Infection with Vpr-positive human immunodeficiency virus type 1 impairs NK cell function indirectly through cytokine dysregulation of infected target cells.
Human immunodeficiency virus type 1 (HIV-1) infection has been implicated in impairing various aspects of NK cell function in viremic condition, and several viral factors contribute to these defects. Here, we evaluated the effect of HIV-1 Vpr on NK cell cytolytic function and cytokine (gamma interferon [IFN-gamma]) production in the context of infection and exposure. Our data indicate that NK cells derived from a peripheral blood mononuclear cell culture infected in vitro with HIV-1 vpr(+) virus or exposed to recombinant Vpr protein exhibited reduced target cell killing in conjunction with diminished expression of CD107a and reduced IFN-gamma production compared to their Vpr-negative counterparts. This Vpr-induced NK cell defect is in part through differential regulation of interleukin-12 and transforming growth factor beta production by the infected target cells and concomitant activation of Smad3 signaling pathway. Collectively, these results illustrate the ability of Vpr to impair NK cell-mediated innate immune functions indirectly by dysregulating multiple cytokines in the infected target cells, thus increasing disease severity and affecting the final outcome in HIV-1 infection.
Majumder
Biswanath
B
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Venkatachari
Narasimhan J
NJ
O'Leary
Shaylee
S
Ayyavoo
Velpandi
V
D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000096:biosynthesis; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
D016207:Cytokines; D052118:Lysosomal-Associated Membrane Protein 1; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1