Critical roles for Akt kinase in controlling HIV envelope-mediated depletion of CD4 T cells

Retrovirology

C David Pauza¹  Haishan Li¹ 

[1] Institute of Human Virology and Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA

关键词: Antiviral therapy;    CD4;    CCR5;    CD4 T cell death;    p38;    Akt;    Envelope;    HIV;   

Others  :  1209117
DOI  :  10.1186/1742-4690-10-60

 received in 2013-02-15, accepted in 2013-05-30,  发布年份 2013

【 摘 要 】

Background

The cell surface receptors CD4 and CCR5 bind CCR5-tropic HIV Envelope (Env) glycoprotein during virus attachment. These same receptors have signaling activities related to normal immune cell functions. We also know that Env binds to CCR5 present at high levels on CD4-negative γδ T cells where it signals through p38 MAP kinase to activate caspases and Fas-independent cell death. Here, we asked whether Env signaling through cellular receptors is responsible for death among uninfected CD4+/CCR5+ T cells and what are the effects of Env on CD4+/CCR5-negative cells that might impact HIV infection. The outcomes of Env binding are analyzed in terms of signal transduction and the effects on cell activation or cell death pathways.

Results

Env binding to CD4 signals through Erk and Akt kinases. Activation of Erk/Akt suppresses p38 due to CCR5 binding, and allows cell survival. When CD4 signaling was blocked by soluble CD4 or protein kinase inhibitors, p38 activation and Fas-independent cell death were increased among uninfected CD4+ CCR5+ T cells. We also noted specific effects of CD4 signaling on CCR5-negative CD4 T cells in tonsil lymphocyte cultures. Exposure to CCR5-tropic HIV Env (BaL strain) increased expression of CXCR5, PD-1, Fas and FasL. Among CD4+/CCR5- T cells expressing high levels of CXCR5 and PD-1, there were substantial amounts of Fas-dependent cell death. Increased CXCR5 and PD-1 expression was blocked by soluble CD4 or specific inhibitors of the Akt kinase, showing a direct relationship between CD4 signaling, T cell activation and Fas-dependent cell death.

Conclusions

Specific inhibition of Akt activation increased Env-dependent cell death of CCR5+ CD4 T cells. The same inhibitor, antibodies blocking the CD4 binding site on gp120, or soluble CD4 also prevented the increase in expression of CXCR5 or PD-1, and reduced the levels of Fas-dependent cell death. The Akt kinase and related signaling events, are key to cell survival that is needed for productive infection, and may be targets for the development of antivirals. Specific inhibitors of Akt would decrease productive infection, by favoring cell death during virus attachment to CD4+ CCR5+ target cells, and reduce immune activation to prevent Fas-dependent death of uninfected CXCR5+ PD-1+ CD4 T cells including T follicular helper cells that share this phenotype.

