Players in the Pathogenesis of the Retroviral Infections

PPRI Team

The team

The team in March 2018

 

Topics

Roles of HBZ in HTLV-1-induced Leukemia

Human T-cell leukemia virus type 1 (HTLV-1) is the first retrovirus found to induce diseases in human. HTLV-1 causes an aggressive neoplastic disease, adult T-cell leukemia (ATL), neurodegenerative diseases, such as HTLV-1 associated myelopathy/tropical spastic paraparesis (TSP/HAM) and inflammatory diseases such as uveitis. HTLV-1 infects around 15 million people in the world and is mainly endemic of the intertropical region like South America, Caribbean island, Africa and south japan. HTLV-1 is a complex retrovirus, which encodes regulatory genes (tax and rex) and several accessory genes, such as p30, p12, p13 and HTLV-1 bZIP factor (HBZ). Among them, tax is thought to play a central role in transformation of infected cells. However, since it is a major target of cytotoxic T-lymphocytes, its expression is often silenced in ATL cells to escape the host immune system. The HBZ gene, first characterized in our laboratory in 2002, is encoded by the minus strand of HTLV-1, and it contains a basic leucine zipper domain. Interestingly enough, while tax is repressed in infected cells, transcription of the HBZ gene was detected in all of the ATL cell lines and primary ATL cases. We have shown that HBZ is able to sustain its own expression in infected cells via a regulation loop with JunD and SP1. We have also shown that HBZ is able to transform cells in vitro.

 

Figure 1. Role of HBZ in the development of ATL

 

Our research on cellular and molecular mechanisms in the HBZ-induced pathogenesis are currently focusing on 2 Axes:

- We are investigating the importance of the interplays between HBZ and AP-1 pathway in HTLV-1 infected cells.

- In collaboration with clinicians, we are trying to understand the role of HBZ in the chemoresistance of ATL cells and to develop new therapeutic approaches against HBZ.

 

ASP, the antisense protein of HIV-1 : Evolution, Immunology, Cellular, and Viral impacts

Our researches focus on an unknown protein of HIV-1, ASP (Antisense Protein). We try to understand how this protein could participate in the pathogenesis of AIDS, including viral latency and chronicity. We use a variety of  approaches ranging from conventional virology, to cell biology, immunology, bioinformatics (Evolution and Conservation) and studies in infected patients.

HIV-1 produces  its conventional proteins from proviral DNA integrated into the genome of the infected cell, through the transcriptional activity of a promoter located in the 5' LTR (Long Terminal Repeat). The integrated genome also has a LTR (3' LTR) at its opposite end. Similarly to HTLV-1 with transcriptional activity leading to the production of the HBZ protein (cf the HBZ project), we showed that the 3’ LTR of HIV-1 has an antisense transcriptional activity (in the opposite direction to that of the 5' LTR) that allows ASP production.

 

 
   

ASP existence was first proposed in 1988, with the observation of an open reading frame on the antisense strand of the proviral genome overlapping the envelope gene (Barbeau et al, Trends microbiol, 2015).

 

 

 Figure 2. Genomic organization of the HIV-1 proviral DNA

 

We aim to understand the role of this protein in the pathogenesis of AIDS and to demonstrate that ASP should be considered the tenth gene of HIV-1. We previously characterized the transcript (Landry et al, Retrovirology, 2007), the cell population in which this protein is expressed (Laverdure et al, J.virol., 2012) and in vivo expression of ASP with the detection of an anti-ASP immune response in infected patients (Bet et al, Retrovirology, 2015).


Our current research especially focuses on:

- Cell biology approaches: ASP production, localization, and degradation (collaboration with Prof. B. Barbeau,Canada)

- ASP impact on viral replication in dendritic cells

- ASP impact on the immunological functions of the dendritic cell

- The evolutionary mechanisms and constraints of ASP in HIV-1 (with O. Gascuel and AM Chifolleau, LIRMM)

- ASP expression and the anti-ASP immune response in patients related to viral latency. (Collaboration with A. Moris, Cimi-Paris and Prof. P. Van de Perre, CHU Montpellier)

Role of extracellular HIV-1 Tat during AIDS

Within HIV-1 infected cells, the viral Tat protein enables the transcription of viral genes and viral multiplication. Nevertheless, despite the absence of signal sequence, most Tat is secreted (Rayne et al, EMBO J. 2010). Accordingly, Tat levels ranging from de 0.2 to 4 nM were observed in the sera of HIV-1 infected patients. We previously showed that, to be secreted, Tat is recruited to the plasma membrane by a very strong and specific interaction with phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2). This interaction requires the membrane insertion of Tat single Trp (Trp11) (Rayne et al, EMBO J. 2010).

