An altered and more efficient mechanism of CCR5 engagement contributes to macrophage tropism of CCR5-using HIV-1 envelopes

Jasminka Sterjovski, Michael Roche, Melissa Churchill, Anne Ellett, William Farrugia, Lachlan Gray, Daniel Cowley, Pantelis Poumbourios, Benhur Lee, Steven Wesselingh, Anthony Cunningham, Paul Ramsland, Paul Gorry

    Research output: Contribution to journalArticle

    47 Citations (Scopus)

    Abstract

    While CCR5 is the principal coreceptor used by macrophage (M)-tropic HIV-1, not all primary CCR5-using (R5) viruses enter macrophages efficiently. Here, we used functionally-diverse R5 envelope (Env) clones to characterize virus-cell interactions important for efficient CCR5-mediated macrophage entry. The magnitude of macrophage entry by Env-pseudotyped reporter viruses correlated with increased immunoreactivity of CD4-induced gp120 epitopes, increased ability to scavenge low levels of cell-surface CCR5, reduced sensitivity to the CCR5 inhibitor maraviroc, and increased dependence on specific residues in the CCR5 ECL2 region. These results are consistent with an altered and more efficient mechanism of CCR5 engagement. Structural studies revealed potential alterations within the gp120 V3 loop, the gp41 interaction sites at the gp120 C- and N-termini, and within the gp120 CD4 binding site which may directly or indirectly lead to more efficient CCR5-usage. Thus, enhanced gp120-CCR5 interactions may contribute to M-tropism of R5 HIV-1 strains through different structural mechanisms.

    Original languageEnglish
    Pages (from-to)269-278
    Number of pages10
    JournalVirology
    Volume404
    Issue number2
    DOIs
    Publication statusPublished - Sep 2010

    Keywords

    • CCR5
    • Env
    • Gp120
    • HIV-1
    • Macrophage tropism
    • Maraviroc

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