Analysis of clinical HIV-1 strains with resistance to maraviroc reveals Strain-specific resistance mutations, variable degrees of resistance, and minimal cross-resistance to other CCR5 antagonists

Jacqueline Kaye Flynn, Paula Clarisa Ellenberg, Renee Duncan, Anne Ellett, Jingling Zhou, Jasminka Sterjovski, Kieran Cashin, Katharina Borm, Lachlan Robert Gray, Marilyn Lewis, Becky Jubb, Mike Westby, Benhur Lee, Sharon Lewin, Melissa Churchill, Michael John Roche, Paul Rene Gorry

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Maraviroc (MVC) is an allosteric inhibitor of human immunodeficiency virus type 1 (HIV-1) entry, and is the only CCR5 antagonist licensed for use as an anti-HIV-1 therapeutic. It acts by altering the conformation of the CCR5 extracellular loops, rendering CCR5 unrecognizable by the HIV-1 envelope (Env) glycoproteins. This study aimed to understand the mechanisms underlying the development of MVC resistance in HIV-1-infected patients. To do this, we obtained longitudinal plasma samples from eight subjects who experienced treatment failure with phenotypically verified, CCR5-tropic MVC resistance. We then cloned and characterized HIV-1 Envs (n = 77) from plasma of pretreatment (n = 36) and treatment failure (n = 41) samples. Our results showed variation in the magnitude of MVC resistance as measured by reductions in maximal percent inhibition of Env-pseudotyped viruses, which was more pronounced in 293-Affinofile cells compared to other cells with similar levels of CCR5 expression. Amino acid determinants of MVC resistance localized to the V3 Env region and were strain specific. We also observed minimal cross-resistance to other CCR5 antagonists by MVC-resistant strains. We conclude that 293-Affinofile cells are highly sensitive for detecting and measuring MVC resistance through a mechanism that is CCR5-dependent yet independent of CCR5 expression levels. The strain-specific nature of resistance mutations suggests that sequence-based diagnostics and prognostics will need to be more sophisticated than simple position scoring to be useful for managing resistance in subjects taking MVC. Finally, the minimal levels of cross-resistance suggests that recognition of the MVC-modified form of CCR5 does not necessarily lead to recognition of other antagonist-modified forms of CCR5.
Original languageEnglish
JournalAIDS Research and Human Retroviruses
Volume33
Issue number12
DOIs
Publication statusPublished - 2017

Cite this

Flynn, Jacqueline Kaye ; Ellenberg, Paula Clarisa ; Duncan, Renee ; Ellett, Anne ; Zhou, Jingling ; Sterjovski, Jasminka ; Cashin, Kieran ; Borm, Katharina ; Gray, Lachlan Robert ; Lewis, Marilyn ; Jubb, Becky ; Westby, Mike ; Lee, Benhur ; Lewin, Sharon ; Churchill, Melissa ; Roche, Michael John ; Gorry, Paul Rene. / Analysis of clinical HIV-1 strains with resistance to maraviroc reveals Strain-specific resistance mutations, variable degrees of resistance, and minimal cross-resistance to other CCR5 antagonists. In: AIDS Research and Human Retroviruses. 2017 ; Vol. 33, No. 12.
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title = "Analysis of clinical HIV-1 strains with resistance to maraviroc reveals Strain-specific resistance mutations, variable degrees of resistance, and minimal cross-resistance to other CCR5 antagonists",
abstract = "Maraviroc (MVC) is an allosteric inhibitor of human immunodeficiency virus type 1 (HIV-1) entry, and is the only CCR5 antagonist licensed for use as an anti-HIV-1 therapeutic. It acts by altering the conformation of the CCR5 extracellular loops, rendering CCR5 unrecognizable by the HIV-1 envelope (Env) glycoproteins. This study aimed to understand the mechanisms underlying the development of MVC resistance in HIV-1-infected patients. To do this, we obtained longitudinal plasma samples from eight subjects who experienced treatment failure with phenotypically verified, CCR5-tropic MVC resistance. We then cloned and characterized HIV-1 Envs (n = 77) from plasma of pretreatment (n = 36) and treatment failure (n = 41) samples. Our results showed variation in the magnitude of MVC resistance as measured by reductions in maximal percent inhibition of Env-pseudotyped viruses, which was more pronounced in 293-Affinofile cells compared to other cells with similar levels of CCR5 expression. Amino acid determinants of MVC resistance localized to the V3 Env region and were strain specific. We also observed minimal cross-resistance to other CCR5 antagonists by MVC-resistant strains. We conclude that 293-Affinofile cells are highly sensitive for detecting and measuring MVC resistance through a mechanism that is CCR5-dependent yet independent of CCR5 expression levels. The strain-specific nature of resistance mutations suggests that sequence-based diagnostics and prognostics will need to be more sophisticated than simple position scoring to be useful for managing resistance in subjects taking MVC. Finally, the minimal levels of cross-resistance suggests that recognition of the MVC-modified form of CCR5 does not necessarily lead to recognition of other antagonist-modified forms of CCR5.",
author = "Flynn, {Jacqueline Kaye} and Ellenberg, {Paula Clarisa} and Renee Duncan and Anne Ellett and Jingling Zhou and Jasminka Sterjovski and Kieran Cashin and Katharina Borm and Gray, {Lachlan Robert} and Marilyn Lewis and Becky Jubb and Mike Westby and Benhur Lee and Sharon Lewin and Melissa Churchill and Roche, {Michael John} and Gorry, {Paul Rene}",
year = "2017",
doi = "10.1089/aid.2017.0097",
language = "English",
volume = "33",
journal = "AIDS Research and Human Retroviruses",
issn = "0889-2229",
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Analysis of clinical HIV-1 strains with resistance to maraviroc reveals Strain-specific resistance mutations, variable degrees of resistance, and minimal cross-resistance to other CCR5 antagonists. / Flynn, Jacqueline Kaye; Ellenberg, Paula Clarisa; Duncan, Renee; Ellett, Anne; Zhou, Jingling; Sterjovski, Jasminka; Cashin, Kieran; Borm, Katharina; Gray, Lachlan Robert; Lewis, Marilyn; Jubb, Becky; Westby, Mike; Lee, Benhur; Lewin, Sharon; Churchill, Melissa; Roche, Michael John; Gorry, Paul Rene.

