Some mechanisms of FLIP expression in inhibition of HIV-1 replication in Jurkat cells, CD4+ T cells and PBMCs

J Cell Physiol. 2013 Dec;228(12):2305-13. doi: 10.1002/jcp.24397.

Abstract

HIV-1 infection and replication are affected by host factors. Recent studies demonstrate that molecules from apoptotic pathways regulate HIV-1 replication. Therefore, studies on effects of host factors that maintain host cell survival and influence HIV-1 replication are critical to understanding the mechanisms of HIV-1 replicative cycle. Using the susceptible Jurkat cell line, CD4(+) T cells, and peripheral blood mononuclear cells (PBMCs), we studied the role of FLIP, an inhibitor of caspase-8, in HIV-1 production. Full length cellular FLIP (cFLIP) inhibited HIV-1 replication in these cells. cFLIP upregulated the expression of viral restriction factors, such as TRIM5, Apobec3G, and Bst2/tetherin, decreased nuclear factor 1C expression and inactivated ERK and p38 induced by HIV-1 in Jurkat cells. cFLIP blocked the trafficking of gp120 and Gag p24 capsid protein into lipid rafts with inhibition of Tsg101 and Alix in ESCRT signaling pathway. cFLIP also promoted Bst2/tetherin trafficking into lipid rafts. These results indicate that cFLIP may inhibit the HIV-1 replication cycle at multiple steps, including viral RNA release, transcription, traffic and assembly. We also found that cFLIP expression downregulated Fas expression and inactivated FADD in the Fas-mediated apoptotic pathway. The inactivated FADD also inhibited HIV-1 replication.

MeSH terms

  • APOBEC-3G Deaminase
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Antiviral Restriction Factors
  • Apoptosis / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / biosynthesis*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Caspase 8 / genetics
  • Caspase 8 / metabolism
  • Cell Line, Tumor
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / metabolism
  • DNA Replication / genetics*
  • Down-Regulation
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / metabolism
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism
  • HIV Core Protein p24 / genetics
  • HIV Core Protein p24 / metabolism
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp120 / metabolism
  • HIV Infections / genetics
  • HIV Infections / metabolism
  • HIV Infections / virology
  • HIV-1 / genetics*
  • Humans
  • Jurkat Cells / metabolism
  • Jurkat Cells / virology*
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / virology*
  • MAP Kinase Signaling System / genetics
  • Membrane Microdomains / genetics
  • Membrane Microdomains / metabolism
  • Membrane Microdomains / virology
  • NFI Transcription Factors / genetics
  • NFI Transcription Factors / metabolism
  • Signal Transduction
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases
  • Up-Regulation
  • Virus Replication / genetics*

Substances

  • Antigens, CD
  • Antiviral Restriction Factors
  • BST2 protein, human
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins
  • Fas-Associated Death Domain Protein
  • GPI-Linked Proteins
  • HIV Core Protein p24
  • HIV Envelope Protein gp120
  • NFI Transcription Factors
  • Tripartite Motif Proteins
  • gp120 protein, Human immunodeficiency virus 1
  • p24 protein, Human Immunodeficiency Virus Type 1
  • TRIM5 protein, human
  • Ubiquitin-Protein Ligases
  • Caspase 8
  • APOBEC-3G Deaminase
  • APOBEC3G protein, human
  • Cytidine Deaminase