Dysregulation of the polo-like kinase pathway in CD4+ T cells is characteristic of pathogenic simian immunodeficiency virus infection.
CD4(+) T-cell dysfunction highlighted by defects within the intracellular signaling cascade and cell cycle has long been characterized as a direct and/or indirect consequence of human immunodeficiency virus (HIV) infection in humans and simian immunodeficiency virus (SIV) infection in rhesus macaques (RM). Dysregulation of the M phase of the cell cycle is a well-documented effect of HIV or SIV infection both in vivo and in vitro. In this study the effect of SIV infection on the modulation of two important regulators of the M phase-polo-like kinases Plk3 and Plk1-was investigated. We have previously shown that Plk3 is markedly downregulated in CD4(+) T cells from SIV-infected disease-susceptible RM but not SIV-infected disease-resistant sooty mangabeys (SM), denoting an association of downregulation with disease progression. Here we show that, in addition to the downregulation, Plk3 exhibits aberrant activation patterns in the CD4(+) T cells from SIV-infected RM following T-cell receptor stimulation. Interestingly, in vitro SIV infection of CD4(+) T cells leads to the upregulation, rather than downregulation, of Plk3, suggesting that different mechanisms operate in vitro and in vivo. In addition, CD4(+) T cells from RM with high viral loads exhibited consistent and significant upregulation of Plk1, concurrent with an aberrant activation-induced Plk1 response, suggesting complex mechanisms of SIV-induced M-phase abnormalities in vivo. Altogether this study presents a novel mechanism underlying M-phase defects observed in CD4(+) T cells from HIV or SIV-infected disease-susceptible humans and RM which may contribute to aberrant T-cell responses and disease pathogenesis.
Bostik
Pavel
P
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA. pbostik@emory.edu
Dodd
Geraldine L
GL
Villinger
Francois
F
Mayne
Ann E
AE
Ansari
Aftab A
AA
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000473:pathology* / Q000821:virology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D016665:Cercocebus atys; D015536:Down-Regulation; D006801:Humans; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D008938:Mitosis; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D016097:Simian Acquired Immunodeficiency Syndrome / Q000503:physiopathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity*; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation; D000097869:Polo-Like Kinase 1; D000097868:Polo-like Kinases
D018797:Cell Cycle Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1; C486256:PLK3 protein, human; D000097868:Polo-like Kinases