In: AIDS Research and Human Retroviruses, Vol. 33, No. 12, 2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Analysis of clinical HIV-1 strains with resistance to maraviroc reveals Strain-specific resistance mutations, variable degrees of resistance, and minimal cross-resistance to other CCR5 antagonists

AU - Flynn, Jacqueline Kaye

AU - Ellenberg, Paula Clarisa

AU - Duncan, Renee

AU - Ellett, Anne

AU - Zhou, Jingling

AU - Sterjovski, Jasminka

AU - Cashin, Kieran

AU - Borm, Katharina

AU - Gray, Lachlan Robert

AU - Lewis, Marilyn

AU - Jubb, Becky

AU - Westby, Mike

AU - Lee, Benhur

AU - Lewin, Sharon

AU - Churchill, Melissa

AU - Roche, Michael John

AU - Gorry, Paul Rene

PY - 2017

Y1 - 2017

N2 - Maraviroc (MVC) is an allosteric inhibitor of human immunodeficiency virus type 1 (HIV-1) entry, and is the only CCR5 antagonist licensed for use as an anti-HIV-1 therapeutic. It acts by altering the conformation of the CCR5 extracellular loops, rendering CCR5 unrecognizable by the HIV-1 envelope (Env) glycoproteins. This study aimed to understand the mechanisms underlying the development of MVC resistance in HIV-1-infected patients. To do this, we obtained longitudinal plasma samples from eight subjects who experienced treatment failure with phenotypically verified, CCR5-tropic MVC resistance. We then cloned and characterized HIV-1 Envs (n = 77) from plasma of pretreatment (n = 36) and treatment failure (n = 41) samples. Our results showed variation in the magnitude of MVC resistance as measured by reductions in maximal percent inhibition of Env-pseudotyped viruses, which was more pronounced in 293-Affinofile cells compared to other cells with similar levels of CCR5 expression. Amino acid determinants of MVC resistance localized to the V3 Env region and were strain specific. We also observed minimal cross-resistance to other CCR5 antagonists by MVC-resistant strains. We conclude that 293-Affinofile cells are highly sensitive for detecting and measuring MVC resistance through a mechanism that is CCR5-dependent yet independent of CCR5 expression levels. The strain-specific nature of resistance mutations suggests that sequence-based diagnostics and prognostics will need to be more sophisticated than simple position scoring to be useful for managing resistance in subjects taking MVC. Finally, the minimal levels of cross-resistance suggests that recognition of the MVC-modified form of CCR5 does not necessarily lead to recognition of other antagonist-modified forms of CCR5.

AB - Maraviroc (MVC) is an allosteric inhibitor of human immunodeficiency virus type 1 (HIV-1) entry, and is the only CCR5 antagonist licensed for use as an anti-HIV-1 therapeutic. It acts by altering the conformation of the CCR5 extracellular loops, rendering CCR5 unrecognizable by the HIV-1 envelope (Env) glycoproteins. This study aimed to understand the mechanisms underlying the development of MVC resistance in HIV-1-infected patients. To do this, we obtained longitudinal plasma samples from eight subjects who experienced treatment failure with phenotypically verified, CCR5-tropic MVC resistance. We then cloned and characterized HIV-1 Envs (n = 77) from plasma of pretreatment (n = 36) and treatment failure (n = 41) samples. Our results showed variation in the magnitude of MVC resistance as measured by reductions in maximal percent inhibition of Env-pseudotyped viruses, which was more pronounced in 293-Affinofile cells compared to other cells with similar levels of CCR5 expression. Amino acid determinants of MVC resistance localized to the V3 Env region and were strain specific. We also observed minimal cross-resistance to other CCR5 antagonists by MVC-resistant strains. We conclude that 293-Affinofile cells are highly sensitive for detecting and measuring MVC resistance through a mechanism that is CCR5-dependent yet independent of CCR5 expression levels. The strain-specific nature of resistance mutations suggests that sequence-based diagnostics and prognostics will need to be more sophisticated than simple position scoring to be useful for managing resistance in subjects taking MVC. Finally, the minimal levels of cross-resistance suggests that recognition of the MVC-modified form of CCR5 does not necessarily lead to recognition of other antagonist-modified forms of CCR5.

U2 - 10.1089/aid.2017.0097

DO - 10.1089/aid.2017.0097

M3 - Article

VL - 33

JO - AIDS Research and Human Retroviruses

JF - AIDS Research and Human Retroviruses

SN - 0889-2229

IS - 12

ER -