Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility

Abstract

f Hypersusceptibility (HS) to inhibition by different antiretroviral drugs (ARVs) among diverse HIV-infected individuals may be a misnomer because clinical response to treatment is evaluated in relation to subtype B infections while drug susceptibility of the infecting virus, regardless of subtype, is compared to a subtype B HIV-1 laboratory strain (NL4-3 or IIIB). Mounting evidence suggests that HS to different ARVs may result in better treatment outcome just as drug resistance leads to treatment failure. We have identified key amino acid polymorphisms in the protease coding region of a non-B HIV-1 subtype linked to protease inhibitor HS, namely, 17E and 64M in CRF02_AG. These HS-linked polymorphisms were introduced in the BD6-15 CRF02_AG molecular clone and tested for inhibition using a panel of protease inhibitors. In general, suspected HS-linked polymorphisms did increase susceptibility to specific protease inhibitors such as amprenavir and atazanavir, but the combination of the 17E/64M polymorphisms showed greater HS. These two mutations were found at low frequencies but linked in a sequence database of over 700 protease sequences of CRF02_AG. In direct head-to-head virus competitions, CRF02_AG harboring the 17E/64M polymorphisms also had higher replicative fitness than did the 17E or the 64M polymorphism in the CFR02_AG clone. These findings suggest that subtype-specific, linked polymorphisms can result in hypersusceptibility to ARVs. Considering the potential benefit of HS to treatment outcome, screening for potential HS-linked polymorphisms as well as preexisting drug resistance mutations in treatment-naïve patients may guide the choice of ARVs for the best treatment outcome.

Genetic diversity and antiretroviral resistance-associated mutation profile of treated and naive HIV-1 infected patients from the Northwest and Southwest regions of Cameroon

“…Santos et al . demonstrated the susceptibility of CRF02 (A/G) subtype to protease inhibitors such as nelfinavir and ritonavir when compared to B, C, F and G [57]. Unfortunately, of all the different subtypes in existence, only subtype B has been extensively studied in terms of drug resistance [56,58].…”

HIV-1 Genetic Variability and Clinical Implications

“…Similarly, the M89 polymorphism in subtypes A, C, and CRF01_AE (L89 in subtype B) preferentially leads to the emergence under drug pressure of the M89T mutation, which confers high-level resistance to nelfinavir, atazanavir, and lopinavir [192]. There is also in vitro evidence that CRF2_AG viruses with the 17E/64M polymorphisms demonstrate hypersusceptibility to certain PIs (nelfinavir, atazanavir, and indinavir) [193]. …”

Are subtype differences important in HIV drug resistance?

“…Similarly, the M89 polymorphism in subtypes A, C, and CRF01_AE (L89 in subtype B) preferentially leads to the emergence under drug pressure of the M89T mutation, which confers high-level resistance to nelfinavir, atazanavir and lopinavir [37]. There is also in vitro evidence that CRF2_AG viruses with the 17E/64M polymorphisms demonstrate hypersusceptibility to certain protease inhibitors (nelfinavir, atazanavir and indinavir) [38].…”