Abstract
BackgroundMaturation inhibitors (MIs) potently block HIV-1 maturation by inhibiting the cleavage of the capsid protein and spacer peptide 1 (CA-SP1). Bevirimat (BVM), a highly efficacious first-in-class MI against HIV-1 subtype B isolates, elicited sub-optimal efficacy in clinical trials due to polymorphisms in the CA-SP1 region of the Gag protein (SP1:V7A). HIV-1 subtype C inherently contains this polymorphism thus conferring BVM resistance, however it displayed sensitivity to second generation BVM analogs.ResultsIn this study, we have assessed the efficacy of three novel second-generation MIs (BVM analogs: CV-8611, CV-8612, CV-8613) against HIV-1 subtype B and C isolates. The BVM analogs were potent inhibitors of both HIV-1 subtype B (NL4-3) and subtype C (K3016) viruses. Serial passaging of the subtype C, K3016 virus strain in the presence of BVM analogs led to identification of two mutant viruses—Gag SP1:A1V and CA:I201V. While the SP1:A1V mutant was resistant to the MIs, the CA:I120V mutant displayed partial resistance and a MI-dependent phenotype. Further analysis of the activity of the BVM analogs against two additional HIV-1 subtype C strains, IndieC1 and ZM247 revealed that they had reduced sensitivity as compared to K3016. Sequence analysis of the three viruses identified two polymorphisms at SP1 residues 9 and 10 (K3016: N9, G10; IndieC1/ZM247: S9, T10). The N9S and S9N mutants had no change in MI-sensitivity. On the other hand, replacing glycine at residue 10 with threonine in K3016 reduced its MI sensitivity whereas introducing glycine at SP1 10 in place of threonine in IndieC1 and ZM247 significantly enhanced their MI sensitivity. Thus, the specific glycine residue 10 of SP1 in the HIV-1 subtype C viruses determined sensitivity towards BVM analogs.ConclusionsWe have identified an association of a specific glycine at position 10 of Gag-SP1 with an MI susceptible phenotype of HIV-1 subtype C viruses. Our findings have highlighted that HIV-1 subtype C viruses, which were inherently resistant to BVM, may also be similarly predisposed to exhibit a significant degree of resistance to second-generation BVM analogs. Our work has strongly suggested that genetic differences between HIV-1 subtypes may produce variable MI sensitivity that needs to be considered in the development of novel, potent, broadly-active MIs.Graphic abstract
Highlights
Maturation inhibitors (MIs) potently block Human Immunodeficiency virus (HIV)-1 maturation by inhibiting the cleavage of the capsid protein and spacer peptide 1 (CA-SP1 region of the Gag protein (SP1))
BVM analogs inhibit HIV‐1 subtype B and C viruses Several C-28 analogs of BVM have been reported to be active against the HIV-1 subtype B NL4-3 virus, the NL4-3 SP1 V7A mutant, multiple HIV-1 primary isolates, and HIV-1 subtype C viruses [16, 17]
Our results strongly suggested that polymorphism at residue 10 in the HIV-1 subtype C Gag-SP1 region played a crucial role in regulating the sensitivity of the HIV-1 subtype C viruses against the BVM analogs
Summary
Maturation inhibitors (MIs) potently block HIV-1 maturation by inhibiting the cleavage of the capsid protein and spacer peptide 1 (CA-SP1). Long term usage of antiretroviral drugs can decrease the drug tolerability and lead to emergence of drug resistant viruses necessitating a continued requirement for the development of new anti-HIV drugs [3,4,5] In this regard, maturation inhibitors (MIs) represent a promising novel class of anti-HIV compounds. HIV maturation involves a highly ordered sequential cleavage of the full-length Gag polyprotein by the viral protease to produce mature virions. The maturation inhibitors (MIs) bind to the HIV Gag protein instead and block the access of the protease enzyme to cleave Gag. the cleavage of CA and SP1 is inhibited which is essential to produce mature capsid protein
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