A combination of polymorphic mutations in V3 loop of HIV-1 gp120 can confer noncompetitive resistance to maraviroc

Yuan, Yuzhe; Maeda, Yosuke; Terasawa, Hiromi; Monde, Kazuaki; Harada, Shinji; Yusa, Kosuke

doi:10.1016/j.virol.2011.02.019

Cited by 25 publications

(33 citation statements)

References 33 publications

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“…With other classes of antiretroviral drugs, there are hundreds of published reports on the in vitro selection of drug resistance by multiple research groups. However, in vitro patterns of resistance to CCR5 antagonists with overlapping CCR5 binding sites is limited to just seven published studies, yet each study describes a different mutational pathway to resistance (20,(23)(24)(25)(35)(36)(37).…”

Section: Resultsmentioning

confidence: 99%

HIV-1 Resistance to Maraviroc Conferred by a CD4 Binding Site Mutation in the Envelope Glycoprotein gp120

Ratcliff

Shi

Arts

2013

J Virol

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Maraviroc (MVC) is a CCR5 antagonist that inhibits HIV-1 entry by binding to the coreceptor and inducing structural alterations in the extracellular loops. In this study, we isolated MVC-resistant variants from an HIV-1 primary isolate that arose after 21 weeks of tissue culture passage in the presence of inhibitor. gp120 sequences from passage control and MVC-resistant cultures were cloned into NL4-3 via yeast-based recombination followed by sequencing and drug susceptibility testing. Using 140 clones, three mutations were linked to MVC resistance, but none appeared in the V3 loop as was the case with previous HIV-1 strains resistant to CCR5 antagonists. Rather, resistance was dependent upon a single mutation in the C4 region of gp120. Chimeric clones bearing this N425K mutation replicated at high MVC concentrations and displayed significant shifts in 50% inhibitory concentrations (IC 50 s), characteristic of resistance to all other antiretroviral drugs but not typical of MVC resistance. Previous reports on MVC resistance describe an ability to use a drug-bound form of the receptor, leading to reduction in maximal drug inhibition. In contrast, our structural models on K425 gp120 suggest that this resistant mutation impacts CD4 interactions and highlights a novel pathway for MVC resistance.

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Section: Resultsmentioning

confidence: 99%

HIV-1 Resistance to Maraviroc Conferred by a CD4 Binding Site Mutation in the Envelope Glycoprotein gp120

Ratcliff

Shi

Arts

2013

J Virol

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“…One study showed that reverse mutations at positions 316 and 323 in the V3 loop of maraviroc-resistant HIV-1 variants to their original sequence restored wild-type susceptibility to maraviroc, while reversion of either mutation resulted in a partially sensitive virus with reduced maximal inhibition (Westby et al, 2007). In another recent study maraviroc-resistant variants were isolated from the V3 loop library virus (HIV-1(V3lib)) containing the T199K and T275M plus 5 mutations in the V3 loop, namely I304V; F312W; T314A; E317D; I318V (Yuan et al, 2011). Furthermore, the same study showed that the profile of HIV-1(JR-FL) pseudotype containing I304V/F312W/T314A/E317D/I318V ( Figure 7A) in the V3 loop alone revealed a typical non-competitive resistance to maraviroc (Yuan et al, 2011).…”

Section: Point Mutations Associated With Resistance To Attachment Inhmentioning

confidence: 99%

“…In another recent study maraviroc-resistant variants were isolated from the V3 loop library virus (HIV-1(V3lib)) containing the T199K and T275M plus 5 mutations in the V3 loop, namely I304V; F312W; T314A; E317D; I318V (Yuan et al, 2011). Furthermore, the same study showed that the profile of HIV-1(JR-FL) pseudotype containing I304V/F312W/T314A/E317D/I318V ( Figure 7A) in the V3 loop alone revealed a typical non-competitive resistance to maraviroc (Yuan et al, 2011). Generally, amino acids mutations in the V3 loop may include known polymorphism as well as novel substitutions, insertions, and deletions.…”

Section: Point Mutations Associated With Resistance To Attachment Inhmentioning

confidence: 99%

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

Khati¹,

Millroy²

2012

Point Mutation

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“…Although maraviroc (MVC), which is the first and currently only approved CCR5 antagonist for the treatment of CCR5-tropic (R5) HIV-1 infected patients, and another CCR5 inhibitor, vicriviroc (VCV), can efficiently suppress HIV-1 replication, drug-resistant variants can arise both in vitro and in vivo using drug-bound CCR5 for cellular entry (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The presence of MVC-resistant HIV-1 variants may be due to the outgrowth of pre-existing CXCR4-tropic (X4) HIV-1 viruses (19,20) or the selection of MVC-resistant R5 mutants (12,17).…”

Section: Introductionmentioning

confidence: 99%

“…The presence of MVC-resistant HIV-1 variants may be due to the outgrowth of pre-existing CXCR4-tropic (X4) HIV-1 viruses (19,20) or the selection of MVC-resistant R5 mutants (12,17). MVCresistant mutations are commonly detected in the gp120 V3 loop and are strain-specific (3,12,16,21,22).…”

Section: Introductionmentioning

confidence: 99%

Impact of the Maraviroc-Resistant Mutation M434I in the C4 Region of HIV-1 gp120 on Sensitivity to Antibody-Mediated Neutralization

et al. 2016

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SUMMARY:We previously reported that a maraviroc (MVC)-resistant human immunodeficiency virus type 1variant, generated using in vitro selection, exhibited high sensitivity to several neutralizing monoclonal antibodies (NMAbs) and autologous plasma IgGs. The MVC-resistant variant acquired 4 sequential mutations in gp120: T297I, M434I, V200I, and K305R. In this study, we examined the mutation most responsible for conferring enhanced neutralization sensitivity of the MVC-resistant variant to several NMAbs and autologous plasma IgGs. The virus with the first resistant mutation, T297I, was sensitive to all NMAbs, whereas the passage control virus was not. The neutralization sensitivity of the variant greatly increased following its acquisition of the second mutation, M434I, in the C4 region. The M434I mutation conferred the greatest neutralizing sensitivity among the 4 MVC-resistant mutations. Additionally, the single M434I mutation was sufficient for the enhanced neutralization of the virus by NMAbs, autologous plasma IgGs, and heterologous sera relative to that of the parental virus.

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A combination of polymorphic mutations in V3 loop of HIV-1 gp120 can confer noncompetitive resistance to maraviroc

Cited by 25 publications

References 33 publications

HIV-1 Resistance to Maraviroc Conferred by a CD4 Binding Site Mutation in the Envelope Glycoprotein gp120

HIV-1 Resistance to Maraviroc Conferred by a CD4 Binding Site Mutation in the Envelope Glycoprotein gp120

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

Impact of the Maraviroc-Resistant Mutation M434I in the C4 Region of HIV-1 gp120 on Sensitivity to Antibody-Mediated Neutralization

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