Players in the Pathogenesis of the Retroviral Infections

PPRI Team

The team in January 2021
From left to right: JM Mesnard, J Wenker, J Tram, A. Houmey, C Ounadjela, JM Peloponese, M. Abrantes, L. Espert, A. Gross, C. Chopart, M. Mombled, V. Hebmann, E. Fourgous, B. Pradel, N. Chazal, B. Beaumelle

Topics

Groupe 1 : Roles of HBZ in HTLV-1-induced leukemia (Responsable : Jean-Marie Peloponese)
Groupe 2 : ASP, the antisens protein of HIV-1: Evolution, Immunological, Cellular and Viral impacts (Responsable : Antoine Gross)
Groupe 3 : Role of extracellular Tat during AIDS (Responsable : Bruno Beaumelle)
Groupe 4 : Autophagy and viral infections (Responsable : Lucile Espert)

1. 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.
 
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.
 
2. ASP, the antisense protein of HIV-1 : Evolution, Immunology, Cellular, and Viral impacts
Our research project focuses on the HIV-1 ASP protein (AntiSense Protein). Using several experimental approaches (virology, cell biology, immunology, bioinformatics, studies in HIV-1 infected patients), our project aims to determine the function of this protein and to understand its role in the pathogenesis of AIDS (viral latency, chronicity). HIV-1 produces its proteins from the integrated proviral DNA (consisting of two LTR5' and one LTR3') through transcriptional activity of a promoter located in the LTR-5' (Long Terminal Repeat). However, like HTLV-1 which has a transcriptional activity leading to the production of the HBZ protein (see HBZ project), we have shown that the HIV-1 LTR-3' also has an antisense transcriptional activity allowing the production of the ASP protein.


It was first predicted in 1988, that there may be an Open Reading Frame (ORF) on the negative strand of the Human Immunodeficiency Virus type 1 (HIV-1) genome that could encode a protein named AntiSense Protein (ASP) (Savoret et al., Frontiers in Microbiol, 2021). Despite early skepticism and the lack of specific tools to selectively identify rare antisense transcripts and detect a strongly hydrophobic protein like ASP, the presence of antisense transcripts was observed (Landry et al., Retrovirology, 2007) as well as the presence of CD8+ T cells directed against several ASP peptides in HIV-1-infected patients (Bet et al., Retrovirology, 2015). Recently, the presence of ASP-specific antibodies was detected in the plasma of HIV-1-infected individuals (Savoret et al., 2020) further suggesting that ASP is expressed and immunogenic in vivo. Finally, using an evolutionary study developed in collaboration with LIRMM informaticians and performed on more than 23,000 sequences, we demonstrated that the ASP gene emerged during the emergence of the pandemic HIV-1 in the early twentieth century (Cassan et al., PNAS, 2016).



Our current research focuses on:
- The study of ASP function and its relationship with infection and immune response.
- The link between ASP and the immune status of the HIV_1 infected patient under antiretroviral treatment.
- The evolutionary mechanisms of ASP in HIV-1.

COVID-19: More recently, we have initiated studies on SARS-CoV-2, in particular on some poorly studied proteins of the virus by focusing on cell biology aspects and antibody response in patients.

Grants:
- Fédération Hospitalo-Universitaires Infection Chronique (FHU Inch): 2020-2023: Doctoral fellowship(3 years) - collaboration with Dr. Alain Mackinson (at infectious and tropical diseases department at Montpellier Hospital)
- Sidaction: 2020-2023 : Doctoral fellowship (3 years)
- Sidaction: 2019: Doctoral fellowship (1 year) for the fourth year thesis
- "Direction des relations avec les entreprises du CNRS": 2019-2020
- UM/CHU: 2015-2018: Doctoral fellowship (3 years)
- "CNRS mission Interdisciplinarité" 2013-2016 