We also showed that circulating Tat can enter uninfected cells by endocytosis, before translocating from endosomes to the cytosol using the cytosolic chaperone Hsp90 (Vendeville et al, Mol Biol Cell 2004). Indeed, at endosomal pH (pH < 6.0), Tat inserts into membranes using Trp side chain. We also identified Tat "low pH sensor" (Yezid et al, 2009). For details on Tat transcellular traffic, please see the review by Debaisieux et al, (Traffic 2012) whose key points are recapitulated in the figure 3.

 



Figure 3. Tat transcellular traffic



Circulating Tat can thus enter various type of cells and affect their biological activity. Hence, Tat acts as a viral toxin. Our studies also indicate that the very strong Tat-PI(4,5)P2 interaction enables Tat to interfere with the various machineries that uses this phosphoinositide to address proteins to the plasma membrane. It is actually the case for most membrane traffic involving the plasma membrane, and we indeed showed that Tat interferes with the regulated secretion of granules (SG on the Figure) by neuronal cells (Tryoen, et al, J Cell  Sci 2013), and phagocytosis mediated by Fc- or mannose-receptors that enable pathogen capture (Debaisieux et al, Nat Commun 2015). Tat target, i.e. the protein which recruitment is prevented by Tat, is different in these two machineries: annexine A2 in the case of neurosecretion and cdc42 for phagocytosis.

Our present projects aim to widen these results to other PI(4,5)P2-dependent machineries, as well as to elucidate the mechanisms of Tat secretion regulation and to develop inhibitors of extracellular Tat.

2018

  1. Gazon H, Barbeau B, Mesnard JM, Péloponèse JM Jr (2018). Hijacking of the AP-1 signaling pathway during development of ATL. Front. Microbiol. 2018 Jan 15;8:2686.

2017

  1. Cassan É, Arigon-Chifolleau AM, Mesnard JM, Gross A, Gascuel O. (2017). The tenth gene of HIV. Med Sci (Paris). 2017 May;33(5):484-485.
  2. Terol M, Gazon H, Lemasson I, Duc Dodon M, Barbeau B, Césaire R, Mesnard JM, Péloponèse JM (2017) HBZ-mediated shift of JunD from growth suppressor to tumor promoter in leukemic cells by inhibition of ribosomal protein S25 expression. Leukemia 2017 Oct;31(10):2235-2243.
  3. Jean-Baptiste D, Belrose G, Meniane JC, Lézin A, Jeannin S, Mesnard JM, Olindo S, Peloponese JM Jr*and Césaire R* (2017) Differential Effects of AZD-1208 and SMI-4a, Two Pim-1 Kinase Inhibitors on Primary HAM/TSP and ATL Cells. Ann Carcinog. 2017 2(1): 1008
  4. Beaumelle B, Tóth P, Malak OA, Chopard C, Loussouarn G, Vitale N. (2017) Phosphatidylinositol (4,5)-bisphosphate-mediated pathophysiological effect of HIV-1 Tat protein. Biochimie. 2017 Oct;141:80-85.

2016

  1. Gallo, R.C. ,  Willems, L.,  Hasegawa, H.,  Accolla, R.,  Bangham, C.,  Bazarbachi, A.,  Bertazzoni, U.,  De Freitas Carneiro-Proietti, A.B.,  Cheng, H.,  Chieco-Bianchi, L.,  Ciminale, V.,  Gessain, A.,  Gotuzzo, E.,  Hall, W,  Harford, J,  Hermine, O,  Jacobson, S.,  Macchi, B.,  Macpherson, C.  Mahieux, R.,  Matsuoka, M.,  McSweegan, E.,  Murphy, E.L.,  Péloponèse, J.-M.,  Reis, J.,  Simon, V.,  Tagaya, Y.,  Taylor, G.P.,  Watanabe, T.,  Yamano, Y. (2016) Screening transplant donors for HTLV-1 and -2. Blood Volume 128, Issue 26, 29 December 2016, Pages 3029-3031.
  2. Willems L, Hasegawa H, Accolla R, Bangham C, Bazarbachi A, Umberto Bertazzoni U, Carneiro-Proietti AB, Cheng H, Chieco-Bianchi L, Ciminale V, Coelho-dos-Reis Reis J, Esparza J, Gallo RC, Antoine Gessain A, Gotuzzo E, Hall W, Harford J, Hermine O o, Jacobson S , Macchi B, Macpherson C, Renaud Mahieux R, Matsuoka M, Murphy E, Peloponese JM, Simon V, Yutaka  Tagaya Y,Graham T , Watanabe T, Yamano Y (2016) Reducing the global burden of HTLV-1 infection: an agenda for research and action Antiviral Res. 2016 Nov 10. pii: S0166-3542(16)30625-8.
  3. Cassan E, Arigon-Chifolleau AM, Mesnard JM, Gross A, Gascuel O. (2016) Concomitant emergence of the antisense protein gene of HIV-1 and of the pandemic. Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):11537-11542.
  4. Gazon H, Belrose G, Terol M, Meniane JC, Mesnard JM, Césaire R, Peloponese JM Jr. (2016) Impaired expression of DICER and some microRNAs in HBZ expressing cells from acute adult T-cell leukemia patients. Oncotarget. 2016 May 4;7(21):30258-75
  5. Rayne F, Debaisieux S, Tu A, Chopard C, Tryoen-Toth P, Beaumelle B. (2016) Detecting HIV-1 Tat in Cell Culture Supernatants by ELISA or Western Blot.  Methods Mol Biol. 2016;1354:329-42.

 2015

  1. Mesnard J.-M., Barbeau B., Césaire R., and Péloponèse J.-M. (2015) Roles of HTLV-1 basic Zip Factor (HBZ) in Viral Chronicity and Leukemic Transformation. Potential New Therapeutic Approaches to Prevent and Treat HTLV-1-Related Diseases. Viruses 7: 6490-6505.
  2. Espert L., and Beaumelle B. (2015) Autophagy restricts HIV-1 infection. Oncotarget 6: 20752-20753
  3. Babon A, Wurceldorf T, Almunia C, Pichard S, Chenal A, Buhot C, Beaumelle B, and Gillet D. (2015) Bee venom phospholipase A2 as a membrane-binding vector for cell surface display or internalization of soluble proteins. Toxicon.
  4. Espert L., Beaumelle B., and Vergne I. (2015) Autophagy in Mycobacterium tuberculosis and HIV infections. Infect. Microbiol. 5: 49.
  5. Barbeau B. and Mesnard J.-M. (2015) Does chronic infection in retroviruses have a sense? Trends Microbiol. 23: 367-375.
  6. Debaisieux S., Lachambre S., Gross A., Mettling C., Besteiro S., Yezid H., Henaff D., Chopard C., Mesnard J.-M., and Beaumelle B. (2015) HIV-1 Tat inhibits phagocytosis by preventing the recruitment of Cdc42 to the phagocytic cup. Nat. Commun. 6: 6211. Recommended in F1000Prime as being of special significance in its field
  7. Sagnier S., Daussy C.F., Beaumelle B., Borel S., Robert-Hebmann V., Faure M., Blanchet F.P., Biard-Piechaczyk M. and Espert L. (2015) Autophagy restricts HIV-1 infection by selectively degrading Tat in CD4 T lymphocytes. J. Virol. 89: 615-625.
  8. Torresilla C., Mesnard J.-M., and Barbeau B. (2015) Reviving an old HIV-1 gene: the HIV-1 antisense protein. HIV Res. 13: 117-124.
  9. Bet A., Maze E.A., Bansal A., Sterrett S, Gross A., Samri A., Guihot A., Katlama C., Theodorou I., Mesnard J.-M., MorisA., Goepfert P.A., and Cardinaud S. (2015) The HIV-1 Antisense Protein (ASP) induces CD8 T cell responses during chronic infection. Retrovirology. 12: 15 (Highly accessed).

