The Role of ERK1/2 Signaling Pathway in Nef Protein Upregulation of the Expression of the Intercellular Adhesion Molecule 1 in Endothelial Cells

Abstract

Human immunodeficiency virus (HIV)-infected patients have increased rates of atherosclerotic cardiovascular diseases because the highly active antiretroviral therapy (HAART) decreased the morbidity and mortality of the disease. Endothelial dysfunction is possibly the most plausible link between HIV infection and related expression of cell adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) on the endothelial cells. HIV-1 accessory protein negative regulate factor (Nef) has been shown to be very important for high virus replication and disease progression. Nef could upregulate the expression of ICAM-1 in the pathogenesis of HIV infection. Here, we provide evidence that the HIV-1 Nef can transcriptionally induce the expression of ICAM-1 in stable expressed Nef vascular endothelial cells. Nef-induced ICAM-1 upregulation requires the activation of the downstream kinase extracellular signal-regulated kinase (ERK). Flow cytometry (FCM) results showed that the percentage of ICAM-1 positive cells in Nef-expressed cells and control cells was (35.3% ± 2.2%) and (12.5% ± 0.8%), respectively (P < .01). Furthermore, inhibition of Nef activity by ERK mitogen-activated protein kinase (MAPK) inhibitor effectively blocked ICAM-1 upregulation, suggesting that ERK MAPK activation is an important initiating event in Nef-mediated ICAM-1 expression in Nef-expressed cells. These data demonstrate an important signaling event of Nef in HIV-1 pathogenesis.

Keywords

HIV-1 Nef ICAM-1 Erk phosphorylation endothelial cells

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References

Farrugia PM , Lucariello R. , Coppola JT Human immunodeficiency virus and atherosclerosis. Cardiol Rev. 2009;17(5):211-215.

Monsuez JJ , Charniot JC , Escaut L. , et al. HIV-associated vascular diseases: structural and functional changes, clinical implications. Int J Cardiol. 2009;133(3):293-306.

Hag AM , Kristoffersen US , Pedersen SF , Gutte H. , Lebech AM , Kjaer A. Regional gene expression of LOX-1, VCAM-1, and ICAM-1 in aorta of HIV-1 transgenic rats. PLoS One. 2009; 4(12):e8170.

Garrido M. , Mozos A. , Martínez A. , et al. HIV-1 upregulates intercellular adhesion molecule-1 gene expression in lymphoid tissue of patients with chronic HIV-1 infection. J Acquir Immune Defic Syndr. 2007;46(3):268-274.

Mu H. , Chai H. , Lin PH , Yao Q. , Chen C. Current update on HIV-associated vascular disease and endothelial dysfunction . World J Surg. 2007;31(4):632-643.

Crotti A. , Neri F. , Corti D. , et al. Nef alleles from human immunodeficiency virus type 1-infected long-term-non-progressor hemophiliacs with or without late disease progression are defective in enhancing virus replication and CD4+ down-regulation. J Virol. 2006;80(21):10663-10674.

Calugi G. , Montella F. , Favalli C. , Benedetto A. Entire genome of a strain of human immunodeficiency virus type 1 with a deletion of Nef that was recovered 20 years after primary infection: large pool of proviruses with deletions of env. J Virol. 2006;80(23): 11892-11896.

Foster JL , Garcia JV HIV-1 Nef: at the crossroads. Retrovirology. 2008;5(1):84.

Schrager JA , Derminassian V. , Marsh JW HIV Nef increases T cell ERK MAP kinase activity. J Biol Chem . 2002;277(8):6137-6142.

10.

Yang F. , Liu CQ , Liu FY , Zhang W. , Wang LL Construction, expression, purification of HIV-1 Nef and preparation its antibody . Chin Cell Mol Immunol. 2008;24(7):703-705.

11.

Witte V. , Laffert B. , Gintschel P. , et al. Induction of HIV transcription by Nef involves Lck activation and protein kinase C theta raft recruitment leading to activation of ERK1/2 but not NF kappa B. J Immunol. 2008;181(12):8425-8432.

12.