3. Role of extracellular HIV-1 Tat during AIDS
Previous work
Our group studies the intracellular and transcellular transport of HIV-1 Tat protein. This protein is well known and studied because it is required for the transcription of viral genes. Its concentration and activation level regulate cell exit from latency. We showed that Tat is secreted using an unconventionnal pathway based on Tat binding to PI(4,5)P2 on the inner leaflet of the plasma membrane (Rayne et al, 2010). Circulating  Tat can then interact with a number of cell types using receptors such as the LRP. We found that Tat is then endocytosed using the clathrin/AP-2 pathway (Vendeville et al, 2004). Once in endosomes, low pH triggers a conformational change inducing Tat membrane insertion. Tat single Trp (Trp11) is required for this insertion process (Yezid et al, 2009). Tat translocation to the cytosol is catalyzed by Hsp90, a cytosolic chaperone (Vendeville et al, 2004). Once in the cytosol Tat induces a number of cell responses, for instance the secretion of pro-inflammatory cytokines by monocytes (Rayne et al, 2004). Incoming Tat also binds to PI(4,5)P2. Recombinant Tat shows an affinity for this phosphoinositide that is much higher than that of cell proteins because Tat inserts the sidechain of its Trp in the membrane upon PI(4,5)P2 binding (Debaisieux et al, 2012). In uninfected cells, Tat is palmitoylated and this modification will further stabilize its membrane association and inhibit secretion. Tat palmitoylation requires the prolylisomerase cyclophilin A (CypA). Tat is not palmitoylated in infected cells because CypA is encapsidated by HIV-1 (~200 CypA/virion), thereby clearing the cell of CypA and enabling efficient Tat secretion by infected cells (Chopard et al, 2018) (Fig.2). In uninfected cells, Tat palmitoylation makes Tat resident on PI(4,5)P2, thereby severely perturbating the assembly and function of different cell machineries using this phosphoinositide. We accordingly showed that circulating Tat prevents the recruitment of annexin 2 and cdc42, thereby perturbating neurosecretion (collaboration with the group of Nicolas Vitale, INCI, Strasbourg (Tryoen-Toth et al, 2013)) and phagocytosis (Debaisieux et al, 2015), respectively (Fig.1). Tat also affects the function of ionic channels in cardiomyocytes (collaboration with the group of Gildas Loussouarn, INSERM, Nantes) (Es-Salah-Lamoureux et al, 2016). It should be noted that HIV patients indeed show these dysfunctions.
Our results are summarized in Figs. 1 et 2. These projects were funded by the ANRS, Sidaction and FRM and performed by Fabienne Rayne (PostDoc), Agnés Vendeville, Hocine Yezid, Solène Debaisieux, Christophe Chopard, Bao Viet Tong et Malvina Schatz (PhDs).

*Present work
We are interested in the effect of Tat on the multiplication of opportunistic pathogens following HIV infection (collaborations Laurent Kremer and Laura Picas from IRIM, Oliver Neyrolles and Christel Verollet from IPBS Toulouse), in a potential  mechanism of Tat encapsidation (collaboration Mickaël Blaise and Laurent Chaloin from IRIM, Pierre-Emmanuel Milhiet and Jean-François Guichou, CBS Montpellier) and in the development of new HIV latency reversing agents (collaboration L. Chaloin), molecules that were just patented. These projects are funded by Sidaction and SATT AXLR.


4. Autophagy and viral infections
To infect a cell, replicate and spread, all pathogens must counteract, or use to their advantage, a powerful cellular defense mechanism called "autophagy." Our group "Autophagy and Viral Infections" is pioneer in the discovery of the role of autophagy during HIV-1 infection and has been studying this topic for several years. Recently, our research program was enriched by the study of the relationships between autophagy and a new pathogen, the SARS-CoV2. In particular, we are investigating the signaling pathways involved in the induction of this process by viral envelope proteins. We are also studying the effects of autophagy on the innate immune response and on cellular homeostasis.

