, Tenerife, Spain
  • V. HAUCKE and M. LEHMANN, FMP, Berlin, Germany
  • T. JOHANSEN, UiT, Tromso, Norway
  • S. TOOZE, The Francis Crick Institute, Londres, UK
  • K. TOKUNAGA, NIID, Tokyo, Japan

Membres de l’équipe

Martine Biard – Team Leader - DR2 CNRS - HDR

Fabien Blanchet – CR INSERM - HDR

Lucile Espert – CR CNRS - HDR

Véronique Robert-Hebmann - IR - CNRS

Ghizlane Maarifi – Post-doctoral researcher - LABEX EpiGenMed

Mathilde Galais – PhD Student - LABEX EpiGenMed

 

 

 

Alumni

PhD Students:

2014-20147


Laure PAPIN –
Sidaction

Characterization of the early steps of HIV-1 entry in Dendritic Cells

 

2013-2016


Jamal ALFAISAL
– ERASMUS MUNDUS

Autophagy inhibition in HIV-1-infected CD4 T Lymphocytes. The role of Vif and Vpr accessory proteins.



Coralie DAUSSY
– MRT Scholarship

Role of selective autophagy during HIV-1 infection of CD4 T Lymphocytes

 

2012-2015


Sophie BOREL
MRT Scholarship

Role of autophagy in HIV-1-infected CD4 T lymphocytes

 

2011-2015


Sophie SAGNIER – ANRS/Sidaction

Autophagy, une mechanism involved in HIV-1 physiopathology

 

Stagiaires :

2017

Justine LAGISQUET – M2 (Parcours) – Montpellier

Alice MACHADO – M2 (Parcours) - Montpellier

 

2016

Mathilde GALAIS – M2 Université Libre de Bruxelles – Belgique

Sixtine FAURE – M2 (parcours) - Montpellier

 

2015

Andrea WERKEYN - L2 Biologie parcours Ingénierie de la Santé Université de Montpellier

Lucille PENALVA-MOUSSET – L3 Physiologie animale et neurosciences, Université de Montpellier

 

2014

Brieux CHARDES – 1ère année du Diplôme de Formation Approfondie en Sciences Pharmaceutiques (DFASP-1), Faculté de Pharmacie, Université de Montpellier

Sophie BRANKA – L3 Biologie Cellulaire et physiologie, Université de Toulouse

 

2013

Laure PAPIN, M2 Interactions micro-organismes, hôtes et environnement (IMHE), Université de Montpellier

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Team Leader


Martine Biard

DR2 CNRS, HDR

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In Brief

Autophagy is a lysosomal degradation process involved in cellular homeostasis and in innate and adaptative immunities against pathogens.
Our team studies the role of autophagy during viral infections, in particular HIV-1.EnregistrerEnregistrer

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IRIM
Institut de Recherche en Infectiologie de Montpellier
UMR 9004 - CNRS / UM
1919 route de Mende - 34293 Montpellier cedex 5
FRANCE

 

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