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Gastvortrag Joke MM den Haan

Datum: 29 November 2019
Zusammenfassung: CD169+ macrophages in lymphoid organs: Border patrol against infections and opportunity for vaccination strategies
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Kontakt
Sektion für Virologie
Department für Hygiene,
Mikrobiologie, Sozialmedizin
Medizinische Universität IBK

Peter-Mayr-Straße 4b
A-6020 Innsbruck

Tel.: 0512/9003-71701
Fax: 0512/9003-73701
E-Mail: virologie@i-med.ac.at
Molecular therapy of HIV infection
Members of project group:

  • Lisa Egerer, Dr. phil.nat.,  staff scientist
  • Janine Kimpel, Dr. phil.nat., staff scientist
  • Reinhard Tober, PhD student
  • Manuela Lunardon, technician


Achievements and Aims

Antiviral drugs suppress HIV-1 replication efficiently and have lead to a considerable increase in life expectancy and quality of life of individuals with HIV infection. However, the virus is not eliminated and the drugs must be given life-long. Current research now aims to develop more potent, i.e. curative therapeutics. We are developing an innovative gene therapy for HIV infection involving transfer of an antiviral gene to the target cells of HIV. As technically only a minor fraction of the target cells for HIV-1 in the patient can be genetically modified, this approach relies on the selective advantage and outgrowth of the protected cell population. Therefore, genes that inhibit prior to integration of the provirus are therapeutically most effective, as only these genes are expected to lead to an accumulation of non-infected, gene-protected cells (von Laer et al., 2006). Post-integration inhibitory genes will confer a selective advantage to cells harboring a suppressed provirus, leading to expansion of a latent virus reservoir. Accordingly, our approach aims at inhibition of virus entry.

Entry of HIV-1 into the target cell is a complex, multi-step process. Ultimately, the HIV-1 transmembrane envelope glycoprotein gp41 mediates fusion of the viral and cellular membranes. This process can be inhibited very effectively by C peptides derived from the C-terminal heptad repeat of gp41. C peptides interact with the trimeric coiled coil structure formed by the gp41 N-terminal heptad repeat and thereby lock gp41 in a fusion incompetent state. We engineered the inhibitory C46 peptide for expression on the cell membrane of CD4+ T cells (maC46), leading to high local concentration of peptide at the site of its antiviral action. (Egelhofer et al, 2004). MaC46 inhibits replication of different HIV-1 strains in cell lines and primary T cell cultures. Resistance to the maC46 does not develop rapidly (Hermann et al., 2009). Cells expressing maC46 are selected out in mixed (maC46 positive and -negative cells) HIV-1-infected T-cell cultures and in infected humanized mice (Kimpel et al., 2010). A pilot study with M87o in 10 advanced AIDS patients has been performed with J. van Lunzen in Hamburg as the principle investigator. No toxic side effects were observed. Gene marked cells have been detected now for more than 7 years, albeit at levels of below 1%.  No effect on the viral load was observed, but T helper cell counts have increased significantly (van Lunzen et al., 2007).

To improve antiviral efficacy even at low levels of gene modification, an in vivo secretable antiviral entry inhibitory (iSAVE) C peptide has now been developed (Egerer et al., 2011, Brauer et al., 2013). Success of this iSAVE strategy does not depend on in vivo selection of gene-modified cells and allows inhibition of HIV-1 replication also if only a minor proportion of cells are genetically modified. Currently, we are optimizing this promising new therapeutic approach.


References

  • Egelhofer M., Brandenburg, G., Martinius, H., Schult-Dietrich, P., Melikyan, G., Kunert, R., Baum, C., Choi, I., Alexandrov, A., von Laer, D.: Inhibition of HIV-1 entry in cells expressing gp41-derived peptides. J. Virol. 78:568 - 575, 2004.

  • von Laer, D., Hasselmann, S., Hasselmann, K.: Impact of gene-modified T cells on HIV infection dynamics. J. Theor. Biol. 238(1):60-77, 2006.

  • Van Lunzen, J., Glaunsinger, T., Stahmer, I., von Baehr, V., Baum, C., Schilz, A., Kuehlcke, K., Naundorf, S., Martinius, H., Hermann, F., Giroglou, T., Newrzela, S., Choi, I., Brauer, F., Brandenburg, G., Alexandrov, A., von Laer, D.: Transfer of autologous gene-modified T lymphocytes in HIV-infected patients with severe immunodeficiency. Mol. Ther. 15:1024-1033, 2007.

  • Hermann, F.G., Egerer, L., Brauer, F., Dietrich, U. von Laer, D.: Mutations in gp120 contribute to reduced sensitivity to the membrane-anchored fusion inhibitor maC46. J. Virol. 83:4844-4853, 2009.

  • Kimpel, J., Braun, S.S., Qui, G., Wong, F.E., Conolle, M., Brendel, C., Schmitz, J.E., Humeau, L.M., Dropulic, B., Rossi, J.J., *von Laer, D., *Johnson, R.P.: Survival of the fittest: Selection of vector-transduced cells during HIV-1 replication. PLoS One. 5(8):e12357, (Aug23) 2010. *contributed equally

  • Egerer, L., Volk, A., Kahle, J., Kimpel, J., Brauer, F., Hermann, F.G., von Laer, D.: Secreted Antiviral Entry Inhibitory (SAVE) Peptides for Gene Therapy of HIV infection. Mol Ther. 19(7):1236-44, 2011.
  • Brauer , F., Schmidt, K., Zahn, R.C., Richter, C., Radeke, H.H., Schmitz, J.E., von Laer, D., Egerer, L.: A rationally engineered anti-HIV peptide fusion inhibitor with greatly reduced immunogenicity. antimicrob Agents Chemother. 2013 Feb;57(2):679-88.

  • Younan, P.M., Polacino, P., Kolwaski, J.P., Peterson, C.W., Maurice, N.J., Williams, N.P., Ho, O., Trobridge, G.D., von Laer, D., Prlic, M., Beard, B.C., Derosa, S., Hu, S.L., Kiem, H.P.: Positive selection of mC46-expressing CD4+ T cells and maintenance of virus specific immunity in a primate AIDS model. Blood. 2013 July 11;122(2):179-87.