A. Role of autophagy in HIV-1 CD4+ T lymphocytes infection
Envelope glycoproteins (Env), more precisely the fusogenic activity of gp41, expressed at the surface of infected cells, are responsible for autophagy triggering in target CD4+ T cells. Consistently, we have observed that autophagy is induced very rapidly, in the very early stages of infection, in target CD4+ T cells (Sagnier S et al, JVirol, 2015). This first contact between the viruses and the target cells evolves towards two different situations (see the model below) :
- Target cells are not productively infected because the viral cycle is interrupted after the entry step. In this case, autophagy is not inhibited and ultimately leads to apoptosis of the so-called "uninfected" target cells (Espert L et al, J Clin Invest, 2006). In this case, Env-induced autophagy results in an excessive reactive oxygen species production in bystander CD4+ T cells, leading to their death by apoptosis. Our results show that this process is responsible for the selective degradation of peroxisomes, which are essential cellular organelles involved in the control of oxidative stress (Daussy C et al, Autophagy, 2020).
- Target cells are productively infected (the provirus is integrated into the host cell and new viral particles are produced). In this case, the autophagic process is induced rapidly after virus entry (Sagnier S et al, J Virol 2015), then it is controlled by the HIV-1 Vpr protein (Alfaisal J et al, Biol cell, 2019) and then totally inhibited, in the late stages of the replication cycle, by the HIV-1 Vif protein (Borel S et al, AIDS, 2015). Autophagy has a strong anti-HIV potential because, it selectively degrades the viral transactivator Tat, a protein absolutely necessary for the replication of the virus (Sagnier S et al, J Virol, 2015). In all cases, an oxidative stress, dependent on membrane fusion, is induced in the target cells and this oxidative stress is involved in the induction of autophagy by Env. Interestingly, our results, as well as those of other groups, indicate that autophagy, induced by Env in the 1st stages of CD4+ T cell infection, would favor virus replication.

Relationships between autophagy and HIV-1 in CD4+ T lymphocytes
 
Our research program aims at determining :
  1. What are the signaling pathways, activated by the gp41 fusogenic function, involved in autophagy induction ?
  2. What are the mechanisms leading to Env-induced accumulation of reactive oxygen species in bystander CD4+ T cells and consequently to their apoptosis?
  3. What is the role of Env-induced autophagy in the first steps of HIV-1 infection?
  4. What are the selectively degraded substrates upon Env-induced autophagy in different contexts in CD4+ T cells infection?
Our projects are funded by ANRS and Sidaction.

B. Role of autophagy during SARS-CoV2 infection
Recently, we have decided to use our expertise, acquired on the relationships between HIV-1 infection and autophagy, to study the interactions between this process and SARS-CoV2 infection. In this context, our projects are to determine:
  1. How the SARS-CoV2 envelope glycoprotein (Spike) induces autophagy and what is the role of this process during infection?
  2. What are the cellular targets degraded by Spike-induced autophagy?
  3. How does SARS-CoV2 regulate autophagy during its replication and what are the consequences?
 

 

Publications (2015-2021)