Tobiume M. , Takahoko M. , Yamada T. , Tatsumi M. , Iwamoto A. , Matsuda M. Inefficient enhancement of viral infectivity and CD4+ down-regulation by human immunodeficiency virus type 1 Nef from Japanese long-term nonprogressors. J Virol. 2002; 76(12):5959-5965.

13.

Hanna Z. , Weng X. , Kay DG , Poudrier J. , Lowell C. , Jolicoeur P. The pathogenicity of human immunodeficiency virus (HIV) type 1 Nef in CD4C/HIV transgenic mice is abolished by mutation of its SH3-binding domain, and disease development is delayed in the absence of Hck. J Virol. 2001;75(19): 9378-9392.

14.

Priceputu E. , Rodrigue I. , Chrobak P. , et al. The Nef-mediated AIDS-like disease of CD4C/human immunodeficiency virus transgenic mice is associated with increased Fas/FasL expression on T cells and T-cell death but is not prevented in Fas-, FasL-, tumor necrosis factor receptor 1-, or interleukin-1beta-converting enzyme-deficient or Bcl2-expressing transgenic mice. J Virol . 2005;79(10):6377-6391.

15.

Hanna Z. , Priceputu E. , Hu C. , Vincent P. , Jolicoeur P. HIV-1 Nef mutations abrogating downregulation of CD4 affect other Nef functions and show reduced pathogenicity in transgenic mice. Virology . 2006;346(1):40-52.

16.

Voelkel NF , Cool CD , Flores S. From viral infection to pulmonary arterial hypertension: a role for viral proteins. AIDS. 2008; 22(suppl 3):S49-S53.

17.

Marecki JC , Cool CD , Parr JE , et al. HIV-1 Nef is associated with complex pulmonary vascular lesions in SHIV-Nef-infected macaques. Am J Respir Crit Care Med. 2006;174(4):437-445.

18.

Jolly C. , Mitar I. , Sattentau QJ Adhesion molecule interactions facilitate human immunodeficiency virus type 1-induced virological synapse formation between T cells. J Virol. 2007; 81(24):13916-13921.

19.

Wang JH , Kwas C. , Wu L. Intercellular adhesion molecule 1 (ICAM-1), but not ICAM-2 and -3, is important for dendritic cell-mediated human immunodeficiency virus type 1 transmission . J Virol. 2009;83(9):4195-4204.

20.

Hioe CE , Chien PC Jr , Lu C. , et al. LFA-1 expression on target cells promotes human immunodeficiency virus type 1 infection and transmission. J Virol. 2001;75(2):1077-1082.

21.

Tardif MR , Gilbert C. , Thibault S. , Fortin JF , Tremblay MJ LFA-1 antagonists as agents limiting human immunodeficiency virus type 1 infection and transmission and potentiating the effect of the fusion inhibitor T-20 . Antimicrob Agents Chemother. 2009; 53(11):4656-4666.

22.

Dhawan S. , Puri RK , Kumar A. , Duplan H. , Masson JM , Aggarwal BB Human immunodeficiency virus-1-tat protein induces the cell surface expression of endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 in human endothelial cells. Blood. 1997;90(4):1535-1544.

23.

Stins MF , Shen Y. , Huang SH , Gilles F. , Kalra VK , Kim KS Gp 120 activates children’s brain endothelial cells via CD4. J Neuro-virol. 2001;7(2):125-134.

24.

Choi J. , Walker J. , Boichuk S. , et al. Human endothelial cells enhance human immunodeficiency virus type 1 replication in CD4+ T cells in a Nef-dependent manner in vitro and in vivo. J Virol. 2005;79(1):264-276.

25.

Nishimoto S. , Nishida E. MAPK signalling: ERK5 versus ERK1/ 2. EMBO Rep. 2006;7(8):782-786.

26.

Choi J. , Walker J. , Talbert-Slagle K. , Wright P. , Pober JS , Alexander L. Endothelial cells promote human immunodeficiency virus replication in nondividing memory T cells via Nef-, Vpr-, and T-cell receptor-dependent activation of NFAT. J Virol. 2005;79(17):11194-11204.