Linkages between HIV-1 specificity for CCR5 or CXCR4 and in vitro usage of alternative coreceptors during progressive HIV-1 subtype C infection

Kieran Cashin, Martin R Jakobsen, Jasminka Sterjovski, Michael John Roche, Anne Ellett, Jacqueline Kaye Flynn, Katharina Borm, Maelenn Gouillou, Melissa Churchill, Paul R Gorry

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Abstract

Background: Human immunodeficiency virus type 1 (HIV-1) subtype C (C-HIV) is spreading rapidly and is now responsible for >50 of HIV-1 infections worldwide, and >95 of infections in southern Africa and central Asia. These regions are burdened with the overwhelming majority of HIV-1 infections, yet we know very little about the pathogenesis of C-HIV. In addition to CCR5 and CXCR4, the HIV-1 envelope glycoproteins (Env) may engage a variety of alternative coreceptors for entry into transfected cells. Whilst alternative coreceptors do not appear to have a broad role in mediating the entry of HIV-1 into primary cells, characterizing patterns of alternative coreceptor usage in vitro can provide valuable insights into mechanisms of Env-coreceptor engagement that may be important for HIV-1 pathogenesis.Results: Here, we characterized the ability of luciferase reporter viruses pseudotyped with HIV-1 Envs (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naive subjects experiencing progression from chronic to advanced C-HIV infection over an approximately 3-year period, who either exclusively maintained CCR5-using (R5) variants (n = 20 subjects) or who experienced a coreceptor switch to CXCR4-using (X4) variants (n = 1 subject), to utilize alternative coreceptors for entry. At a population level, CCR5 usage by R5 C-HIV Envs was strongly linked to usage of FPRL1, CCR3 and CCR8 as alternative coreceptors, with the linkages to FPRL1 and CCR3 usage becoming statistically more robust as infection progressed from chronic to advanced stages of disease. In contrast, acquisition of an X4 Env phenotype at advanced infection was accompanied by a dramatic loss of FPRL1 usage. Env mutagenesis studies confirmed a direct link between CCR5 and FPRL1 usage, and showed that the V3 loop crown, but not other V3 determinants of CCR5-specificity, was the principal Env determinant governing the ability of R5 C-HIV Envs from one particular subject to engage FPRL1.Conclusions: Our results suggest that, in the absence of coreceptor switching, the ability of R5 C-HIV viruses to engage certain alternative coreceptors in vitro, in particular FPRL1, may reflect an altered use of CCR5 that is selected for during progressive C-HIV infection, and which may contribute to C-HIV pathogenicity. ? 2013 Cashin et al.; licensee BioMed Central Ltd.
Original languageEnglish
Pages (from-to)1 - 10
Number of pages10
JournalRetrovirology
Volume10
Issue number1 (Art. No.: 98)
DOIs
Publication statusPublished - 2013

