Type I interferon induction and elimination of memory T cells by HIV and other primate lentiviruses
Final Report Abstract
Altogether, we made some progress in elucidating why HIV-1 causes AIDS while some SIVs do not cause disease in their natural hosts. We found that Nef-mediated downmodulation of TCR-CD4 and Vpu dependent inhibition of NF-kB represent alternative ways to suppress antiviral gene expression. The latter is associated with increased inflammatory responses and HIV-1 characteristic features hence most likely contributing to the high levels of inflammation that drive AIDs. However, monkeys have evolved effective protective mechanisms to prevent chronic inflammation and disease. We also provide first evidence that Vpu and Nef functionally cooperate to allow efficient viral replication in vivo. Other studies provided novel insight into viral immune sensing and the role of the accessory protein Vpu, Vpr and Nef in modulating immune activation. Assays for the identification of circulating factors modulating HIV-induced inflammation from peptide libraries have been established and we identified IL-27 as potent inducer of antiviral factors, especially GBP5. Thus, the project yielded interesting results but also opened new questions for future studies.
Publications
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(2014).Limited HIV Infection of Central Memory and Stem Cell Memory CD4+ T Cells Is Associated with Lack of Progression in Viremic Individuals. PLoS Pathog. 10:e1004345
Klatt NR, Bosinger SE, Peck M, Richert-Spuhler LE, Heigele A, Gile JP, Patel N, Taaffe J, Julg B, Camerini D, Torti C, Martin JN, Deeks SG, Sinclair E, Hecht FM, Lederman MM, Paiardini M, Kirchhoff F, Brenchley JM, Hunt PW, and Silvestri G
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(2015). Differential regulation of NF-B- mediated proviral and antiviral host gene expression by primate lentiviral Nef and Vpu proteins. Cell Reports 10:586-599
Sauter D, Hotter D, Van Driessche B, Stürzel CM, Kluge SF, Wildum S, Yu H, Baumann B, Wirth T, Hahn BH, Van Lint C, and Kirchhoff, F
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(2016). HIV Triggers a cGAS-Dependent, Vpu- and Vpr-Regulated Type I Interferon Response in CD4+ T Cells. Cell Rep. 17: 413-424
Vermeire, J., Roesch, F., Sauter, D., Rua, R., Hotter, D., Van Nuffel, A., Vanderstraeten, H., Naessens, E., Iannucci, V., Landi, A., Witkowski, W., Baeyens, A., Kirchhoff, F., Verhasselt, B.
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(2016). Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance. MBio. 16;7: e00934-16
Kmiec, D., Iyer, S.S., Stürzel, C.M., Sauter, D., Hahn, B.H., Kirchhoff F.
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(2017) Primate lentiviruses use at least three alternative strategies to suppress NF-κB-mediated immune activation. PLoS Pathog. 13, e1006598
Hotter D, Krabbe T, Reith E, Gawanbacht A, Rahm N, Ayouba A, Van Driessche B, Van Lint C, Peeters M, Kirchhoff F, Sauter D
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(2018). Sooty mangabey genome sequence provides insight into AIDS resistance in a natural SIV host. Nature 553, 77-81
Palesch D, Bosinger SE, Tharp GK, Vanderford TH, Paiardini M, Chahroudi AM, Johnson ZP, Kirchhoff F, Hahn BH, Norgren RB Jr, Patel NB, Sodora DL, Dawoud R, Harris RH, Liu Y, Raveendran M, Han Y, English A, Thomas GWC, Hahn MW, Pipes L, Mason CE, Muzny DM, Gibbs R, Worley K, Sauter D, Rogers J, Silvestri G
