Emergence of a drug-dependent human immunodeficiency virus type 1 variant during therapy with the T20 fusion inhibitor. Academic Article uri icon

Overview

abstract

  • The fusion inhibitor T20 belongs to a new class of anti-human immunodeficiency virus type 1 (HIV-1) drugs designed to block entry of the virus into the host cell. However, the success of T20 has met with the inevitable emergence of drug-resistant HIV-1 variants. We describe an evolutionary pathway taken by HIV-1 to escape from the selective pressure of T20 in a treated patient. Besides the appearance of T20-resistant variants, we report for the first time the emergence of drug-dependent viruses with mutations in both the HR1 and HR2 domains of envelope glycoprotein 41. We propose a mechanistic model for the dependence of HIV-1 entry on the T20 peptide. The T20-dependent mutant is more prone to undergo the conformational switch that results in the formation of the fusogenic six-helix bundle structure in gp41. A premature switch will generate nonfunctional envelope glycoproteins (dead spikes) on the surface of the virion, and T20 prevents this abortive event by acting as a safety pin that preserves an earlier prefusion conformation.

publication date

  • November 1, 2004

Research

keywords

  • Anti-HIV Agents
  • HIV Envelope Protein gp41
  • HIV-1
  • Membrane Fusion
  • Peptide Fragments

Identity

PubMed Central ID

  • PMC525057

Scopus Document Identifier

  • 7644236011

Digital Object Identifier (DOI)

  • 10.1128/JVI.78.22.12428-12437.2004

PubMed ID

  • 15507629

Additional Document Info

volume

  • 78

issue

  • 22