Cite this

Cashin, Kieran ; Jakobsen, Martin R ; Sterjovski, Jasminka ; Roche, Michael John ; Ellett, Anne ; Flynn, Jacqueline Kaye ; Borm, Katharina ; Gouillou, Maelenn ; Churchill, Melissa ; Gorry, Paul R. / Linkages between HIV-1 specificity for CCR5 or CXCR4 and in vitro usage of alternative coreceptors during progressive HIV-1 subtype C infection. In: Retrovirology. 2013 ; Vol. 10, No. 1 (Art. No.: 98). pp. 1 - 10.
@article{0c8e5119d24849d38f9e27da5d6ea10a,
title = "Linkages between HIV-1 specificity for CCR5 or CXCR4 and in vitro usage of alternative coreceptors during progressive HIV-1 subtype C infection",
abstract = "Background: Human immunodeficiency virus type 1 (HIV-1) subtype C (C-HIV) is spreading rapidly and is now responsible for >50 of HIV-1 infections worldwide, and >95 of infections in southern Africa and central Asia. These regions are burdened with the overwhelming majority of HIV-1 infections, yet we know very little about the pathogenesis of C-HIV. In addition to CCR5 and CXCR4, the HIV-1 envelope glycoproteins (Env) may engage a variety of alternative coreceptors for entry into transfected cells. Whilst alternative coreceptors do not appear to have a broad role in mediating the entry of HIV-1 into primary cells, characterizing patterns of alternative coreceptor usage in vitro can provide valuable insights into mechanisms of Env-coreceptor engagement that may be important for HIV-1 pathogenesis.Results: Here, we characterized the ability of luciferase reporter viruses pseudotyped with HIV-1 Envs (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naive subjects experiencing progression from chronic to advanced C-HIV infection over an approximately 3-year period, who either exclusively maintained CCR5-using (R5) variants (n = 20 subjects) or who experienced a coreceptor switch to CXCR4-using (X4) variants (n = 1 subject), to utilize alternative coreceptors for entry. At a population level, CCR5 usage by R5 C-HIV Envs was strongly linked to usage of FPRL1, CCR3 and CCR8 as alternative coreceptors, with the linkages to FPRL1 and CCR3 usage becoming statistically more robust as infection progressed from chronic to advanced stages of disease. In contrast, acquisition of an X4 Env phenotype at advanced infection was accompanied by a dramatic loss of FPRL1 usage. Env mutagenesis studies confirmed a direct link between CCR5 and FPRL1 usage, and showed that the V3 loop crown, but not other V3 determinants of CCR5-specificity, was the principal Env determinant governing the ability of R5 C-HIV Envs from one particular subject to engage FPRL1.Conclusions: Our results suggest that, in the absence of coreceptor switching, the ability of R5 C-HIV viruses to engage certain alternative coreceptors in vitro, in particular FPRL1, may reflect an altered use of CCR5 that is selected for during progressive C-HIV infection, and which may contribute to C-HIV pathogenicity. ? 2013 Cashin et al.; licensee BioMed Central Ltd.",
author = "Kieran Cashin and Jakobsen, {Martin R} and Jasminka Sterjovski and Roche, {Michael John} and Anne Ellett and Flynn, {Jacqueline Kaye} and Katharina Borm and Maelenn Gouillou and Melissa Churchill and Gorry, {Paul R}",
year = "2013",
doi = "10.1186/1742-4690-10-98",
language = "English",
volume = "10",
pages = "1 -- 10",
journal = "Retrovirology",
issn = "1742-4690",
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Cashin, K, Jakobsen, MR, Sterjovski, J, Roche, MJ, Ellett, A, Flynn, JK, Borm, K, Gouillou, M, Churchill, M & Gorry, PR 2013, 'Linkages between HIV-1 specificity for CCR5 or CXCR4 and in vitro usage of alternative coreceptors during progressive HIV-1 subtype C infection', Retrovirology, vol. 10, no. 1 (Art. No.: 98), pp. 1 - 10. https://doi.org/10.1186/1742-4690-10-98

Linkages between HIV-1 specificity for CCR5 or CXCR4 and in vitro usage of alternative coreceptors during progressive HIV-1 subtype C infection. / Cashin, Kieran; Jakobsen, Martin R; Sterjovski, Jasminka; Roche, Michael John; Ellett, Anne; Flynn, Jacqueline Kaye; Borm, Katharina; Gouillou, Maelenn; Churchill, Melissa; Gorry, Paul R.

In: Retrovirology, Vol. 10, No. 1 (Art. No.: 98), 2013, p. 1 - 10.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Linkages between HIV-1 specificity for CCR5 or CXCR4 and in vitro usage of alternative coreceptors during progressive HIV-1 subtype C infection