2014

  1. Arpin-André C, Laverdure S., Barbeau B., Gross A., and Mesnard J.-M. (2014) Construction of a reporter vector for analysis of bidirectional transcriptional activity of retrovirus LTR. Plasmid 74: 45-51.
  2. Lachambre S., Chopard C., and Beaumelle B. (2014) Preliminary characterization of nanotubes connecting T cells and their use by HIV-1. Biol. Cell. 106:394-404.
  3. Larocque E., André-Arpin C., Borowiak M., Lemay G., Switzer W.M., Duc Dodon M., Mesnard J.-M., and Barbeau B. (2014) Human T-cell Leukemia virus type 3 (HTLV-3) and HTLV-4 antisense transcripts-encoded proteins interact and transactivate Jun family-dependent transcription via their atypical bZIP motif. J. Virol. 88: 8956-8970.
  4. Polakowski N*., Térol M.*, Hoang K., NASH I., Laverdure S., Gazon H., Belrose G., Mesnard J.-M., Cesaire R., Péloponèse J.-M., and Lemasson I. (2014) HBZ stimulates BDNF/TrkB autocrine/paracrine signaling to promote survival of HTLV-1-infected T-cells. J. Virol. 88: 13482-13494. Co-first authors.

2013

  1. Tryoen-Tóth P., Beaumelle B., Bader M.F., Vitale N. (2013) HIV-associated cognitive disorder: Tat perturbs neurosecretion Med. Sci. (Paris) 29: 1069-1070.
  2. Barbeau B., Péloponèse J.-M., and Mesnard J.-M. (2013) Functional comparison of antisense proteins of HTLV-1 and HTLV-2 in viral pathogenesis. Frontiers Microbiol. 4: 226.
  3. Sarkis S., Belrose G., Péloponèse J.-M., Césaire R., Mesnard J.-M., and Gross A. (2013) Increased osteopontin expression in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patient cells is associated with IL-17 expression. Clin. Virol. 58: 295-298.
  4. Tryoen-Tóth P., Chasserot-Golaz S., Tu A., Gherib P., Bader M.-F., Beaumelle B., and Vitale N. (2013) HIV-1 Tat protein inhibits neurosecretion by binding to phosphatidylinositol 4,5-bisphosphate. Cell. Sci. 126: 454-463.
  5. Torresilla C., Larocque E., Landry S., Halin M., Coulombe Y., Masson J.-Y., Mesnard J.-M., and Barbeau B. (2013) Detection of the HIV-1 minus strand-encoded antisense protein and its association with autophagy. J. Virol. 87: 5089-5105.
  6. Borowiak M., Kuhlmann A.-S, Girard S., Gazzolo L., Mesnard J.-M., Jalinot P., and Duc Dodon M. (2013) HTLV-1 bZIP factor impedes the menin tumor suppressor and upregulates JunD-mediated transcription of the hTERT gene. Carcinogenesis 34: 2664-2672.
  7. Vitale N., Beaumelle B., Bader M.F., and Tryoen-Tóth P. (2013) HIV-1 Tat protein perturbs diacylglycerol production at the plasma membrane of neurosecretory cells during exocytosis. Commun Integr Biol. 6(5): e25145.

2012

  1. Laverdure S., Gross A., Clerc I., Arpin-André C., Beaumelle B., Barbeau B., and Mesnard J.-M. (2012) HIV-1 antisense transcription is preferentially activated in primary monocyte-derived cells. J. Virol. 86: 13785-13789.
  2. Wurm T., Wright D., Polakowski N., Mesnard J.-M., and Lemasson I. (2012) The HTLV-1-encoded protein HBZ directly inhibits the acetyl-transferase activity of p300/CBP. Nucleic Acids Res. 40: 5910-5925.
  3. Debaisieux S., Rayne F., Yezid H., and Beaumelle B. (2012) The ins and outs of HIV-1 Tat. Traffic 13: 355-63
  4. Gazon H., Lemasson I., Polakowski N., Césaire R., Matsuoka M., Barbeau B., Mesnard J.-M., and Peloponese J.-M. (2012) Human T-cell leukemia virus type 1 (HTLV-1) bZIP factor requires cellular transcription factor JunD to upregulate HTLV-1 antisense transcription from the 3' LTR. J. Virol. 86: 9070-9078.
  5. Macaire, Riquet A., Moncollin V., Biemont-Trescol M.-C., Duc Dodon M., Hermine O., Debaud A.L., Mahieux R., Mesnard J.-M., Pierre M., Gazzolo L., Bonnefoy N., and Valentin H. (2012) Tax-induced expression of the antiapoptotic Bfl-1 protein contributes to survival of HTLV-1-infected T-cells. J. Biol. Chem. 287: 21357-370.

