GENETICS AND ECOLOGY OF VIRUSES: UMR-S-941
 
Head Department: Prof. François CLAVEL
Tel.: +33 (0)1 57 27 67 64
 
 
 
 
 

Secretariat : Arlette Malepou

Tel.: 33(0)1 57 27 67 58

Fax: 33(0)1 57 27 68 04
Mail: arlette.malepou@inserm.fr
 
 
 
 

Team 1 - HIV-1, HIV-2 and restriction factors
François Clavel, Professor, francois.clavel@inserm.fr
Allan Hance, DR1 Inserm, allan.hance@inserm.fr
Béatrice Labrosse, CR1 Inserm, beatrice.labrosse@inserm.fr
Benjamin Perche, PhD Student, benjamin.perche@inserm.fr


Team 2 – HIV-1 replication and evolution
Fabrizio Mammano, DR2 Inserm, fabrizio.mammano@inserm.fr
Sentob Saragosti, DR2 Inserm, sentob.saragosti@inserm.fr
Sylvie Rato, Post-Doc ANRS, sylvie.rato@inserm.fr
Blandine Monel, Post-Doc, blandine.monel@inserm.fr
Azaria Remion, PhD Student, azaria.remion@inserm.fr
Bénédicte Vanwalscappel, PhD Student, benedicte.vanwalscappel@inserm.fr
 

Team 3 – Trafficking Avenir group
Nathalie Arhel, CR1 CNRS, nathalie.arhel@inserm.fr
Juliette Fernandez, Engineer Inserm, juliette.fernandez@inserm.fr
Kathleen Gärtner, Post-Doc Avenir, kathleen.gartner@inserm.fr
Anthony Machado, M2/PhD student, anthony_mac@hotmail.fr
 

Team 4 – Tropical and infectious diseases service
Jean-Michel Molina, Professor, jean-michel.molina@sls.aphp.fr
Sébastien Gallien, Assistant Professor, sebastien.gallien@sls.aphp.fr
 

Team 5 – Microbiology service
François Simon, Professor, francois.simon@sls.aphp.fr
Constance Delaugerre, Assistant Professor, constance.delaugerre@sls.aphp.fr
Jérôme Le-Goff, Assistant Professor, jerome.le-goff@sls.aphp.fr 

 
 
 
The INSERM unit U941 has extensive experience in studying evolution, diversity and phenotypic changes affecting HIV-1 populations in vivo.  This experience has mainly been acquired while studying HIV drug resistance in treated patients.  We are now widening our research focus to the study of HIV evolution under selective pressure by adaptive immunity, innate immunity and intrinsic immunity. A distinctive feature of our research activity is its positioning at the interface between fundamental virology and physiopathology. We have developed dedicated experimental approaches that allow the phenotypic characterization of patient-derived viruses. By comparing the genotypic and phenotypic characteristics of virus isolates issued from clinical cohorts, we evaluate the nature and the potency of different selective pressures acting on the virus populations. In parallel, we study the impact of virus evolution on the physiopathology of HIV infection.

In the infected host, retroviruses are subjected to a variety of selective pressures that lead to constant viral evolution. Retroviral evolution in vivo, however, is far from being linear, as it involves complex populations of competing viral quasi-species that fluctuate over time and across infected compartments. The diversity of these populations changes over time as a function of changes in selective pressure but also through extensive genetic exchanges by recombination between viral species.

Here below is a list of currently ongoing projects in our Unit.

The cost of HIV resistance to adaptive immunity
It has been known for some time that HIV-1 variants escaping CTLs through mutations in some HLA B*27 or B*57 epitopes in Gag exhibit a variable loss in replicative capacity.  The group led by Allan J. Hance in our laboratory has recently observed that part of this replicative defect is the consequence of hypersusceptibility of these viruses to human TRIM5a, a restriction factor until now considered as nearly inactive on HIV-1.  This is the first observation of concerted pressure of adaptive and intrinsic immunity on HIV-1.  The main objective of this project is currently to evaluate the role of HIV susceptibility to TRIM5a in spontaneous control of HIV infection and disease progression in vivo.

Role of restriction factors in the attenuated pathogenicity of HIV-2
HIV-2, essentially found in West Africa, is significantly less replicative, transmissible and pathogenic than HIV-1.  The virus has been transmitted to humans from mangabey monkey species, and may be poorly adapted to replication in a human cellular environment.  The group led by Béatrice Labrosse currently examines the susceptibiliy of a wide panel of primary HIV-2 viruses to human restriction factors TRIM5a, APOBEC3 and tetherin.  Their central hypothesis is that HIV-2 may be more susceptible than HIV-1 to these restriction factors, and that significant differences may exist between different HIV-2 strains, which may affect their ability to replicate and induce disease in humans.
   
HIV resistance to type I interferon in vivo and in vitro
Early studies have established that IFN can exert a significant antiviral effect on HIV-1, but the mechanisms of this activity are intricate and yet poorly defined.  The project led by Fabrizio Mammano aims at identifying genetic changes imparted on HIV by IFN treatment.  Selection of IFN-resistant strains is being conducted in vitro.  In vivo, this team will examine changes in viral populations in patients treated by IFN because of HCV co-infection, using deep sequencing technology. Identification of the genetic changes in different regions of the viral genome will help defining the mechanisms of the antiviral activity of IFN against HIV and lead way to possibilities of improving this activity, opening opportunities to make IFN a potentially important partner in treatment of HIV-infected subjects.

HIV drug resistance
Inserm U941 is still engaged in active research on the mechanisms and evolution of HIV drug resistance. Constance Delaugerre is tracking novel resistance evolution pathways in patients receiving new antiretroviral drugs, most notably integrase inhibitors, and testing the extent that natural HIV polymorphisms can influence the phenotypic expression and the evolutionary fate of particular resistance mutations.

Clinical trials
The researchers of the infectious diseases department participate in several national and international clinical trials, aimed at improving both HIV treatment and prevention strategies. In addition, the continued interaction within our unit between clinicians and fundamental virologists, creates a stimulating environment, in which customized experimental approaches are developed to explore current issues of the physiopathology of HIV infection.
 

 

 
  1. Mammano, F., Trouplin, V., Zennou, V., and Clavel, F. (2000). Retracing the evolutionary pathways of human immunodeficiency virus type 1 resistance to protease inhibitors: virus fitness in the absence and in the presence of drug. J Virol 74, 8524-8531.

     
  2. Stoddart, C.A., Liegler, T.J., Mammano, F., Linquist-Stepps, V.D., Hayden, M.S., Deeks, S.G., Grant, R.M., Clavel, F., and McCune, J.M. (2001). Impaired replication of protease inhibitor-resistant HIV-1 in human thymus. Nat Med 7, 712-718.

     
  3. Lecossier, D., Bouchonnet, F., Clavel, F., and Hance, A.J. (2003). Hypermutation of HIV-1 DNA in the absence of the Vif protein. Science 300, 1112.
     
  4. Clavel, F., and Hance, A.J. (2004). HIV drug resistance. N Engl J Med 350, 1023-1035.
     
  5. Esnault, C., Heidmann, O., Delebecque, F., Dewannieux, M., Ribet, D., Hance, A.J., Heidmann, T., and Schwartz, O. (2005). APOBEC3G cytidine deaminase inhibits retrotransposition of endogenous retroviruses. Nature 433, 430-433.
     
  6. Labrosse, B., Morand-Joubert, L., Goubard, A., Rochas, S., Labernardiere, J.L., Pacanowski, J., Meynard, J.L., Hance, A.J., Clavel, F., and Mammano, F. (2006). Role of the envelope genetic context in the development of enfuvirtide resistance in human immunodeficiency virus type 1-infected patients. J Virol 80, 8807-8819.
     
  7. Nora, T., Charpentier, C., Tenaillon, O., Hoede, C., Clavel, F., and Hance, A.J. (2007). Contribution of recombination to the evolution of human immunodeficiency viruses expressing resistance to antiretroviral treatment. J Virol 81, 7620-7628.
     
  8. Molina, J.M., Andrade-Villanueva, J., Echevarria, J., Chetchotisakd, P., Corral, J., David, N., Moyle, G., Mancini, M., Percival, L., Yang, R., Thiry, A., Mcgrath, D., Castle Study Team. (2008). Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the castle study. Lancet. 372(9639), 646-55.
     
  9. Dam, E., Quercia, R., Glass, B., Descamps, D., Launay, O., Duval, X., Krausslich, H.G., Hance, A.J., and Clavel, F. (2009). Gag mutations strongly contribute to HIV-1 resistance to protease inhibitors in highly drug-experienced patients besides compensating for fitness loss. PLoS Pathog 5, e1000345.
     
  10. Plantier, J.C., Leoz, M., Dickerson, J.E., De Oliveira, F., Cordonnier, F., Lemee, V., Damond, F., Robertson, D.L., and Simon, F. (2009). A new human immunodeficiency virus derived from gorillas. Nat Med 15, 871-872.
     
  11. Vendrame, D., Sourisseau, M., Perrin, V., Schwartz, O., and Mammano, F. (2009) Partial inhibition of HIV-1 replication by type-I interferons: impact of cell-to-cell viral transfer. J. Virol. 83, 10527-10537.
     
  12. Beaumont, E., Vendrame, D., Verrier, B., Roch, E., Biron, F., Barin, F., Mammano, F., and Brand, D. (2009). Matrix and envelope coevolution revealed in a patient followed since primary HIV infection. J. Virol. 83, 9875-9889.
     
  13. Battivelli, E., Lecossier, D., Matsuoka, S., Migraine, J., Clavel, F., and Hance, A.J. (2010). Strain-specific differences in the impact of human TRIM5{alpha}, different TRIM5{alpha} alleles, and the inhibition of capsid-cyclophilin A interactions on the infectivity of HIV-1. J Virol. 84, 11010-9.
     
  14. Delaugerre, C., Charreau, I., Braun, J., Néré, M.L., De Castro, N., Yeni, P., Ghosn, J., Aboulker, J.P., Molina, J.M., Simon, F., Anrs 138 study group. (2010). Time course of total HIV-1 DNA and 2-Long-Terminal Repeat circles in patients with controlled plasma viremia switching to a raltegravir-containing regimen. AIDS. 24(15), 2391-5.
     
  15. Gallien, S., Delaugerre, C., Charreau, I., Braun, J., Boulet, T., Barrail-Tran, A., De Castro, N., Molina, J.M., Kuritzkes, D.R. (2011). Emerging integrase inhibitor resistance mutations in raltegravir-treated HIV-1-infected patients with low-level viremia. AIDS. 25(5), 665-9.
     
  16. Molina, JM, Cahn, P., Grinsztejn, B., Lazzarin, A., Mills, A., Saag, M., Supparatpinyo, K., Walmsley, S., Crauwels, H., Rimsky, L.T., Vanveggel, S., Boven, K., Echo Study Group. (2011). Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (Echo): a phase 3 randomised double-blind active-controlled trial. Lancet.  378(9787), 238-46.






     

 

 

 

APHP CANCEROPÔLE ÎLE-DE-FRANCE CEA CNRS EPHE HOPITAL ST LOUIS ILE DE FRANCE INCA INSERM Intranet