In vitro selection and characterization of human immunodeficiency virus type 2 with decreased susceptibility to lopinavir.
Lopinavir (LPV)-ritonavir has demonstrated durable antiviral activity in human immunodeficiency virus type 1 (HIV-1)-infected antiretroviral-naïve and protease inhibitor (PI)-experienced patients. However, information on LPV activity against HIV-2 and the patterns of mutations in HIV-2 in response to selection by LPV is limited. The activity of LPV against three strains of HIV-2 was assessed and compared to activity against a reference HIV-1 strain. LPV demonstrated activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2(MS) and HIV-2(CBL-23)) tested. On the other hand, approximately 10-fold-reduced susceptibility was observed with the third HIV-2 strain, HIV-2(CDC310319). Passage of HIV-2(MS) with increasing concentrations of LPV selected mutations V47A and D17N in the HIV-2 protease gene. The introduction of both 17N and 47A either individually or together into HIV-2(ROD) molecular infectious clones showed that the single V47A substitution in HIV-2 resulted in a substantial reduction in susceptibility to LPV. In contrast, this mutant retained wild-type susceptibility to other PIs and appeared to be hypersusceptible to atazanavir and saquinavir.
Masse
Sherie
S
Antiviral Research, Global Pharmaceutical Research and Development, AP52N-1 Rm. 1133, 200 Abbott Park Road, Abbott Park, IL 60064, USA. Sherie.masse@abbott.com
Lu
Xiaozhi
X
Dekhtyar
Tatyana
T
Lu
Liangjun
L
Koev
Gennadiy
G
Gao
Feng
F
Mo
Hongmei
H
Kempf
Dale
D
Bernstein
Barry
B
Hanna
George J
GJ
Molla
Akhteruzzaman
A
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral; D024882:Drug Resistance, Viral; D016655:HIV Core Protein p24 / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015498:HIV-2 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D061466:Lopinavir; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D011744:Pyrimidinones / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D016655:HIV Core Protein p24; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D012194:RNA-Directed DNA Polymerase