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

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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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      16002691

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