Macrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5

Hamid Salimiseyedabad, Michael Roche, Nicholas Webb, Lachlan Robert Gray, Kelechi Chikere, Jasminka Sterjovski, Anne Ellett, Steven L Wesselingh, Paul A Ramsland, Benhur Lee, Melissa Churchill, Paul R Gorry

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26 Citations (Scopus)

Abstract

BR-derived HIV-1 strains have an exceptional ability to enter macrophages via mechanisms involving their gp120 Env that remain incompletely understood. Here, we used cell-based affinity-profiling methods and mathematical modeling to generate quantitative VERSA metrics that simultaneously measure Env-CD4 and Env-CCR5 interactions. These metrics were analyzed to distinguish the phenotypes of M-tropic and non-M-tropic CCR5-using HIV-1 variants derived from autopsy BRs and LNs, respectively. We show that highly M-tropic Env variants derived from brain can be defined by two distinct and simultaneously occurring phenotypes. First, BR-derived Envs demonstrated an enhanced ability to interact with CD4 compared with LN-derived Envs, permitting entry into cells expressing scant levels of CD4. Second, BR-derived Envs displayed an altered mechanism of engagement between CD4-bound gp120 and CCR5 occurring in tandem. With the use of epitope mapping, mutagenesis, and structural studies, we show that this altered mechanism is characterized by increased exposure of CD4-induced epitopes in gp120 and by a more critical interaction between BR-derived Envs and the CCR5 N-terminus, which was associated with the predicted presence of additional atomic contacts formed at the gp120-CCR5 N-terminus interface. Our results suggest that BR-derived HIV-1 variants with highly efficient macrophage entry adopt conformations in gp120 that simultaneously alter the way in which the Env interacts with CD4 and CCR5.
Original languageEnglish
Pages (from-to)113 - 126
Number of pages14
JournalJournal of leukocyte biology
Volume93
Issue number1
DOIs
Publication statusPublished - 2013

Cite this

Salimiseyedabad, Hamid ; Roche, Michael ; Webb, Nicholas ; Gray, Lachlan Robert ; Chikere, Kelechi ; Sterjovski, Jasminka ; Ellett, Anne ; Wesselingh, Steven L ; Ramsland, Paul A ; Lee, Benhur ; Churchill, Melissa ; Gorry, Paul R. / Macrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5. In: Journal of leukocyte biology. 2013 ; Vol. 93, No. 1. pp. 113 - 126.
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abstract = "BR-derived HIV-1 strains have an exceptional ability to enter macrophages via mechanisms involving their gp120 Env that remain incompletely understood. Here, we used cell-based affinity-profiling methods and mathematical modeling to generate quantitative VERSA metrics that simultaneously measure Env-CD4 and Env-CCR5 interactions. These metrics were analyzed to distinguish the phenotypes of M-tropic and non-M-tropic CCR5-using HIV-1 variants derived from autopsy BRs and LNs, respectively. We show that highly M-tropic Env variants derived from brain can be defined by two distinct and simultaneously occurring phenotypes. First, BR-derived Envs demonstrated an enhanced ability to interact with CD4 compared with LN-derived Envs, permitting entry into cells expressing scant levels of CD4. Second, BR-derived Envs displayed an altered mechanism of engagement between CD4-bound gp120 and CCR5 occurring in tandem. With the use of epitope mapping, mutagenesis, and structural studies, we show that this altered mechanism is characterized by increased exposure of CD4-induced epitopes in gp120 and by a more critical interaction between BR-derived Envs and the CCR5 N-terminus, which was associated with the predicted presence of additional atomic contacts formed at the gp120-CCR5 N-terminus interface. Our results suggest that BR-derived HIV-1 variants with highly efficient macrophage entry adopt conformations in gp120 that simultaneously alter the way in which the Env interacts with CD4 and CCR5.",
author = "Hamid Salimiseyedabad and Michael Roche and Nicholas Webb and Gray, {Lachlan Robert} and Kelechi Chikere and Jasminka Sterjovski and Anne Ellett and Wesselingh, {Steven L} and Ramsland, {Paul A} and Benhur Lee and Melissa Churchill and Gorry, {Paul R}",
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language = "English",
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Salimiseyedabad, H, Roche, M, Webb, N, Gray, LR, Chikere, K, Sterjovski, J, Ellett, A, Wesselingh, SL, Ramsland, PA, Lee, B, Churchill, M & Gorry, PR 2013, 'Macrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5', Journal of leukocyte biology, vol. 93, no. 1, pp. 113 - 126. https://doi.org/10.1189/jlb.0612308

Macrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5. / Salimiseyedabad, Hamid; Roche, Michael; Webb, Nicholas; Gray, Lachlan Robert; Chikere, Kelechi; Sterjovski, Jasminka; Ellett, Anne; Wesselingh, Steven L; Ramsland, Paul A; Lee, Benhur; Churchill, Melissa; Gorry, Paul R.

