title: Complex patterns of protease inhibitor resistance among antiretroviral treatment-experienced HIV-2 patients from Senegal: implications for second-line therapy.
abstract: Protease inhibitor (PI)-based antiretroviral therapy (ART) can effectively suppress HIV-2 plasma load and increase CD4 counts; however, not all PIs are equally active against HIV-2, and few data exist to support second-line therapy decisions. To identify therapeutic options for HIV-2 patients failing ART, we evaluated the frequency of PI resistance-associated amino acid changes in HIV-2 sequences from a cohort of 43 Senegalese individuals receiving unboosted indinavir (n = 18 subjects)-, lopinavir/ritonavir (n = 4)-, or indinavir and then lopinavir/ritonavir (n = 21)-containing ART. Common protease substitutions included V10I, V47A, I54M, V71I, I82F, I84V, L90M, and L99F, and most patients harbored viruses containing multiple changes. Based on genotypic data, we constructed a panel of 15 site-directed mutants of HIV-2ROD9 containing single- or multiple-treatment-associated amino acid changes in the protease-encoding region of pol. We then quantified the susceptibilities of the mutants to the HIV-2 "active" PIs saquinavir, lopinavir, and darunavir using a single-cycle assay. Relative to wild-type HIV-2, the V47A mutant was resistant to lopinavir (6.3-fold increase in the mean 50% effective concentration [EC50]), the I54M variant was resistant to darunavir and lopinavir (6.2- and 2.7-fold increases, respectively), and the L90M mutant was resistant to saquinavir (3.6-fold increase). In addition, the triple mutant that included I54M plus I84V plus L90M was resistant to all three PIs (31-, 10-, and 3.8-fold increases in the mean EC50 for darunavir, saquinavir, and lopinavir, respectively). Taken together, our data demonstrate that PI-treated HIV-2 patients frequently harbor viruses that exhibit complex patterns of PI cross-resistance. These findings suggest that sequential PI-based regimens for HIV-2 treatment may be ineffective.
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, School of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Dana N
authors.initials: DN
authors.lastname: Raugi
authors.forename: Robert A
authors.initials: RA
authors.lastname: Smith
authors.forename: Selly
authors.initials: S
authors.lastname: Ba
authors.forename: Macoumba
authors.initials: M
authors.lastname: Toure
authors.forename: Fatou
authors.initials: F
authors.lastname: Traore
authors.forename: Fatima
authors.initials: F
authors.lastname: Sall
authors.forename: Charlotte
authors.initials: C
authors.lastname: Pan
authors.forename: Lindsey
authors.initials: L
authors.lastname: Blankenship
authors.forename: Alexandra
authors.initials: A
authors.lastname: Montano
authors.forename: Julia
authors.initials: J
authors.lastname: Olson
authors.forename: Ndeye Mery
authors.initials: NM
authors.lastname: Dia Badiane
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Kiviat
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Hawes
authors.forename: Papa Salif
authors.initials: PS
authors.lastname: Sow
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Gottlieb
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000187:drug effects*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000187:drug effects / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D015498:HIV-2 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010802:Phylogeny; D012675:Senegal; D017422:Sequence Analysis, DNA
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D016333:HIV Protease