Regulation of LFA-1 activity through cytoskeleton remodeling and signaling components modulates the efficiency of HIV type-1 entry in activated CD4+ T lymphocytes.
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.
Research Center in Infectious Diseases, Centre Hospitalier de l'Université Laval (CHUL) Research Center, and Faculty of Medicine, Laval University, 2705 Laurier Boulevard, Quebec, Canada G1V 4G2.
Mélanie R
MR
Tardif
Michel J
MJ
Tremblay
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000821:virology*; D002154:Calpain / Q000502:physiology; D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D003599:Cytoskeleton / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism / Q000502:physiology*; D008561:Membrane Fusion / Q000276:immunology; D016853:Muromonab-CD3 / Q000494:pharmacology; D051966:Phospholipase C gamma; D010835:Phytohemagglutinins / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism / Q000502:physiology; D051746:ZAP-70 Protein-Tyrosine Kinase
D000276:Adjuvants, Immunologic; D016169:Lymphocyte Function-Associated Antigen-1; D016853:Muromonab-CD3; D010835:Phytohemagglutinins; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002154:Calpain; D013755:Tetradecanoylphorbol Acetate