Longitudinal analysis of CCR5 and CXCR4 usage in a cohort of antiretroviral therapy-naive subjects with progressive HIV-1 subtype C infection

Martin R Jakobsen, Kieran Cashin, Michael Roche, Jasminka Sterjovski, Anne Ellett, Katharina Borm, Jacqueline Kaye Flynn, Christian Erikstrup, Maelenn Gouillou, Lachlan Robert Gray, Nitin K Saksena, Bin Wang, Damian F Purcell, Per Kallestrup, Rutendo Zinyama-Gutsire, Exnevia Gomo, Henrik Ullum, Lars Ostergaard, Benhur Lee, Paul Allen Ramsland & 2 others Melissa Churchill, Paul R Gorry

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Abstract

HIV-1 subtype C (C-HIV) is responsible for most HIV-1 cases worldwide. Although the pathogenesis of C-HIV is thought to predominantly involve CCR5-restricted (R5) strains, we do not have a firm understanding of how frequently CXCR4-using (X4 and R5X4) variants emerge in subjects with progressive C-HIV infection. Nor do we completely understand the molecular determinants of coreceptor switching by C-HIV variants. Here, we characterized a panel of HIV-1 envelope glycoproteins (Envs) (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naive subjects who experienced progression from chronic to advanced stages of C-HIV infection, and show that CXCR4-using C-HIV variants emerged in only one individual. Mutagenesis studies and structural models suggest that the evolution of R5 to X4 variants in this subject principally involved acquisition of an Ile-Gly insertion in the gp120 V3 loop and replacement of the V3 Gly-Pro-Gly crown with a Gly-Arg-Gly motif, but that the accumulation of additional gp120 scaffold mutations was required for these V3 loop changes to confer functional effects. In this context, either of the V3 loop changes could confer possible transitional R5X4 phenotypes, but when present together they completely abolished CCR5 usage and conferred the X4 phenotype. Our results show that the emergence of CXCR4-using strains is rare in this cohort of untreated individuals with advanced C-HIV infection. In the subject where X4 variants did emerge, alterations in the gp120 V3 loop were necessary but not sufficient to confer CXCR4 usage.
Original languageEnglish
Article numbere65950
Number of pages13
JournalPLoS ONE
Volume8
Issue number6
DOIs
Publication statusPublished - 2013

Cite this

Jakobsen, Martin R ; Cashin, Kieran ; Roche, Michael ; Sterjovski, Jasminka ; Ellett, Anne ; Borm, Katharina ; Flynn, Jacqueline Kaye ; Erikstrup, Christian ; Gouillou, Maelenn ; Gray, Lachlan Robert ; Saksena, Nitin K ; Wang, Bin ; Purcell, Damian F ; Kallestrup, Per ; Zinyama-Gutsire, Rutendo ; Gomo, Exnevia ; Ullum, Henrik ; Ostergaard, Lars ; Lee, Benhur ; Ramsland, Paul Allen ; Churchill, Melissa ; Gorry, Paul R. / Longitudinal analysis of CCR5 and CXCR4 usage in a cohort of antiretroviral therapy-naive subjects with progressive HIV-1 subtype C infection. In: PLoS ONE. 2013 ; Vol. 8, No. 6.
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title = "Longitudinal analysis of CCR5 and CXCR4 usage in a cohort of antiretroviral therapy-naive subjects with progressive HIV-1 subtype C infection",
abstract = "HIV-1 subtype C (C-HIV) is responsible for most HIV-1 cases worldwide. Although the pathogenesis of C-HIV is thought to predominantly involve CCR5-restricted (R5) strains, we do not have a firm understanding of how frequently CXCR4-using (X4 and R5X4) variants emerge in subjects with progressive C-HIV infection. Nor do we completely understand the molecular determinants of coreceptor switching by C-HIV variants. Here, we characterized a panel of HIV-1 envelope glycoproteins (Envs) (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naive subjects who experienced progression from chronic to advanced stages of C-HIV infection, and show that CXCR4-using C-HIV variants emerged in only one individual. Mutagenesis studies and structural models suggest that the evolution of R5 to X4 variants in this subject principally involved acquisition of an Ile-Gly insertion in the gp120 V3 loop and replacement of the V3 Gly-Pro-Gly crown with a Gly-Arg-Gly motif, but that the accumulation of additional gp120 scaffold mutations was required for these V3 loop changes to confer functional effects. In this context, either of the V3 loop changes could confer possible transitional R5X4 phenotypes, but when present together they completely abolished CCR5 usage and conferred the X4 phenotype. Our results show that the emergence of CXCR4-using strains is rare in this cohort of untreated individuals with advanced C-HIV infection. In the subject where X4 variants did emerge, alterations in the gp120 V3 loop were necessary but not sufficient to confer CXCR4 usage.",
author = "Jakobsen, {Martin R} and Kieran Cashin and Michael Roche and Jasminka Sterjovski and Anne Ellett and Katharina Borm and Flynn, {Jacqueline Kaye} and Christian Erikstrup and Maelenn Gouillou and Gray, {Lachlan Robert} and Saksena, {Nitin K} and Bin Wang and Purcell, {Damian F} and Per Kallestrup and Rutendo Zinyama-Gutsire and Exnevia Gomo and Henrik Ullum and Lars Ostergaard and Benhur Lee and Ramsland, {Paul Allen} and Melissa Churchill and Gorry, {Paul R}",
year = "2013",
doi = "10.1371/journal.pone.0065950",
language = "English",
volume = "8",
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Jakobsen, MR, Cashin, K, Roche, M, Sterjovski, J, Ellett, A, Borm, K, Flynn, JK, Erikstrup, C, Gouillou, M, Gray, LR, Saksena, NK, Wang, B, Purcell, DF, Kallestrup, P, Zinyama-Gutsire, R, Gomo, E, Ullum, H, Ostergaard, L, Lee, B, Ramsland, PA, Churchill, M & Gorry, PR 2013, 'Longitudinal analysis of CCR5 and CXCR4 usage in a cohort of antiretroviral therapy-naive subjects with progressive HIV-1 subtype C infection', PLoS ONE, vol. 8, no. 6, e65950. https://doi.org/10.1371/journal.pone.0065950

