title: Genetic and structural analysis of HIV-1 Rev responsive element related to V38A and T18A enfuvirtide resistance mutations.
abstract: BACKGROUND
  For the expression of late viral genes, HIV-1 efficiently exploits the nuclear export by using Rev viral protein, which specifically binds the RNA Rev Responsive Element (RRE). This region is contained within the gp120-gp41 encoding sequence. Enfuvirtide is the first approved HIV-1 fusion-inhibitor, and gp41 codons associated with primary enfuvirtide-resistance (amino-acids 36-45) are localized within the RRE structure. We previously found the co-presence of V38A+T18A resistance mutations in patients failing enfuvirtide.
  
  
  METHODS
  Collecting 476 and 135 HIV-1 B-subtype gp41 sequences from enfuvirtide-naïve and enfuvirtide-treated patients, respectively, two mutations previously found associated with enfuvirtide treatment, T18A and V38A, were analyzed. Moreover, the RNA secondary structure was displayed by CONTRAfold-software and the gp41 evolutionary pathways by a mutagenetic tree.
  
  
  RESULTS
  By modeling the RRE structure, we show that the T18 and V38 codons are base pairing within the RRE-stem-IIA, an important domain involved in Rev binding. While a structural RRE impairment in the presence of V38A alone was found, a restoration of the original RRE structure occurred in co-presence of V38A+T18A. By mutagenetic tree analysis, a compensatory evolution confirming our hypothesis on the structural modification mechanism was observed.
  
  
  CONCLUSIONS
  We show that enfuvirtide pressure may also affect specific RRE domains involved in Rev binding, thus requiring a compensatory evolution able to preserve the secondary structure of the RRE.
authors.affiliation: University of Rome Tor Vergata, Rome, Italy. salvatore.dimonte @ uniroma2.it
authors.forename: Salvatore
authors.initials: S
authors.lastname: Dimonte
authors.forename: Fabio
authors.initials: F
authors.lastname: Mercurio
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
authors.forename: Carlo-Federico
authors.initials: CF
authors.lastname: Perno
authors.forename: Francesca
authors.initials: F
authors.lastname: Ceccherini-Silberstein
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology*; D020029:Base Pairing; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015752:Genes, env / Q000235:genetics*; D015700:HIV Envelope Protein gp41 / Q000235:genetics* / Q000494:pharmacology*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D009690:Nucleic Acid Conformation; D010446:Peptide Fragments / Q000494:pharmacology*; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D012367:RNA, Viral; C514787:gp41 protein, Human immunodeficiency virus 1; D000077560:Enfuvirtide