2011

  1. Clerc I., Laverdure S., Torresilla C., Landry S., Borel S., Vargas A., Arpin-André C., Gay B., Briant L., Gross A., Barbeau B., and Mesnard J.-M. (2011) Polarized expression of the membrane ASP protein derived from HIV-1 antisense transcription in T cells. Retrovirology 8: 74 (Highly accessed).
  2. Belrose G., Gross A., Olindo S., Lezin A., Dueymes M., Komla-Soukha I., Smadja D., Tanaka Y., Willems L., Mesnard J.-M., Peloponese J.-M., and Césaire R. (2011) Effects of valproate on Tax and HBZ expression in HTLV-1 and HAM/TSP T lymphocytes. Blood 118: 2483-2491.
  3. Méré J., Chopard C., Bonhoure A., Morlon-Guyot J., and Beaumelle B. (2011) Increasing stability and toxicity of Pseudomonas exotoxin by attaching an antiproteasic Peptide. Biochemistry 50: 10052-10060.
  4. Barbeau and Mesnard J.-M. (2011). Making sense out of antisense transcription in Human T-cell lymphotropic viruses (HTLVs)? Viruses 3: 456-468.

2010

  1. Rayne F.*, Debaisieux S.*, Yezid H., Lin Y.-L., Mettling C., Konate K., Chazal N., Arold S.-T., Pugnière M., Sanchez F., Bonhoure A., Briant L., Loret E., Roy C., and Beaumelle B. (2010) Phosphatidylinositol-(4,5)-bisphosphate enables efficient secretion of HIV-1 Tat by infected T-cells. EMBO J. 29: 1348-1362. *Co-first authors.
  2. Rayne F., Debaisieux S., Bonhoure A., and Beaumelle B. (2010) HIV-1 Tat is unconventionally secreted through the plasma membrane. Biol. Int. 34: 409-413.
  3. Stechmann B., Bai S., Gobbo E., Lopez R., Merer G., Pinchard S., Panigai L., Tenza D., Raposo G., Beaumelle B., Sauvaire D., Gillet D., Johannes L., and Barbier J. (2010) Inhibition of retrograde transport protects mice from lethal ricin challenge. Cell 141: 231-242.
  4. Polakowski N., Heather G., Mesnard J.-M., and Lemasson I. (2010) Expression of a protein involved in bone resorption, Dkk1, is activated by HTLV-1 bZIP factor through its activation domain. Retrovirology 7, 61 (Highly accessed).
  5. Kinjo T., Ham-Terhune J., Peloponese J.-M., and Jeang K.-T. (2010) Induction of reactive oxygen species by human T-cell leukemia virus type 1 tax correlates with DNA damage and expression of cellular senescence marker. J. Virol. 84: 5431-5437.
  6. Duc-Dodon M., Barbeau B., et Mesnard J.-M. (2010) Leucémies T induites par HTLV-1 : y a-t-il un avant et un après HBZ ? Sci. (Paris) 26: 385-390.
  7. Barbeau B., Devaux C., and Mesnard J.-M. (2010) Antisense transcription in Human T-cell Leukemia Virus type 1: discovery of a new viral gene. In “Recent advances in human retroviruses: Principles of replication and pathogenesis”. Edited by Andrew ML Lever (Cambridge UK), Kuan-Teh Jeang (NIH, USA) and Ben Berkhout (AMC, The Netherlands). World Scientific Pub. (Singapore), p105-128.