Longitudinal analysis of CCR5 and CXCR4 usage in a cohort of antiretroviral therapy-naive subjects with progressive HIV-1 subtype C infection. / Jakobsen, Martin R; Cashin, Kieran; Roche, Michael; Sterjovski, Jasminka; Ellett, Anne; Borm, Katharina; Flynn, Jacqueline Kaye; Erikstrup, Christian; Gouillou, Maelenn; Gray, Lachlan Robert; Saksena, Nitin K; Wang, Bin; Purcell, Damian F; Kallestrup, Per; Zinyama-Gutsire, Rutendo; Gomo, Exnevia; Ullum, Henrik; Ostergaard, Lars; Lee, Benhur; Ramsland, Paul Allen; Churchill, Melissa; Gorry, Paul R.

In: PLoS ONE, Vol. 8, No. 6, e65950, 2013.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Longitudinal analysis of CCR5 and CXCR4 usage in a cohort of antiretroviral therapy-naive subjects with progressive HIV-1 subtype C infection

AU - Jakobsen, Martin R

AU - Cashin, Kieran

AU - Roche, Michael

AU - Sterjovski, Jasminka

AU - Ellett, Anne

AU - Borm, Katharina

AU - Flynn, Jacqueline Kaye

AU - Erikstrup, Christian

AU - Gouillou, Maelenn

AU - Gray, Lachlan Robert

AU - Saksena, Nitin K

AU - Wang, Bin

AU - Purcell, Damian F

AU - Kallestrup, Per

AU - Zinyama-Gutsire, Rutendo

AU - Gomo, Exnevia

AU - Ullum, Henrik

AU - Ostergaard, Lars

AU - Lee, Benhur

AU - Ramsland, Paul Allen

AU - Churchill, Melissa

AU - Gorry, Paul R

PY - 2013

Y1 - 2013

N2 - HIV-1 subtype C (C-HIV) is responsible for most HIV-1 cases worldwide. Although the pathogenesis of C-HIV is thought to predominantly involve CCR5-restricted (R5) strains, we do not have a firm understanding of how frequently CXCR4-using (X4 and R5X4) variants emerge in subjects with progressive C-HIV infection. Nor do we completely understand the molecular determinants of coreceptor switching by C-HIV variants. Here, we characterized a panel of HIV-1 envelope glycoproteins (Envs) (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naive subjects who experienced progression from chronic to advanced stages of C-HIV infection, and show that CXCR4-using C-HIV variants emerged in only one individual. Mutagenesis studies and structural models suggest that the evolution of R5 to X4 variants in this subject principally involved acquisition of an Ile-Gly insertion in the gp120 V3 loop and replacement of the V3 Gly-Pro-Gly crown with a Gly-Arg-Gly motif, but that the accumulation of additional gp120 scaffold mutations was required for these V3 loop changes to confer functional effects. In this context, either of the V3 loop changes could confer possible transitional R5X4 phenotypes, but when present together they completely abolished CCR5 usage and conferred the X4 phenotype. Our results show that the emergence of CXCR4-using strains is rare in this cohort of untreated individuals with advanced C-HIV infection. In the subject where X4 variants did emerge, alterations in the gp120 V3 loop were necessary but not sufficient to confer CXCR4 usage.

AB - HIV-1 subtype C (C-HIV) is responsible for most HIV-1 cases worldwide. Although the pathogenesis of C-HIV is thought to predominantly involve CCR5-restricted (R5) strains, we do not have a firm understanding of how frequently CXCR4-using (X4 and R5X4) variants emerge in subjects with progressive C-HIV infection. Nor do we completely understand the molecular determinants of coreceptor switching by C-HIV variants. Here, we characterized a panel of HIV-1 envelope glycoproteins (Envs) (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naive subjects who experienced progression from chronic to advanced stages of C-HIV infection, and show that CXCR4-using C-HIV variants emerged in only one individual. Mutagenesis studies and structural models suggest that the evolution of R5 to X4 variants in this subject principally involved acquisition of an Ile-Gly insertion in the gp120 V3 loop and replacement of the V3 Gly-Pro-Gly crown with a Gly-Arg-Gly motif, but that the accumulation of additional gp120 scaffold mutations was required for these V3 loop changes to confer functional effects. In this context, either of the V3 loop changes could confer possible transitional R5X4 phenotypes, but when present together they completely abolished CCR5 usage and conferred the X4 phenotype. Our results show that the emergence of CXCR4-using strains is rare in this cohort of untreated individuals with advanced C-HIV infection. In the subject where X4 variants did emerge, alterations in the gp120 V3 loop were necessary but not sufficient to confer CXCR4 usage.

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3688867/pdf/pone.0065950.pdf

U2 - 10.1371/journal.pone.0065950

DO - 10.1371/journal.pone.0065950

M3 - Article

VL - 8

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 6

M1 - e65950

ER -