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    Efficiency of bridging-sheet recruitment explains HIV-1 R5 envelope glycoprotein sensitivity to soluble CD4 and macrophage tropism

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    Authors
    O'Connell, Olivia J.
    Repik, Alexander
    Reeves, Jacqueline D.
    Gonzalez-Perez, Maria Paz
    Quitadamo, Briana
    Anton, Elizabeth D.
    Duenas-Decamp, Maria J.
    Peters, Paul J.
    Lin, Rongheng
    Zolla-Pazner, Susan
    Corti, Davide
    Wallace, Aaron
    Wang, Shixia
    Kong, Xiang-Peng
    Lu, Shan
    Clapham, Paul R.
    Show allShow less
    UMass Chan Affiliations
    Department of Microbiology and Physiological Systems
    Program in Molecular Medicine
    Department of Medicine, Division of Infectious Diseases and Immunology
    Document Type
    Journal Article
    Publication Date
    2013-01-01
    Keywords
    Antibodies, Monoclonal
    Antibodies, Neutralizing
    Antigens, CD4
    HIV Antibodies
    HIV Envelope Protein gp120
    HIV-1
    Humans
    Macrophages
    Models, Biological
    Receptors, HIV
    Recombinant Proteins
    *Viral Tropism
    *Virus Attachment
    Amino Acids, Peptides, and Proteins
    Carbohydrates
    Cells
    Cellular and Molecular Physiology
    Immunology and Infectious Disease
    Microbiology
    Virology
    Viruses
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    Link to Full Text
    http://dx.doi.org/10.1128/JVI.01834-12
    Abstract
    HIV-1 R5 viruses vary extensively in their capacity to infect macrophages. R5 viruses that confer efficient infection of macrophages are able to exploit low levels of CD4 for infection and predominate in brain tissue, where macrophages are a major target for infection. HIV-1 R5 founder viruses that are transmitted were reported to be non-macrophage-tropic. Here, we investigated the sensitivities of macrophage-tropic and non-macrophage-tropic R5 envelopes to neutralizing antibodies. We observed striking differences in the sensitivities of Env(+) pseudovirions to soluble CD4 (sCD4) and to neutralizing monoclonal antibodies (MAbs) that target the CD4 binding site. Macrophage-tropic R5 Envs were sensitive to sCD4, while non-macrophage-tropic Envs were significantly more resistant. In contrast, all Envs were sensitive to VRC01 regardless of tropism, while MAb b12 conferred an intermediate neutralization pattern where all the macrophage-tropic and about half of the non-macrophage-tropic Envs were sensitive. CD4, b12, and VRC01 share binding specificities on the outer domain of gp120. However, these antibodies differ in their ability to induce conformational changes on the trimeric envelope and in specificity for residues on the V1V2 loop stem and beta20-21 junction that are targets for CD4 in recruiting the bridging sheet. These distinct specificities of CD4, b12, and VRC01 likely explain the observed differences in Env sensitivity to inhibition by these reagents and provide an insight into the envelope mechanisms that control macrophage tropism. We present a model where the efficiency of bridging-sheet recruitment by CD4 is a major determinant of HIV-1 R5 envelope sensitivity to soluble CD4 and macrophage tropism.
    Source

    J Virol. 2013 Jan;87(1):187-98. doi: 10.1128/JVI.01834-12. Epub 2012 Oct 10. Link to article on publisher's site

    DOI
    10.1128/JVI.01834-12
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/29997
    PubMed ID
    23055568
    Related Resources

    Link to Article in PubMed

    Rights
    Publisher PDF posted as allowed by the publisher's author rights policy at http://journals.asm.org/site/misc/ASM_Author_Statement.xhtml.
    ae974a485f413a2113503eed53cd6c53
    10.1128/JVI.01834-12
    Scopus Count
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