2021
  1. Savoret J., Mesnard J.-M., Gross A., and Chazal N. (2021) Antisense transcripts and antisense protein : a new perspective on human immunodeficiency virus type 1. Front. Microbiol. 11: 625941.
  2. Romain Ragimbeau, Leila El Kebriti, Elise Fourgous, Abdelhay Boulahtouf, Giuseppe Arena, Lucile Espert, Nadine Houédé, Céline Gongora and Sophie Pattingre. BAG6 is a new receptor of mitophagy that induces mitochondrial fragmentation and PINK1/PARKIN signaling. FASEB J. (2021) Feb;35(2):e21361
  3. Daniel J. Klionsky,…. Lucile Espert,. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th Edition). Autophagy. 2021 Feb 8;1-382.
  4. Romina Cabrera-Rodríguez, Silvia Pérez-Yanes, Judith Estévez-Herrera, Daniel Márquez-Arce, Cecilia Cabrera, Lucile Espert, Julia Blanco, Agustin Valenzuela-Fernández. (2021) The Interplay of HIV and Autophagy in Early Infection. Front Microbiol.  Apr 28;12:661446.
  5. Charlotte Martinat, Arthur Cormier, Joёlle Tobaly-Tapiero, Noé Palmic, Nicoletta Casartelli, Si’Ana A. Coggins, Julian Buchrieser, Mirjana Persaud, Felipe Diaz-Griffero, Lucile Espert, Guillaume Bossis, Pascale Lesage, Olivier Schwartz, Baek Kim, Florence Margottin-Goguet, Ali Saïb, Alessia Zamborlini. SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells. Nature Communications. (2021) Jul 28;12(1):4582.
2020
  1. Savoret J., Chazal N., Moles J.-P., Tuaillon E., Boufassa F., Meyer L., Lecuroux F., Lambotte O., Van de Perre P., Mesnard J.-M., and Gross A. (2020) A pilot study of the humoral response against the AntiSense Protein (ASP) in HIV-1-infected patients. Front. Microbiol. 11: 20.
  2. Matsuoka M. and Mesnard J.-M. (2020) HTLV-1 bZIP factor: the key viral gene for pathogenesis. Retrovirology 17: 2.
  3. Chazal N, de Rocquigny H, Roussel P, Bouaziz S, Barré-Sinoussi F, Delfraissy JF, Darlix JL. The three lives of Pierre Boulanger. Retrovirology. (2020) Apr 30;17(1):9.
  4. Coralie F Daussy, Mathilde Galais, Baptiste Pradel, Véronique Robert-Hebmann, Sophie Sagnier, Sophie Pattingre, Martine Biard-Piechaczyk and Lucile Espert. HIV-1 Env induces pexophagy and an oxidative stress leading to uninfected CD4+ T cell death. Autophagy. (2020) Oct 19:1-10.
  5. Baptiste Pradel, Véronique Robert-Hebmann, Lucile Espert. Regulation of Innate Immune Responses by Autophagy: A Goldmine for Viruses. Frontiers in Immunology. (2020) Oct 6;11:578038.
  6. Bruno Beaumelle & Laurent Chaloin. (2020) Composés pour leur utilisation pour la réactivation du VIH dans des cellules latentes infectées par le VIH". Brevet FR2005250.
2019
  1. Jamal Alfaisal, Alice Machado, Mathilde Galais, Véronique Robert-Hebmann, Laetitia Arnauné-Pelloquin, Lucile Espert*, Martine Biard-Piechaczyk*. * Co-Last authors. HIV-1 Vpr inhibits autophagy during the early steps of infection of CD4 T cells. Biol Cell. (2019) Dec;111(12):308-318.
  2. Mathilde Galais, Baptiste Pradel, Isabelle Vergne, Véronique Robert-Hebmann, Lucile Espert, Martine Biard-Piechaczyk. LAP (LC3-associated phagocytosis): phagocytosis or autophagy? Med Sci (Paris). (2019) Aug-Sep;35(8-9):635-642.
  3. Romina Cabrera-Rodriguez, Véronique Hebmann, Silvia Marfil, Maria Pernas, Sara Marrero-Hernandez, Cecilia Cabrera, Victor Urrea, Concepcion Casado, Isabel Olivares, Daniel Marquez-Arce, Silvia Perez-Yanes, Judith Estevez-Herrera, Bonaventura Clotet, Lucile Espert, Cecilio Lopez-Galindez, Martine Biard-Piechaczyk, Agustin Valenzuela-Fernandez and Julia Blanco. HIV-1 envelope glycoproteins isolated from Viremic Non-Progressor HIV infected individuals are fully functional and cytopathic. Sci Rep. (2019) 3; 9(1):5544.
  4. Neyret A, Gay B, Cransac A, Briant L, Coric P, Turcaud S, Laugâa P, Bouaziz S, Chazal N. Insight into the mechanism of action of EP-39, a bevirimat derivative that inhibits HIV-1 maturation. (2019). Antiviral Res. Apr;164:162-175. doi: 10.1016/j.antiviral.2019.02.014
  5. Kara H, Chazal N, Bouaziz S. Is Uracil-DNA Glycosylase UNG2 a New Cellular Weapon Against HIV-1? (2019) Curr HIV Res. 2019;17(3):148-160.
  6. Matkovic R, Bernard E, Fontanel S, Eldin P, Chazal N, Hassan Hersi D, Merits A, Péloponèse JM Jr, Briant L. The host DHX9 DExH Box helicase is recruited to Chikungunya virus replication complexes for optimal genomic RNA translation. (2019). Journal of Virology. 2019 Feb 5;93(4):e01764-18.

2018
  1. Cate C., Larocque E., Peloponese J.-M, Mesnard J.-M., Rassart E. et Barbeau B. (2018) Les protéines antisens des virus HTLV. Virologie 22, 183-191.
  2. Chopard C., Tong P.B.V., Tóth P., Schatz M., Yezid H., Debaisieux S., Mettling C., Gross A., Pugnière M., Tu A., Strub J.-M., Mesnard J.-M., Vitale N., and Beaumelle B. (2018) Cyclophilin A enables specific HIV-1 Tat palmitoylation and accumulation in uninfected cells. Nat. Commun. 9(1): 2251.
  3. Schatz M., Tong P.B.V., and Beaumelle B. (2018) Unconventional secretion of viral proteins. Semin. Cell. Dev. Biol. 83: 8-11.
  4. 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.
  5. Gross A., Mesnard J.-M., Savoret J. (2018) Méthode d’identification de cellules infectées. Brevet FR1872978
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.
  5. Majdoul Sahila, Cosette Jérémie, Seye Ababacar Khalil, Bernard Eric, Frin Sophie, Holic Nathalie, Chazal Nathalie, Briant Laurence, Espert Lucile, Galy Anne, Fenard David. Peptides derived from evolutionarily conserved domains in Beclin-1 and Beclin-2 enhance the entry of lentiviral vectors into human cells. J Biol Chem., (2017) 292(45):18672-18681
  6. Isabelle Vergne, Frank Lafont, Lucile Espert, Audrey Esclatine, Martine Biard-Piechaczyk. Autophagie et maladies infectieuses. Médecine et Sciences. (2017) Mar; 33(3):312-318.
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. Babon A, Wurceldorf T, Almunia C, Pichard S, Chenal A, Buhot C, Beaumelle B, and Gillet D. (2016) Bee venom phospholipase A2 as a membrane-binding vector for cell surface display or internalization of soluble proteins. Toxicon. 2016 Jun 15;116:56-62
  5. 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
  6. 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.
  7. Daussy CF, Espert L. L'autophagie sélective au cours des infections virales. Virologie (Montrouge). 2016 Aug 1;20(4):196-206.
  8. Klionsky DJ,...., Espert L,et al. Guidelines for the use and interpretation of assays for monitering autophagy (3rd edition). Autophagy. 2016;12(1):1-222.
  9. Chazal and L. Briant. Chikungunya Virus: Advances in Biology, Pathogenesis, and Treatment. Chikungunya Virus Entry and Replication (2016). Springer (Editors: Okeoma,Chioma M).
  10. Es-Salah-Lamoureux Z, Jouni M, Malak OA, Belbachir N, Al Sayed ZR, Gandon-Renard M, Lamirault G, Gauthier C, Baró I, Charpentier F, Zibara K, Lemarchand P, Beaumelle B, Gaborit N, Loussouarn G. HIV-Tat induces a decrease in IKr and IKsvia reduction in phosphatidylinositol-(4,5)-bisphosphate availability. J Mol Cell Cardiol. 2016 Oct;99:1-13.
 2015
  1. Espert L., and Beaumelle B. (2015) Autophagy restricts HIV-1 infection. Oncotarget 6: 20752-20753
  2. Espert L., Beaumelle B., and Vergne I. (2015) Autophagy in Mycobacterium tuberculosis and HIV infections. Infect. Microbiol. 5: 49.
  3. Barbeau B. and Mesnard J.-M. (2015) Does chronic infection in retroviruses have a sense? Trends Microbiol. 23: 367-375.
  4. 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
  5. Fargette M, Frutos R, Merlin A, Ravel P, Baskoro Tunggul Satoto T, Andayani E, Damayanti S, Kister G, Nghia ND, Bardie Y, Cornillot E, Devaux C, Moulia C, Gavotte L, Briant L, Chazal N & Libourel. (2015). Observatoire Scientifique en Appui à la GEstion Sanitaire sur un territoire (OSAGE-S). Dynamiques Environnementales.
  6. Bernard, E., Hamel, R., Neyret, A., Ekchariyawa, P., Molles, jp., Simmons, G., Chazal, N., Desprès, P., Missé, D & Briant, L. Human Keratinocytes restric CHikungunya virus replication at post-fusion step. Virology (2015). Feb;476:1-10.
  7. Besteiro, S., Blanc-Potard A, Bonazzi M, Briant L, Chazal N, Cornillot E, Lentini G, Matkovic, R. Sanosyan A, Tuaillon E, Van de Perre P. Montpellier Infectious Diseases - Pôle Rabelais (MID) 3rd annual meeting (2015). Infect Genet Evol. Jun;32:161-4.
  8. 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.
  9. 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.
  10. 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).
  11. Borel S, Robert-Hebmann V, Alfaisal J, Jain A, Faure M, Espert L, Chaloin L, Paillart JC, Johansen T, Biard-Piechaczyk M (2015). HIV-1 viral infectivity factor interacts with microtubule-associated light chain 3 and inhibits autophagy. AIDS. 2015 Jan 28;29(3):275-86.

Scientific Collaborations

Local:

  • BESTEIRO S., DIMNP - UMR5235, Montpellier
  • CHALOIN L., IRIM - UMR9004, Montpellier
  • BRIAND L., IRIM -UMR9004, Montpellier
  • GASCUEL O., LIRMM, Montpellier
  • MAKINSON Alain, CHU de Montpellier et UMR TransVIHMI (IRD UMI 233 – INSERM U 1175)
  • 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
  • GOUJON C, IRIM - UMR9004, Montpellier
  • GAUDIN R, IRIM - UMR9004, Montpellier

National:

  • 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
  • FAURE M., CIRI, INSERM U111, Université de Lyon
  • ESCLATINE A., I2BC, CNRS UMR9198, Université de Paris-Saclay
  • ZAMBORLINI A., I2BC, CNRS UMR9198, Université de Paris-Saclay

International:

  • 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
  • BLANCO J., IrsiCaixa, Badalona, Spain
  • VALENZUELA-FERNANDEZ A., Universidad de la Laguna, Tenerife, Spain
  • CABRERA C., IrsiCaixa, Badalona, Spain
  • BEHRENDS C., Medical Faculty, Ludwig-Maximilians-Universität München, Germany

Team Members

Team leaders:

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.

 

Group1: Roles of HBZ in HTLV-1-induced Leukemia


They worked with us:
Eva Meunier - Master 2 Research (Biologie-Santé), Montpellier
Marie Térol - PhD student
Hélène Gazon - PhD student

 

Group2: ASP, the antisense protein of HIV-1 : Evolution, Immunology, Cellular, and Viral impacts


They worked with us: 
Juliette Savoret - PhD student
Christophe Chopart - Post-doctorant
Charlotte André - Ingineer
Elodie Cassan - PhD student


Group3: Role of extracellular HIV-1 Tat during AIDS
  • Bruno Beaumelle – DR2 CNRS - HDR
  • Camille Ounadjela - Ingineer CNRS
  • Maxime Jansen - Master 2 Research
  • Laetitia Marty - Master 2 Research

They worked with us:
Bao Viet Tong Phuoc - PhD student
Malvina Schatz - PhD student
Simon Lachambre - Ingineer


Group4: Autophagy and viral infections


They worked with us:
Elise Fourgous - Ingineer (Sidaction)
Mathilde Galais - PhD student
Jamal Alfaisal - PhD student
Coralie Daussy - PhD student
Sophie Borel - PhD student
Sophie Sagnier - PhD student









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Post-doctoral positions, PhD, Internships