2009

  1. Halin M., Douceron E., Clerc I., Journo C., Ko N.L., Landry S., Murphy E.L., Gessain A., Lemasson I., Mesnard J.-M., Barbeau , and Mahieux R. (2009) Human T-cell leukemia virus type 2 produces a spliced antisense transcript encoding a protein that lacks a classical bZIP domain but still inhibits Tax2-mediated transcription. Blood 114: 2427-2438.
  2. Clerc I., Hivin P., Rubbo P.-A., Lemasson I., Barbeau B., and Mesnard J.-M. (2009) Propensity for HBZ-SP1 isoform of HTLV-I to inhibit c-Jun activity correlates with sequestration of c-Jun into nuclear bodies rather than inhibition of its DNA-binding activity. Virology 391: 195-202.
  3. Suemori K., Fujiwara H., Ochi T., Ogawa T., Matsuoka M., Matsumoto T., Mesnard J.-M., and Yasukawa M. (2009) HBZ is an immunogenic protein but not a target antigen for HTLV-1-specific cytotoxic T lymphocytes. Gen. Virol. 90: 1806-1811.
  4. Peloponese J.-M., Yasunaga J., Kinjo T., Watashi K., and Jeang K.-T. (2009) Peptidylproline cis-trans-isomerase Pin1 interacts with human T-cell leukemia virus type 1 tax and modulates its activation of NF-kappaB. J. Virol. 83: 3238-3248.
  5. Landry, Halin M., Vargas A., Lemasson I., Mesnard J.-M., and Barbeau B. (2009) Upregulation of human T-cell leukaemia virus type 1 antisense transcription by the viral Tax protein. J. Virol. 83: 2048-2054.
  6. Yezid H, Konate K, Debaisieux S, Bonhoure A, and Beaumelle B. (2009) Mechanism for HIV-1 Tat insertion into the endosome membrane. Biol. Chem. 284: 22736-22746.

2008

  1. Clerc I., Polakowski N., Arpin-André C., Cook P., Barbeau B., Mesnard J.-M.*, and Lemasson I.* (2008) An interaction between the HTLV-1 bZIP factor (HBZ) and the KIX domain of p300/CBP contributes to the downregulation of Tax-dependent viral transcription by HBZ. Biol. Chem. 283: 23903-23913. *Co-corresponding authors.
  2. Iha H.*, Peloponese -M.*, Verstrepen L., Zapart G., Ikeda F., Smith C., Starost M., Yedavalli V., Heyninck K., Dikic I., Beyaert R., and Jeang K.-T. (2008) Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-kappaB activation. EMBO J. 27: 629-641. *Co-first authors.

 

Scientific Collaborations

Locals :

  • BESTEIRO S., DIMNP - UMR5235, Montpellier
  • CHALOIN L., IRIM - UMR9004, Montpellier
  • ESPERT L., IRIM - UMR9004, Montpellier
  • BRIAND L., IRIM -UMR9004, Montpellier
  • GASCUEL O., LIRMM, Montpellier
  • GUICHOU J.-F., CBS, CNRS UMR 5048- INSERM U 1054, Montpellier
  • KREMER L., IRIM – UMR9004, Montpellier
  • MELI A. INSERM U1046 - CNRS UMR 9214, Montpellier
  • METTLING C., IGH, UPR 1142 CNRS, Montpellier
  • VAN DE PERRE P., INSERM U1058, Montpellier

 Nationals :

  • ECHARD A., Institut Pasteur, Paris
  • CESAIRE R., Centre Hospitalier Universitaire de Fort-de-France, Martinique
  • LOUSSOUARN G., UMR 1087 INSERM-CNRS UMR 6291, Nantes
  • MORIS A., CIMI-Paris, Paris
  • VERGNE I., IPBS, UMR 5089 CNRS, Toulouse
  • VITALE N., INCI-UPR3212 CNRS, Strasbourg

Internationals :

  • BARBEAU B., Université du Québec à Montréal, Canada
  • BELMONTE S., IHEM-CONICET, Mendoza, Argentina
  • LEMASSON L., Brody School of Medicine , East Carolina University, USA
  • MATSUOKA M., Kyoto University, Japan
  • THOMAS-KRESS A., Virologisches Institut - Klinische und Molekulare Virologie Universitätsklinikum Erlangen - Germany

Team members

Jean-Michel Mesnard’s work has led to the study of a new category of retroviral proteins, the antisense proteins, whose exact function remains to be defined. Importantly these proteins have been added to the list of known retroviral proteins (enzymatic proteins encoded by pol, structural proteins encoded by gag and env, factors regulating viral expression encoded by tat/tax or rev/rex, and auxiliary proteins). For the discovery of HBZ (HTLV-1 bZIP factor), Jean-Michel Mesnard received in 2013 the Basic Science Award of International Retrovirology Association during the 17th International Conferences on Human Retrovirology in Montreal.



After a 7 years post-doctoral in NIAID (Bethesda , USA), Jean-Marie Peloponese entered at the CNRS in 2008 in the team directed by J.-M. Mesnard. He is studying the role of the HBZ protein in the HTLV-1 pathogenesis.

After a postdoc at the Myles H Center for AIDS and Human Retrovirus (University of Virginia, USA) Nathalie Chazal was recruited as Associate Professor (Faculty of Medicine, University Montpellier). Nathalie Chazal works in the team led by J.-M. Mesnard. She is studying the role of ASP antisense protein of HIV-1 and its implication in the pathophysiology of HIV-1.


After she gratuated of a Research Master in Immunology in Marseille, Juliette Savoret joined our team in 2015 as a PhD student supervised by Antoine Gross. She received an interface grant from the CHU-UM. She works in collaboration with the CHU of Montpellier on clinical aspects concerning ASP, the antisense protein of HIV-1.

Malvina Schatz obtained a Research Master in Infectiology in Tours in 2013. Then, she worked at the Pasteur Institute of Paris as an engeneer to work on the dialog between Natural Killer cells, dentritic cells and T-lymphocytes during HIV-1 infection. In 2015, she obtained a PhD student grant and joined our team to study different aspects of the HIV-1 Tat protein under Bruno Beaumelle's supervision.

After his diploma in Pharmacy in Vietnam and a Research Master in Pharmaceutics in Lyon (Grant from Rhône-Alpes Region), Phuoc-Bao-Viet TONG joined our team in 2015 to realise his PhD in Virology (Grant from the French Embassy in Vietnam). He works on the HIV-1 Tat protein under Bruno Beaumelle's supervision.


  • Eva Meunier - Internship Master 2 Biologie Santé Montpellier



They worked with us :

Charlotte André - Ingeneer Assistant
Marie Térol - PhD student
Daniel Henaff - post-doctoral student
Elodie Cassan - PhD student
Simon Lachambre - Ingeneer Assistant
Hélène Gazon - PhD student
Sarkis Sarkis - PhD student
Sylvain Laverdure - PhD student
Isabelle Clerc - PhD student
...



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Post-doctoral positions, PhD, Internships


Offer 1 : PhD thesis

Study of the role of the Fra-2 protein in the development of ATL

 

HTLV-1 (Human T-cell leukemia type 1) is responsible for the development of adult T-cell leukemia (ATL), an aggressive and monoclonal proliferation of CD4 T lymphocytes. Since proviral DNA is not integrated in proximity to a proto-oncogene or tumor suppressor gene, involvement of a HTLV-1 viral protein in transformation of the infected cell has been suggested. It was long thought that this protein was Tax, whose expression is controlled by a promoter localized in the 5 'LTR (Long Terminal Repeat) of the proviral DNA. However, a recent analysis showed that out of a total of 426 leukemic clones from infected patients, only one of these clones was still capable of producing transcripts from the 5 'LTR. Conversely, the so-called antisense transcription, initiated from the 3 'LTR and involved in the production of another viral protein called HBZ (HTLV-1 bZip factor), is not affected at all but is activated.

In the APIR team, we are interested in the roles of AP-1 transcription factors in the development of ATL. In order to better understand their role, we analyzed the expression of Jun and Fos family members in ATL cells freshly isolated from leukemic patients. We observed that the T lymphocytes of asymptomatic patients express a cJun/cFos heterodimer whereas the leukemic cells express a JunD/Fra-2 heterodimer. Regarding the role of AP-1 proteins in carcinogenesis, the commonly accepted model is a change in the expression profile of AP-1 factors plays a key during tumor progression. Numerous studies have shown that the deregulation of cFos or Fra-1 is important for cell transformation; on the other hand, little is known about the role of Fra-2. The objective of this thesis project is to study the role of Fra-2 in the proliferation of HTLV-1 infected cells and in HTLV-1-mediated cell transformation.

For more information please contact:  Dr JM Peloponese Email : Jean-marie.peloponese(at)irim.cnrs.fr 

TEAM LEADER


Bruno Beaumelle


DR2 CNRS
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Jean-Michel MESNARD

DR1 CNRS
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AT A GLANCE

The team is interested in viral proteins whose involvement in infection (HIV-1 Tat) or cell transformation is well established (HBZ, the Human bZIP factor of HTLV-1). We also study the HIV-1 antisense protein (ASP) whose role is still unknown. Our studies aim to identify the function and the biological activity of these proteins both in viral multiplication and in the pathogenic effects linked to infection.

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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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