title: Molecular strategies to design an escape-proof antiviral therapy.
abstract: Two antiviral approaches against the human immunodeficiency virus type 1 (HIV-1) were presented at the Antivirals Congress in Amsterdam. The common theme among these two separate therapeutic research lines is the wish to develop a durable therapy that prevents viral escape. We will present a brief overview of these two research lines and focus on our efforts to design an escape-proof anti-HIV therapy. The first topic concerns the class of HIV-1 fusion inhibitors, including the prototype T20 peptide and the improved versions T1249 and T2635, which were all developed by Trimeris-Roche. The selection of T20-resistant HIV-1 strains is a fairly easy evolutionary process that requires a single amino acid substitution in the peptide binding site of the viral envelope glycoprotein (Env) target. The selection of T1249-resistant HIV-1 strains was shown to require a more dramatic amino acid substitution in the viral Env protein, in particular the introduction of charged amino acid residues that cause resistance by charge-repulsion of the antiviral peptide. The third generation peptide T2635 remains active against all these HIV-1 escape variants because the charged residues within this peptide are "masked" by an introduced intra-helical salt bridge. This charge masking concept could facilitate the future design of escape-proof antiviral peptides. The second topic concerns the mechanism of RNA interference (RNAi) that we are currently employing to develop an antiviral gene therapy. One can make human T cells resistant to HIV-1 infection by a stable RNAi-inducing gene transfer, but the virus escapes under therapeutic pressure of a single inhibitor. Several options for a combinatorial RNAi attack to prevent viral escape will be discussed. The simultaneous use of multiple RNAi inhibitors turns out to be the most effective and durable strategy.
authors.affiliation: Laboratory of Experimental Virology, Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, The Netherlands. b.berkhout@amc.uva.nl
authors.forename: Ben
authors.initials: B
authors.lastname: Berkhout
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans
chemical_list: D019380:Anti-HIV Agents