title: The HR2 polymorphism N140I in the HIV-1 gp41 combined with the HR1 V38A mutation is associated with a less cytopathic phenotype.
abstract: BACKGROUND
  Resistance to the fusion inhibitor enfuvirtide (ENF) is achieved by changes in the gp41 subunit of the HIV envelope glycoprotein (Env). Specific ENF-associated mutational pathways correlate with immunological recovery, even after virological failure, suggesting that the acquisition of ENF resistance alters gp41 pathogenicity. To test this hypothesis, we have characterized the expression, fusion capability, induction of CD4+ T cell loss and single CD4+ T cell death of 48 gp41 proteins derived from three patients displaying different amino acids (N, T or I) at position 140 that developed a V38A mutation after ENF-based treatment.
  
  
  RESULTS
  In all cases, intra-patient comparison of Env isolated pre- or post-treatment showed comparable values of expression and fusogenic capacity. Furthermore, Env with either N or T at position 140 induced comparable losses of CD4+ T-cells, irrespective of the residue present at position 38. Conversely, Env acquiring the V38A mutation in a 140I background induced a significantly reduced loss of CD4+ T cells and lower single-cell death than did their baseline controls. No altered ability to induce single-cell death was observed in the other clones.
  
  
  CONCLUSIONS
  Overall, primary gp41 proteins with both V38A and N140I changes showed a reduced ability to induce single cell death and deplete CD4+ T cells, despite maintaining fusion activity. The specificity of this phenotype highlights the relevance of the genetic context to the cytopathic capacity of Env and the role of ENF-resistance mutations in modulating viral pathogenicity in vivo, further supporting the hypothesis that gp41 is a critical mediator of HIV pathogenesis.
authors.affiliation: IrsiCaixa-HIVACAT, Institut de Recerca en Ciències de la Salut Germans Trias i Pujol (IGTP), Hospital Germans Trias, Universitat Autònoma de Barcelona, Catalonia, Spain. ccabrera@irsicaixa.es.
authors.forename: Francesc
authors.initials: F
authors.lastname: Cunyat
authors.forename: Silvia
authors.initials: S
authors.lastname: Marfil
authors.forename: Elisabet
authors.initials: E
authors.lastname: García
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
authors.forename: Nuria
authors.initials: N
authors.lastname: Pérez-Alvárez
authors.forename: Marta
authors.initials: M
authors.lastname: Curriu
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Julià
authors.initials: J
authors.lastname: Blanco
authors.forename: Cecilia
authors.initials: C
authors.lastname: Cabrera
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology / Q000821:virology; D002470:Cell Survival; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000008:administration & dosage* / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D006801:Humans; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000494:pharmacology; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D050505:Mutant Proteins; D010446:Peptide Fragments; D037521:Virulence Factors; C514787:gp41 protein, Human immunodeficiency virus 1; D000077560:Enfuvirtide