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.