A V106M Mutation in HIV-1 Clade C Viruses Exposed ...
A V106M Mutation in HIV-1 Clade C Viruses Exposed ...
Objective: We have shown that HIV-1 clade C variants contain a valine codon 106 polymorphism (GTG) that facilitates a V106M transition (GTG
ATG) after selection with efavirenz (EFV). This study evaluates the prevalence of V106 (GTG) and 106M (ATG) codons in clinical isolates as well as the effects of V106M on resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI).
Methods: Genotypic analysis ascertained sequence diversity at codon 106, including both valine polymorphisms (GTA and GTG) and the V106A (GCA) and V106M (ATG) resistance-conferring mutations in B (n = 440) and non-B (n = 84) clinical isolates. Cell-based phenotypic assays were performed to determine the effects of V106M and V106A on levels of resistance to EFV, nevirapine and delavirdine.
Results: Most subtype B isolates harbored GTA (valine) at codon 106 (97% of cases) while the GTG (valine) polymorphism was generally present in clade C viruses (94% of cases). Under conditions of EFV but not nevirapine or delavirdine pressure (n = 8) in tissue culture, clade C isolates developed the V106M mutation (GTG
ATG), conferring high-level (100-1000-fold) cross-resistance to all NNRTI. Generation of V106M recombinant viruses by site-directed mutagenesis confirmed the ability of V106M to confer NNRTI cross-resistance. This mutation also developed in three of six EFV-treated patients harboring clade C infections. In current genotypic interpretative reports (including 15 algorithmic databases), V106A is listed as an nevirapine-specific mutation while V106M is not recognized.
Conclusions: V106M may be a signature mutation in clade C patients treated with EFV and may have the potential to confer high-level multi-NNRTI resistance.
Highly active antiretroviral therapy with the three classes of antiretroviral drugs, namely nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTI and NNRTI) and protease inhibitors (PI) has helped to stabilize disease progression of predominantly subtype B infections in Western countries. However, global epidemics with group M (non-B, A through J) and O clades in resource-poor nations are expanding and it is essential to develop effective management strategies for non-B clade infections. Most commercialized drugs have been studied against clade B viruses and clade B reverse transcriptase (RT) and protease. To date, limited information is available on other subtypes in regard to virological or treatment response.
Efavirenz (EFV) given once daily in combination with two NRTI possesses potent antiviral activity. Recent studies, including preliminary analysis of the ACTG 384 study suggest that a first-line regimen of choice is zidovudine (ZDV)/lamivudine (3TC)/EFV. We have observed that resistance to EFV in clade C viruses can develop in vitro as a result of a V106M mutation that arises due to a natural GTG polymorphism at codon 106 in clade C variants, that is distinct from the nevirapine (NVP)-associated mutation at position 106 (i.e., V106A) commonly seen in clade B viruses. The GTG polymorphism is largely limited to clade C viruses, yielding V106M in EFV-selected cells, while the naturally occurring codon in clade B viruses is GTA. We now show the prevalence of this GTG polymorphism in clinical isolates, the in vitro and in vivo evolution of EFV resistance in isolates carrying this polymorphism, and the consequences of V106M on responses to other NNRTI. We have also confirmed the significance of the V106M mutation by site-directed mutagenesis.
Objective: We have shown that HIV-1 clade C variants contain a valine codon 106 polymorphism (GTG) that facilitates a V106M transition (GTG
ATG) after selection with efavirenz (EFV). This study evaluates the prevalence of V106 (GTG) and 106M (ATG) codons in clinical isolates as well as the effects of V106M on resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI).
Methods: Genotypic analysis ascertained sequence diversity at codon 106, including both valine polymorphisms (GTA and GTG) and the V106A (GCA) and V106M (ATG) resistance-conferring mutations in B (n = 440) and non-B (n = 84) clinical isolates. Cell-based phenotypic assays were performed to determine the effects of V106M and V106A on levels of resistance to EFV, nevirapine and delavirdine.
Results: Most subtype B isolates harbored GTA (valine) at codon 106 (97% of cases) while the GTG (valine) polymorphism was generally present in clade C viruses (94% of cases). Under conditions of EFV but not nevirapine or delavirdine pressure (n = 8) in tissue culture, clade C isolates developed the V106M mutation (GTG
ATG), conferring high-level (100-1000-fold) cross-resistance to all NNRTI. Generation of V106M recombinant viruses by site-directed mutagenesis confirmed the ability of V106M to confer NNRTI cross-resistance. This mutation also developed in three of six EFV-treated patients harboring clade C infections. In current genotypic interpretative reports (including 15 algorithmic databases), V106A is listed as an nevirapine-specific mutation while V106M is not recognized.
Conclusions: V106M may be a signature mutation in clade C patients treated with EFV and may have the potential to confer high-level multi-NNRTI resistance.
Highly active antiretroviral therapy with the three classes of antiretroviral drugs, namely nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTI and NNRTI) and protease inhibitors (PI) has helped to stabilize disease progression of predominantly subtype B infections in Western countries. However, global epidemics with group M (non-B, A through J) and O clades in resource-poor nations are expanding and it is essential to develop effective management strategies for non-B clade infections. Most commercialized drugs have been studied against clade B viruses and clade B reverse transcriptase (RT) and protease. To date, limited information is available on other subtypes in regard to virological or treatment response.
Efavirenz (EFV) given once daily in combination with two NRTI possesses potent antiviral activity. Recent studies, including preliminary analysis of the ACTG 384 study suggest that a first-line regimen of choice is zidovudine (ZDV)/lamivudine (3TC)/EFV. We have observed that resistance to EFV in clade C viruses can develop in vitro as a result of a V106M mutation that arises due to a natural GTG polymorphism at codon 106 in clade C variants, that is distinct from the nevirapine (NVP)-associated mutation at position 106 (i.e., V106A) commonly seen in clade B viruses. The GTG polymorphism is largely limited to clade C viruses, yielding V106M in EFV-selected cells, while the naturally occurring codon in clade B viruses is GTA. We now show the prevalence of this GTG polymorphism in clinical isolates, the in vitro and in vivo evolution of EFV resistance in isolates carrying this polymorphism, and the consequences of V106M on responses to other NNRTI. We have also confirmed the significance of the V106M mutation by site-directed mutagenesis.