title: Impact of the HIV integrase genetic context on the phenotypic expression and in vivo emergence of raltegravir resistance mutations.
abstract: OBJECTIVE
  HIV resistance to the integrase inhibitor raltegravir in treated patients is characterized by distinct resistance pathways. We hypothesize that differences in the in vivo dynamics of HIV resistance to raltegravir are due to the genetic context of the integrase present at baseline.
  
  
  METHODS
  We studied four patients whose viruses evolved towards different resistance pathways. The integrase baseline sequences were inserted into a reference clone. Primary resistance mutations were then introduced and their impact on viral replication capacity (RC) and resistance was measured.
  
  
  RESULTS
  Patients A and B experienced emergence and persistence of mutation N155H under raltegravir therapy. In the integrase sequence from Patient A, N155H conferred potent resistance coupled with a lower impact on RC than Q148H. In Patient B, instead, selection of N155H could be explained by the dramatic loss of RC induced by the alternative Q148H mutation. In Patient C, N155H initially emerged and was later replaced by Q148H. In this integrase context, N155H resulted in higher RC but lower resistance than Q148H. In Patient D, Q148H rapidly emerged without appearance of N155H. This was the only patient for whom Q148H conferred higher RC and resistance than N155H.
  
  
  CONCLUSIONS
  The emergence of different resistance mutations in patients was in full agreement with the impact of mutations in different baseline integrase contexts. Evolution towards different resistance genotypes is thus largely determined by the capacity of different integrase sequences present at baseline to minimize the effect of mutations on virus RC while allowing expression of resistance.
authors.affiliation: INSERM, U941, F-75010 Paris, France Univ Paris Diderot, Sorbonne Paris Cité, IUH, F-75475 Paris, France AP-HP, Groupe Hospitalier Saint-Louis, F-75010 Paris, France.
authors.forename: Thi Thu Nga
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: INSERM, U941, F-75010 Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rato
authors.affiliation: INSERM, U941, F-75010 Paris, France Univ Paris Diderot, Sorbonne Paris Cité, IUH, F-75475 Paris, France AP-HP, Groupe Hospitalier Saint-Louis, F-75010 Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Molina
authors.affiliation: INSERM, U941, F-75010 Paris, France Univ Paris Diderot, Sorbonne Paris Cité, IUH, F-75475 Paris, France AP-HP, Groupe Hospitalier Saint-Louis, F-75010 Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Clavel
authors.affiliation: INSERM, U941, F-75010 Paris, France Univ Paris Diderot, Sorbonne Paris Cité, IUH, F-75475 Paris, France AP-HP, Groupe Hospitalier Saint-Louis, F-75010 Paris, France.
authors.forename: Constance
authors.initials: C
authors.lastname: Delaugerre
authors.affiliation: INSERM, U941, F-75010 Paris, France Univ Paris Diderot, Sorbonne Paris Cité, IUH, F-75475 Paris, France fabrizio.mammano@inserm.fr.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Mammano
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D006678:HIV / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D019427:HIV Integrase / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense; D011760:Pyrrolidinones / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase
keywords: evolution; integrase strand transfer inhibitors; resistance mechanisms