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      Regulation of LFA-1 activity through cytoskeleton remodeling and signaling components modulates the efficiency of HIV type-1 entry in activated CD4+ T lymphocytes.

      The Journal of Immunology Author Choice
      Adjuvants, Immunologic, metabolism, physiology, CD4-Positive T-Lymphocytes, drug effects, enzymology, immunology, virology, Calpain, Cell Adhesion, Cell Line, Cytoskeleton, HIV-1, pathogenicity, Humans, Lymphocyte Activation, Lymphocyte Function-Associated Antigen-1, Membrane Fusion, Muromonab-CD3, pharmacology, Phospholipase C gamma, Phytohemagglutinins, Protein-Tyrosine Kinases, Signal Transduction, Tetradecanoylphorbol Acetate, Type C Phospholipases, ZAP-70 Protein-Tyrosine Kinase

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          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.

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