In: Journal of leukocyte biology, Vol. 93, No. 1, 2013, p. 113 - 126.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Macrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5

AU - Salimiseyedabad, Hamid

AU - Roche, Michael

AU - Webb, Nicholas

AU - Gray, Lachlan Robert

AU - Chikere, Kelechi

AU - Sterjovski, Jasminka

AU - Ellett, Anne

AU - Wesselingh, Steven L

AU - Ramsland, Paul A

AU - Lee, Benhur

AU - Churchill, Melissa

AU - Gorry, Paul R

PY - 2013

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N2 - BR-derived HIV-1 strains have an exceptional ability to enter macrophages via mechanisms involving their gp120 Env that remain incompletely understood. Here, we used cell-based affinity-profiling methods and mathematical modeling to generate quantitative VERSA metrics that simultaneously measure Env-CD4 and Env-CCR5 interactions. These metrics were analyzed to distinguish the phenotypes of M-tropic and non-M-tropic CCR5-using HIV-1 variants derived from autopsy BRs and LNs, respectively. We show that highly M-tropic Env variants derived from brain can be defined by two distinct and simultaneously occurring phenotypes. First, BR-derived Envs demonstrated an enhanced ability to interact with CD4 compared with LN-derived Envs, permitting entry into cells expressing scant levels of CD4. Second, BR-derived Envs displayed an altered mechanism of engagement between CD4-bound gp120 and CCR5 occurring in tandem. With the use of epitope mapping, mutagenesis, and structural studies, we show that this altered mechanism is characterized by increased exposure of CD4-induced epitopes in gp120 and by a more critical interaction between BR-derived Envs and the CCR5 N-terminus, which was associated with the predicted presence of additional atomic contacts formed at the gp120-CCR5 N-terminus interface. Our results suggest that BR-derived HIV-1 variants with highly efficient macrophage entry adopt conformations in gp120 that simultaneously alter the way in which the Env interacts with CD4 and CCR5.

AB - BR-derived HIV-1 strains have an exceptional ability to enter macrophages via mechanisms involving their gp120 Env that remain incompletely understood. Here, we used cell-based affinity-profiling methods and mathematical modeling to generate quantitative VERSA metrics that simultaneously measure Env-CD4 and Env-CCR5 interactions. These metrics were analyzed to distinguish the phenotypes of M-tropic and non-M-tropic CCR5-using HIV-1 variants derived from autopsy BRs and LNs, respectively. We show that highly M-tropic Env variants derived from brain can be defined by two distinct and simultaneously occurring phenotypes. First, BR-derived Envs demonstrated an enhanced ability to interact with CD4 compared with LN-derived Envs, permitting entry into cells expressing scant levels of CD4. Second, BR-derived Envs displayed an altered mechanism of engagement between CD4-bound gp120 and CCR5 occurring in tandem. With the use of epitope mapping, mutagenesis, and structural studies, we show that this altered mechanism is characterized by increased exposure of CD4-induced epitopes in gp120 and by a more critical interaction between BR-derived Envs and the CCR5 N-terminus, which was associated with the predicted presence of additional atomic contacts formed at the gp120-CCR5 N-terminus interface. Our results suggest that BR-derived HIV-1 variants with highly efficient macrophage entry adopt conformations in gp120 that simultaneously alter the way in which the Env interacts with CD4 and CCR5.

UR - http://www.ncbi.nlm.nih.gov/pubmed/23077246

U2 - 10.1189/jlb.0612308

DO - 10.1189/jlb.0612308

M3 - Article

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SP - 113

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JO - Journal of leukocyte biology

JF - Journal of leukocyte biology

SN - 0741-5400

IS - 1

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