AU - Cashin, Kieran

AU - Jakobsen, Martin R

AU - Sterjovski, Jasminka

AU - Roche, Michael John

AU - Ellett, Anne

AU - Flynn, Jacqueline Kaye

AU - Borm, Katharina

AU - Gouillou, Maelenn

AU - Churchill, Melissa

AU - Gorry, Paul R

PY - 2013

Y1 - 2013

N2 - Background: Human immunodeficiency virus type 1 (HIV-1) subtype C (C-HIV) is spreading rapidly and is now responsible for >50 of HIV-1 infections worldwide, and >95 of infections in southern Africa and central Asia. These regions are burdened with the overwhelming majority of HIV-1 infections, yet we know very little about the pathogenesis of C-HIV. In addition to CCR5 and CXCR4, the HIV-1 envelope glycoproteins (Env) may engage a variety of alternative coreceptors for entry into transfected cells. Whilst alternative coreceptors do not appear to have a broad role in mediating the entry of HIV-1 into primary cells, characterizing patterns of alternative coreceptor usage in vitro can provide valuable insights into mechanisms of Env-coreceptor engagement that may be important for HIV-1 pathogenesis.Results: Here, we characterized the ability of luciferase reporter viruses pseudotyped with HIV-1 Envs (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naive subjects experiencing progression from chronic to advanced C-HIV infection over an approximately 3-year period, who either exclusively maintained CCR5-using (R5) variants (n = 20 subjects) or who experienced a coreceptor switch to CXCR4-using (X4) variants (n = 1 subject), to utilize alternative coreceptors for entry. At a population level, CCR5 usage by R5 C-HIV Envs was strongly linked to usage of FPRL1, CCR3 and CCR8 as alternative coreceptors, with the linkages to FPRL1 and CCR3 usage becoming statistically more robust as infection progressed from chronic to advanced stages of disease. In contrast, acquisition of an X4 Env phenotype at advanced infection was accompanied by a dramatic loss of FPRL1 usage. Env mutagenesis studies confirmed a direct link between CCR5 and FPRL1 usage, and showed that the V3 loop crown, but not other V3 determinants of CCR5-specificity, was the principal Env determinant governing the ability of R5 C-HIV Envs from one particular subject to engage FPRL1.Conclusions: Our results suggest that, in the absence of coreceptor switching, the ability of R5 C-HIV viruses to engage certain alternative coreceptors in vitro, in particular FPRL1, may reflect an altered use of CCR5 that is selected for during progressive C-HIV infection, and which may contribute to C-HIV pathogenicity. ? 2013 Cashin et al.; licensee BioMed Central Ltd.

AB - Background: Human immunodeficiency virus type 1 (HIV-1) subtype C (C-HIV) is spreading rapidly and is now responsible for >50 of HIV-1 infections worldwide, and >95 of infections in southern Africa and central Asia. These regions are burdened with the overwhelming majority of HIV-1 infections, yet we know very little about the pathogenesis of C-HIV. In addition to CCR5 and CXCR4, the HIV-1 envelope glycoproteins (Env) may engage a variety of alternative coreceptors for entry into transfected cells. Whilst alternative coreceptors do not appear to have a broad role in mediating the entry of HIV-1 into primary cells, characterizing patterns of alternative coreceptor usage in vitro can provide valuable insights into mechanisms of Env-coreceptor engagement that may be important for HIV-1 pathogenesis.Results: Here, we characterized the ability of luciferase reporter viruses pseudotyped with HIV-1 Envs (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naive subjects experiencing progression from chronic to advanced C-HIV infection over an approximately 3-year period, who either exclusively maintained CCR5-using (R5) variants (n = 20 subjects) or who experienced a coreceptor switch to CXCR4-using (X4) variants (n = 1 subject), to utilize alternative coreceptors for entry. At a population level, CCR5 usage by R5 C-HIV Envs was strongly linked to usage of FPRL1, CCR3 and CCR8 as alternative coreceptors, with the linkages to FPRL1 and CCR3 usage becoming statistically more robust as infection progressed from chronic to advanced stages of disease. In contrast, acquisition of an X4 Env phenotype at advanced infection was accompanied by a dramatic loss of FPRL1 usage. Env mutagenesis studies confirmed a direct link between CCR5 and FPRL1 usage, and showed that the V3 loop crown, but not other V3 determinants of CCR5-specificity, was the principal Env determinant governing the ability of R5 C-HIV Envs from one particular subject to engage FPRL1.Conclusions: Our results suggest that, in the absence of coreceptor switching, the ability of R5 C-HIV viruses to engage certain alternative coreceptors in vitro, in particular FPRL1, may reflect an altered use of CCR5 that is selected for during progressive C-HIV infection, and which may contribute to C-HIV pathogenicity. ? 2013 Cashin et al.; licensee BioMed Central Ltd.

UR - http://www.ncbi.nlm.nih.gov/pubmed/24041034

U2 - 10.1186/1742-4690-10-98

DO - 10.1186/1742-4690-10-98

M3 - Article

VL - 10

SP - 1

EP - 10

JO - Retrovirology

JF - Retrovirology

SN - 1742-4690

IS - 1 (Art. No.: 98)

ER -