HIV-1 Vpr suppresses immune activation and apoptosis through regulation of nuclear factor kappa B.
The HIV-1 accessory gene product Vpr can influence viral pathogenesis by affecting viral replication as well as host cell transcription and proliferation. We have investigated the effects of Vpr on host cell activation and confirm that it influences cellular proliferation. However, we have also found that Vpr modulates T-cell receptor (TCR)-triggered apoptosis in a manner similar to that of glucocorticoids. In the absence of TCR-mediated activation, Vpr induces apoptosis whereas in its presence, Vpr interrupts the expected induction of apoptosis. This regulation of apoptosis is linked to Vpr suppression of NF-kappa B activity via the induction of I kappa B, an inhibitor of NF-kappa B. Further, Vpr suppresses expression of IL-2, IL-10, IL-12, TNF alpha and IL-4, all of which are NF-kappa B-dependent. The effects of Vpr could be reversed by RU486. Our finding that Vpr can regulate NF-kappa B supports the hypothesis that some aspects of viral pathogenesis are the consequence of cell dysregulation by Vpr.
Ayyavoo
V
V
Department of Pathology, University of Pennsylvania, Philadelphia 19104, USA.
Mahboubi
A
A
Mahalingam
S
S
Ramalingam
R
R
Kudchodkar
S
S
Williams
W V
WV
Green
D R
DR
Weiner
D B
DB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D016336:Gene Products, vpr / Q000096:biosynthesis / Q000494:pharmacology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007378:Interleukins / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism*; D010835:Phytohemagglutinins; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D018411:Spodoptera; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D054325:vpr Gene Products, Human Immunodeficiency Virus
D016207:Cytokines; D016336:Gene Products, vpr; D007378:Interleukins; D016328:NF-kappa B; D010835:Phytohemagglutinins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D054325:vpr Gene Products, Human Immunodeficiency Virus; D003907:Dexamethasone; D006854:Hydrocortisone