Project : Paving the way toward HIV eradication/control 2010-2015 Acronym: Silent HIV

Human Immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, infects primarily cells of the immune system. The outcome of HIV-1 infection results from complex interactions between viral proteins and host cell factors. In most cases, HIV-1 successfully hijacks cellular pathways and bypasses cellular restriction factors for optimal replication leading to continuous rounds of infection, replication and cell death. Continuous viral replication causes the loss of CD4+T cells and progression to immunodeficiency in infected individuals. However, in certain situations virus replication can be successfully controlled. First, HAART (Highly Active AntiRetroviral Therapy) treatment revealed the existence of a pool of resting memory CD4+ T cells harbouring integrated but silent HIV-1 provirus. Although this situation occurs in a small number of cells, it suggests that intracellular defence mechanisms can be effective against HIV. This long-lived viral reservoir is believed to be the major obstacle against HIV-1 eradication by HAART. Second, HIV-infected individuals who are able to control their virus to undetectable levels for many years in absence of any treatment have been identified and referred to as Elite HIV controllers “EC”. Again, this is a rare situation observed in 0.5% of infected patients. Still, it demonstrates that it is possible to naturally and effectively control HIV replication and disease progression. A common feature of these two situations is that virus replication is controlled at the gene expression level. A major challenge in the HIV field is to understand how these naturally occurring situations where intracellular defence and/or immune response win the battle against HIV. Our project aims at identifying the host factors and define the molecular mechanisms involved in the control of virus replication both in HAART-treated and in EC patients.

Major Contribution

Transcription field

He, N., Chan, C.K., Sobhian, B., Chou, S., Xue, Y., Liu, M., Alber, T., Benkirane, M., Zhou, Q., 2011. Human Polymerase-Associated Factor complex (PAFc) connects the Super Elongation Complex (SEC) to RNA polymerase II on chromatin. Proc. Natl. Acad. Sci. U. S. A. 108, E636-645. https://doi.org/10.1073/pnas.1107107108

Latreille, D., Bluy, L., Benkirane, M., Kiernan, R.E., 2014. Identification of histone 3 variant 2 interacting factors. Nucleic Acids Res. 42, 3542–3550. https://doi.org/10.1093/nar/gkt1355

Sobhian, B., Laguette, N., Yatim, A., Nakamura, M., Levy, Y., Kiernan, R., Benkirane, M., 2010. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol. Cell 38, 439–451. https://doi.org/10.1016/j.molcel.2010.04.012

This manuscript, together with the manuscript from Q.Zhou’s Lab and A.Shillatifard’s Lab discovered the Super Elongation Complex (SEC).

Stadelmayer, B., Micas, G., Gamot, A., Martin, P., Malirat, N., Koval, S., Raffel, R., Sobhian, B., Severac, D., Rialle, S., Parrinello, H., Cuvier, O., Benkirane, M., 2014. Integrator complex regulates NELF-mediated RNA polymerase II pause/release and processivity at coding genes. Nat. Commun. 5, 5531. https://doi.org/10.1038/ncomms6531

This manuscript showed for the first time the involvement of Integrator complex in regulating RNPII pausing and termination at coding genes.

Wagschal, A., Rousset, E., Basavarajaiah, P., Contreras, X., Harwig, A., Laurent-Chabalier, S., Nakamura, M., Chen, X., Zhang, K., Meziane, O., Boyer, F., Parrinello, H., Berkhout, B., Terzian, C., Benkirane, M., Kiernan, R., 2012. Microprocessor, Setx, Xrn2, and Rrp6 co-operate to induce premature termination of transcription by RNAPII. Cell 150, 1147–1157. https://doi.org/10.1016/j.cell.2012.08.004

Yatim, A., Benne, C., Sobhian, B., Laurent-Chabalier, S., Deas, O., Judde, J.-G., Lelievre, J.-D., Levy, Y., Benkirane, M., 2012. NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. Mol. Cell 48, 445–458. https://doi.org/10.1016/j.molcel.2012.08.022

Intrinsic immune response field

Bennasser, Y., Chable-Bessia, C., Triboulet, R., Gibbings, D., Gwizdek, C., Dargemont, C., Kremer, E.J., Voinnet, O., Benkirane, M., 2011. Competition for XPO5 binding between Dicer mRNA, pre-miRNA and viral RNA regulates human Dicer levels. Nat. Struct. Mol. Biol. 18, 323–327. https://doi.org/10.1038/nsmb.1987

Brégnard, C., Benkirane, M., Laguette, N., 2014. DNA damage repair machinery and HIV escape from innate immune sensing. Front. Microbiol. 5, 176. https://doi.org/10.3389/fmicb.2014.00176

Brégnard, C., Guerra, J., Déjardin, S., Passalacqua, F., Benkirane, M., Laguette, N., 2016. Upregulated LINE-1 Activity in the Fanconi Anemia Cancer Susceptibility Syndrome Leads to Spontaneous Pro-inflammatory Cytokine Production. EBioMedicine 8, 184–194. https://doi.org/10.1016/j.ebiom.2016.05.005

Clifford, R., Louis, T., Robbe, P., Ackroyd, S., Burns, A., Timbs, A.T., Wright Colopy, G., Dreau, H., Sigaux, F., Judde, J.G., Rotger, M., Telenti, A., Lin, Y.-L., Pasero, P., Maelfait, J., Titsias, M., Cohen, D.R., Henderson, S.J., Ross, M.T., Bentley, D., Hillmen, P., Pettitt, A., Rehwinkel, J., Knight, S.J.L., Taylor, J.C., Crow, Y.J., Benkirane, M., Schuh, A., 2014. SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage. Blood 123, 1021–1031. https://doi.org/10.1182/blood-2013-04-490847

Laguette, N., Brégnard, C., Hue, P., Basbous, J., Yatim, A., Larroque, M., Kirchhoff, F., Constantinou, A., Sobhian, B., Benkirane, M., 2014. Premature activation of the SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing. Cell 156, 134–145. https://doi.org/10.1016/j.cell.2013.12.011

Laguette, N., Rahm, N., Sobhian, B., Chable-Bessia, C., Münch, J., Snoeck, J., Sauter, D., Switzer, W.M., Heneine, W., Kirchhoff, F., Delsuc, F., Telenti, A., Benkirane, M., 2012. Evolutionary and functional analyses of the interaction between the myeloid restriction factor SAMHD1 and the lentiviral Vpx protein. Cell Host Microbe 11, 205–217. https://doi.org/10.1016/j.chom.2012.01.007

Laguette, N., Sobhian, B., Casartelli, N., Ringeard, M., Chable-Bessia, C., Ségéral, E., Yatim, A., Emiliani, S., Schwartz, O., Benkirane, M., 2011. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474, 654–657. https://doi.org/10.1038/nature10117

Lahouassa, H., Daddacha, W., Hofmann, H., Ayinde, D., Logue, E.C., Dragin, L., Bloch, N., Maudet, C., Bertrand, M., Gramberg, T., Pancino, G., Priet, S., Canard, B., Laguette, N., Benkirane, M., Transy, C., Landau, N.R., Kim, B., Margottin-Goguet, F., 2012. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat. Immunol. 13, 223–228. https://doi.org/10.1038/ni.2236Beyond the seminal discovery of SAMHD1 as the HIV restriction factor, altogether these manuscripts put the bases of the cross talk between DNA repair pathways and innate immune response. Production of proinflammatory cytokine was found to be an intrinsic property of cancer cell.