title: Phenotypic susceptibility of HIV-2 to raltegravir: integrase mutations Q148R and N155H confer raltegravir resistance.
abstract: OBJECTIVE
  Raltegravir is the first integrase strand transfer inhibitor approved for treating HIV-1 infection. Although emerging data suggest that raltegravir may also be useful for HIV-2 treatment, studies addressing the in-vitro susceptibility of HIV-2 to raltegravir are scarce, and the genetic pathways leading to raltegravir resistance in HIV-2 have not been adequately characterized. Our objectives were to directly compare the susceptibilities of HIV-1 and HIV-2 to raltegravir and to examine the role of mutations in HIV-2 integrase in emergent raltegravir resistance.
  
  
  METHODS
  Single-cycle and spreading infection assays were used to quantify the sensitivities of wild-type HIV-1 and HIV-2 strains to raltegravir. HIV-2 integrase mutants were constructed by site-directed mutagenesis, and the replication capacities and raltegravir susceptibilities of the resultant variants were analyzed in single-cycle assays.
  
  
  RESULTS
  Raltegravir showed comparable activity against wild-type HIV-1 and HIV-2 in both single-cycle and spreading infections, with EC(50) values in the low nanomolar range. Amino acid changes Q148R and N155H individually conferred resistance to raltegravir (14-fold and seven-fold, respectively), whereas the Y143C replacement had no statistically significant effect on raltegravir sensitivity. The combination of Q148R with N155H resulted in high-level raltegravir resistance (>1000-fold). In addition, all HIV-2 integrase variants tested showed impairments in replication capacity.
  
  
  CONCLUSIONS
  Our data support clinical studies of raltegravir for treating HIV-2 infection and show that the Q148R and N155H changes alone are sufficient for raltegravir resistance in HIV-2. Further efforts are needed to improve access to HIV-2-active antiretrovirals, including raltegravir, in resource-limited areas where HIV-2 is endemic.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98109, USA. smithra@u.washington.edu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Smith
authors.forename: Dana N
authors.initials: DN
authors.lastname: Raugi
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Kiviat
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Hawes
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: Papa S
authors.initials: PS
authors.lastname: Sow
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Gottlieb
mesh_terms: D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy*; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D015498:HIV-2 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D016297:Mutagenesis, Site-Directed; D011760:Pyrrolidinones / Q000494:pharmacology*; D000068898:Raltegravir Potassium
chemical_list: D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase