Short-Term Monotherapy in HIV-Infected Patients with a Virus Entry Inhibitor Against the gp41 Fusion Peptide

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Science Translational Medicine  22 Dec 2010:
Vol. 2, Issue 63, pp. 63re3
DOI: 10.1126/scitranslmed.3001697

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Anchors Away: Blocking HIV Entry

Combination antiretroviral therapy has been very successful for treating infection with the human immunodeficiency virus (HIV-1), which causes AIDS. However, drug resistance is emerging and there is a need to develop new antiretroviral drugs that work earlier in the virus life cycle, for example, by preventing HIV-1 from entering host cells. Two such virus entry inhibitors, maraviroc and T-20, are in clinical use, but both have drawbacks. Forssmann, Kirchhoff and their colleagues have now developed a new virus entry inhibitor called VIRIP (VIRus-Inhibitory Peptide), a 20-peptide fragment of α1-antitrypsin, an abundant circulating serine protease inhibitor. VIRIP and its optimized derivative VIR-576 are so-called anchoring inhibitors because they prevent the gp41 fusion peptide of HIV-1 from inserting itself into the host cell membrane. This then blocks the next step in the virus life cycle, which is fusion of the virion envelope with the host cell membrane.

Forssmann and co-workers now report on a Phase I/II clinical trial in which 18 HIV-1–infected patients who were not on any other antiretroviral therapy were treated for 10 days with three different doses of VIR-576 (0.5, 1.5, 5.0 g/day). They show that VIR-576 reduced the viral load in the plasma of patients on the highest dose by an order of magnitude and that the drug was well tolerated. Previous studies have shown that the gp41 fusion peptide is essential for HIV-1 entry into host cells, and suggest that it may be difficult for HIV-1 to develop resistance to VIR-576 because the fusion peptide is highly conserved and hardly tolerates changes without loss of function. This anchoring inhibitor, unlike other HIV entry inhibitors, is also active against many different HIV strains and has a different target (the gp41 fusion peptide). Thus, VIR-576 represents a potential new class of HIV entry inhibitor. However, VIR-576 does have some drawbacks too. Because VIR-576 is a peptide, it will be costly and time-consuming to produce and it must be administered intravenously. This has prompted Kirchhoff and colleagues to start searching for a small molecule that would block the gp41 fusion peptide in the same way as VIR-576 but would have the advantage that it could be made cheaper and given orally.


  • Citation: W.-G. Forssmann, Y.-H. The, M. Stoll, K. Adermann, U. Albrecht, K. Barlos, A. Busmann, A. Canales-Mayordomo, G. Giménez-Gallego, J. Hirsch, J. Jiménez-Barbero, D. Meyer-Olson, J. Münch, J. Pérez-Castells, L. Ständker, F. Kirchhoff, R. E. Schmidt, Short-Term Monotherapy in HIV-Infected Patients with a Virus Entry Inhibitor Against the gp41 Fusion Peptide. Sci. Transl. Med. 2, 63re3 (2010).

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