Abstract
Besides interactions between the viral envelope glycoproteins with cell surface receptors, interactions between cell-derived molecules incorporated onto virions and their ligand could also modulate HIV type-1 (HIV-1) entry inside CD4(+) T lymphocytes. Although incorporation of host ICAM-1 within HIV-1 increases both virus attachment and fusion, the precise mechanism through which this phenomenon is occurring is still unclear. We demonstrate in this study that activation of primary human CD4(+) T lymphocytes increases LFA-1 affinity and avidity states, two events promoting the early events of the HIV-1 replication cycle through interactions between virus-embedded host ICAM-1 and LFA-1 clusters. Confocal analyses suggest that HIV-1 is concentrated in microdomains rich in LFA-1 clusters that also contain CD4 and CXCR4 molecules. Experiments performed with specific inhibitors revealed that entry of HIV-1 in activated CD4(+) T cells is regulated by LFA-1-dependent ZAP70, phospholipase Cgamma1, and calpain enzymatic activities. By using laboratory and clinical strains of HIV-1 produced in primary human cells, we demonstrate the importance of the LFA-1 activation state and cluster formation in the initial step of the virus life cycle. Overall, these data provide new insights into the complex molecular events involved in HIV-1 binding and entry.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / metabolism
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Adjuvants, Immunologic / physiology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / enzymology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / virology*
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Calpain / physiology
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Cell Adhesion / immunology
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Cell Line
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Cytoskeleton / immunology
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Cytoskeleton / metabolism*
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Cytoskeleton / virology*
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HIV-1 / immunology*
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HIV-1 / metabolism
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HIV-1 / pathogenicity*
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Humans
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology*
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Lymphocyte Function-Associated Antigen-1 / metabolism
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Lymphocyte Function-Associated Antigen-1 / physiology*
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Membrane Fusion / immunology
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Muromonab-CD3 / pharmacology
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Phospholipase C gamma
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Phytohemagglutinins / pharmacology
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Protein-Tyrosine Kinases / metabolism
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Protein-Tyrosine Kinases / physiology
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Signal Transduction / drug effects
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Signal Transduction / immunology*
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Tetradecanoylphorbol Acetate / pharmacology
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Type C Phospholipases / metabolism
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Type C Phospholipases / physiology
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ZAP-70 Protein-Tyrosine Kinase
Substances
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Adjuvants, Immunologic
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Lymphocyte Function-Associated Antigen-1
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Muromonab-CD3
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Phytohemagglutinins
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Protein-Tyrosine Kinases
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ZAP-70 Protein-Tyrosine Kinase
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ZAP70 protein, human
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Type C Phospholipases
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Phospholipase C gamma
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Calpain
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Tetradecanoylphorbol Acetate