Offer 1 : PhD thesis

Characterization of the HIV-1 antisens protein (ASP) interactions with the autophagic process.
Among the unresolved issues on HIV, a particularly intriguing aspect is the case of the asp gene. The existence of this viral gene was proposed 30 years ago (Miller, Science, 1988), but the studies of the next two decades did not really establish its existence. Indeed, this gene is positioned on the complementary reverse strand of the proviral genome, overlapping of the env gene and allows, thanks to an antisense transcription initiated from the 3’-LTR, the production of the protein ASP (AntiSense Protein). Our team has already discovered hbz, an HTLV-1 retrovirus gene with the same genomic positioning, leading us to study asp. We have developed a set of complementary multidisciplinary approaches in order to definitively establish the existence of asp as an HIV gene. Through evolutionary approaches and the analysis of more than 23,000 virus sequences, we have demonstrated that this 10th HIV gene appeared concomitantly with the emergence of the AIDS pandemic in the early 20th century (Cassan et al, PNAS). We have observed that, within the group of pandemic viruses, ASP showed some variation in the evolved forms depending on the viral subtype considered. Our work, and that of other teams, has also demonstrated that ASP is well expressed in vivo since an anti-ASP immune response can be detected in HIV-infected patients. These results show that ASP is well encoded by the 10th forgotten HIV gene providing the first important information on this protein. Nevertheless, several central questions remain. In particular, it is not understood why the virus has created this gene during its emergence in humans. To date, among the few studies available on ASP, its role linked to the autophagy process is the one that has given some indications.
Autophagy is a cellular mechanism involved in several major functions such as maintaining homeostasis, differentiation, development, and innate and adaptive immunities. This process can (i) degrade viruses (or viral proteins) directly, (ii) allow the degradation of viral antigens and their presentation to major histocompatibility complex (MHC) molecules, or (iii) allow the activation and the regulation of the innate immune response. Autophagic degradation can be highly selective thanks to the intervention of "autophagic receptors", such as p62/SQSTM1, targeting substrates to autophagic machinery through their interaction with the Atg8 family of proteins (mainly LC3). Recently, it has been shown that some autophagic receptors are also able to favour the late stages of autophagy.
Our studies, and others, have shown that autophagy exerts an antiviral activity during HIV-1 infection. Consequently, the virus has evolved to block this process or to use it for its own benefit. Thus, several HIV-1 proteins such as Vif, Nef or Tat, block autophagy at different levels of the mechanism. The role of ASP on autophagy has only been addressed in 2 studies where it is proposed that this viral protein interacts with the p62/SQSTM1 autophagic receptor, leading to its degradation. However, further analysis of the results presented in these publications indicates that ASP is rather an inhibitor of autophagic flux (late degradative step).
We propose to further characterize the impact of ASP on the cellular response to HIV-1 infection, in particular its role on the autophagic process. To this aim, we will analyse:
- The consequences of the interaction between ASP and p62/SQSTM1 on autophagy
-  Whether ASP can interact with other selective autophagy receptors
- The effects of these interactions on viral replication and cellular homeostasis
- The impact of variations between sub-types of ASP on autophagy
The results obtained with this project will be quite innovative as it will help to progress in the understanding of the role of ASP during HIV replication.

For more information, please contact: N Chazal, nathalie.chazal[at]irim.cnrs.fr and L Espert, lucile.espert[at]irim.cnrs.fr

 

Congratulations to Julie who obtained the first young researcher prize for its presentation : "hnRNP proteins A1 and H1 regulate the alternative splicing of HTLV-1 antisense gene HBZ" at the "4th International Caparica Conference in SPLICING 2021 (du 26 au 29 juillet 2021, Portugal)".



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Baptiste is an organizer of the CFATG 1st virtual meeeting (23 - 24 June 2021).


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Julie presents the PhD Pub in this Radio Campus poscast!

Click here to listen!!

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 (HBZ, the Human bZIP factor of HTLV-1) are well established, but also to a viral protein whose function is still unknown (the HIV-1-antisense protein (ASP)). 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. Furthermore, we study the cellular answer to viral infections, in particular the autophagy process.

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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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