Hyper-responsiveness to stimulation of human immunodeficiency virus-infected CD4+ T cells requires Nef and Tat virus gene products and results from higher NFAT, NF-kappaB, and AP-1 induction.
A chronic state of immune hyperactivation is a feature of human immunodeficiency virus type-1 (HIV-1) infection. Studies on the molecular mechanisms by which HIV-1 can modulate the activation state of T cells indicate that both Nef and Tat can alter T cell activation. However, the vast majority of data has been obtained from experiments performed with vectors encoding a single virus protein. We demonstrate that infection of human CD4(+) T lymphocytes with fully infectious HIV-1 leads to a hyper-responsiveness of the interleukin-2 promoter. Hypersensitivity in HIV-1-infected T cells was observed upon stimulation with various agents that are engaging different signal transduction pathways. Experiments performed with recombinant heat stable antigen-encoding HIV-1 indicated that the virus-infected cells are the cells with an enhanced response. Both Nef and Tat are involved in this virus-mediated enhancing effect on interleukin-2 promoter activity. Interestingly, whereas Nef seems to be acting mainly through hyperactivation of nuclear factor of activated T cells (NFAT), Tat acts in an NFAT-independent manner. Mobility shift experiments demonstrated that the HIV-1-associated priming of human T cells for stimulation results in a greater induction of transcription factors recognized as essential players in T cell activation, i.e. NFAT, NF-kappaB, and AP-1. A hyper-responsive state was also established upon HIV-1 infection of a more natural cellular reservoir, i.e. primary CD4(+) T lymphocytes. Considering that the HIV-1 life cycle is tightly regulated by the T cell signaling machinery, the priming for activation of a major viral reservoir represents a means by which this retrovirus can create an ideal cellular microenvironment for its propagation and maintenance.
Fortin
Jean-François
JF
Baxter Laboratory for Genetic Pharmacology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305-5175, USA.
Barat
Corinne
C
Beauséjour
Yannick
Y
Barbeau
Benoit
B
Tremblay
Michel J
MJ
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015693:Gene Products, nef / Q000502:physiology*; D015696:Gene Products, tat / Q000502:physiology*; D015658:HIV Infections / Q000276:immunology* / Q000503:physiopathology; D015497:HIV-1; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus
D004268:DNA-Binding Proteins; D015693:Gene Products, nef; D015696:Gene Products, tat; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D054311:nef Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus