Susceptibility to protease inhibitors in HIV-2 primary isolates from patients failing antiretroviral therapy.
BACKGROUND
Current protease inhibitors (PIs) are designed against HIV-1, and information on their performance against HIV-2 clinical isolates is scarce.


METHODS
Genetic and phenotypic analyses using all available PIs were performed in five HIV-2 primary isolates from two patients on regular follow-up who failed PI-HAART.


RESULTS
HIV-2 proteases before therapy showed amino acids associated with resistance in HIV-1 (pro10V, pro32I, pro36I, pro46I, pro47V, pro71V and pro73A). Phenotypic results showed that indinavir, saquinavir, lopinavir and tipranavir had full activity against wild-type HIV-2. However, a susceptibility reduction was noticed for nelfinavir (6.6-fold) and amprenavir (31-fold). During therapy with lopinavir, one patient developed proV47A, which translated into high-level resistance (13.4- to 41-fold) to indinavir, lopinavir and amprenavir, and hypersusceptibility to saquinavir. All isolates from the other patient had multiple mutations after several PIs failed (proV10I, proV33L, proI54M, proV71I and proI82F). The acquisition of mutations 54M and 82F along with naturally occurring changes resulted in multi-PI-resistant viruses (33- to >1000-fold), and only saquinavir retained full activity.


CONCLUSIONS
Naturally occurring secondary mutations or polymorphisms in the HIV-2 protease may decrease the activity of nelfinavir and amprenavir. Moreover, upon selection of primary resistance mutations, pre-existing secondary changes might play an important role in the acquisition of a multi-PI resistance phenotype in HIV-2.
Rodés
Berta
B
Molecular Biology Laboratory, Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. brodes.hciii@salud.madrid.org
Sheldon
Julie
J
Toro
Carlos
C
Jiménez
Victoria
V
Alvarez
Miguel Angel
MA
Soriano
Vincent
V
D023241:Antiretroviral Therapy, Highly Active; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D015498:HIV-2 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D008969:Molecular Sequence Data; D010641:Phenotype; D017422:Sequence Analysis, DNA; D017211:Treatment Failure
D017320:HIV Protease Inhibitors