【 授权许可】

   
2013 Li and Pauza; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Moir S, Chun TW, Fauci AS: Pathogenic mechanisms of HIV disease. Annu Rev Pathol 2011, 6:223-248.
• [2]Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, Taylor H, Hermankova M, Chadwick K, Margolick J, Quinn TC, et al.: Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997, 387:183-188.
• [3]Embretson J, Zupancic M, Beneke J, Till M, Wolinsky S, Ribas JL, Burke A, Haase AT: Analysis of human immunodeficiency virus-infected tissues by amplification and in situ hybridization reveals latent and permissive infections at single-cell resolution. Proc Natl Acad Sci USA 1993, 90:357-361.
• [4]Douek DC, Roederer M, Koup RA: Emerging concepts in the immunopathogenesis of AIDS. Annu Rev Med 2009, 60:471-484.
• [5]Grossman Z, Meier-Schellersheim M, Sousa AE, Victorino RM, Paul WE: CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat Med 2002, 8:319-323.
• [6]Finkel TH, Tudor-Williams G, Banda NK, Cotton MF, Curiel T, Monks C, Baba TW, Ruprecht RM, Kupfer A: Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med 1995, 1:129-134.
• [7]Igarashi T, Brown CR, Byrum RA, Nishimura Y, Endo Y, Plishka RJ, Buckler C, Buckler-White A, Miller G, Hirsch VM, Martin MA: Rapid and irreversible CD4+ T-cell depletion induced by the highly pathogenic simian/human immunodeficiency virus SHIV(DH12R) is systemic and synchronous. J Virol 2002, 76:379-391.
• [8]Miura Y, Misawa N, Maeda N, Inagaki Y, Tanaka Y, Ito M, Kayagaki N, Yamamoto N, Yagita H, Mizusawa H, Koyanagi Y: Critical contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to apoptosis of human CD4+ T cells in HIV-1-infected hu-PBL-NOD-SCID mice. J Exp Med 2001, 193:651-660.
• [9]Monceaux V, Estaquier J, Fevrier M, Cumont MC, Riviere Y, Aubertin AM, Ameisen JC, Hurtrel B: Extensive apoptosis in lymphoid organs during primary SIV infection predicts rapid progression towards AIDS. AIDS 2003, 17:1585-1596.
• [10]Phenix BN, Badley AD: Influence of mitochondrial control of apoptosis on the pathogenesis, complications and treatment of HIV infection. Biochimie 2002, 84:251-264.
• [11]Hazenberg MD, Hamann D, Schuitemaker H, Miedema F: T cell depletion in HIV-1 infection: how CD4+ T cells go out of stock. Nat Immunol 2000, 1:285-289.
• [12]Ahr B, Robert-Hebmann V, Devaux C, Biard-Piechaczyk M: Apoptosis of uninfected cells induced by HIV envelope glycoproteins. Retrovirology 2004, 1:12. BioMed Central Full Text
• [13]Li H, Pauza CD: HIV envelope-mediated, CCR5/alpha4beta7-dependent killing of CD4-negative gammadelta T cells which are lost during progression to AIDS. Blood 2011, 118:5824-5831.
• [14]Li H, Pauza CD: The alpha4beta7 integrin binds HIV envelope but does not mediate bystander killing of gammadelta T cells. Blood 2012, 120:698-699.
• [15]Medders KE, Sejbuk NE, Maung R, Desai MK, Kaul M: Activation of p38 MAPK is required in monocytic and neuronal cells for HIV glycoprotein 120-induced neurotoxicity. J Immunol 2010, 185:4883-4895.
• [16]Fiala M, Murphy T, MacDougall J, Yang W, Luque A, Iruela-Arispe L, Cashman J, Buga G, Byrns RE, Barbaro G, Arthos J: HAART drugs induce mitochondrial damage and intercellular gaps and gp120 causes apoptosis. Cardiovasc Toxicol 2004, 4:327-337.
• [17]Vlahakis SR, Villasis-Keever A, Gomez TS, Bren GD, Paya CV: Human immunodeficiency virus-induced apoptosis of human hepatocytes via CXCR4. J Infect Dis 2003, 188:1455-1460.
• [18]Vashistha H, Husain M, Kumar D, Singhal PC: Tubular cell HIV-1 gp120 expression induces caspase 8 activation and apoptosis. Ren Fail 2009, 31:303-312.
• [19]Kanmogne GD, Primeaux C, Grammas P: Induction of apoptosis and endothelin-1 secretion in primary human lung endothelial cells by HIV-1 gp120 proteins. Biochem Biophys Res Commun 2005, 333:1107-1115.
• [20]Lin H, Chen W, Luo L, Wu C, Wang Q, Liu Y: Cytotoxic effect of HIV-1 gp120 on primary cultured human retinal capillary endothelial cells. Mol Vis 2011, 17:3450-3457.
• [21]Trushin SA, Algeciras-Schimnich A, Vlahakis SR, Bren GD, Warren S, Schnepple DJ, Badley AD: Glycoprotein 120 binding to CXCR4 causes p38-dependent primary T cell death that is facilitated by, but does not require cell-associated CD4. J Immunol 2007, 178:4846-4853.
• [22]Vlahakis SR, Algeciras-Schimnich A, Bou G, Heppelmann CJ, Villasis-Keever A, Collman RG, Paya CV: Chemokine-receptor activation by env determines the mechanism of death in HIV-infected and uninfected T lymphocytes. J Clin Invest 2001, 107:207-215.
• [23]Jacotot E, Krust B, Callebaut C, Laurent-Crawford AG, Blanco J, Hovanessian AG: HIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and independent mechanisms. Apoptosis 1997, 2:47-60.
• [24]Holm GH, Zhang C, Gorry PR, Peden K, Schols D, De Clercq E, Gabuzda D: Apoptosis of bystander T cells induced by human immunodeficiency virus type 1 with increased envelope/receptor affinity and coreceptor binding site exposure. J Virol 2004, 78:4541-4551.
• [25]Trushin SA, Algeciras-Schimnich A, Vlahakis SR, Bren GD, Warren S, Schnepple DJ, Badley AD: Glycoprotein 120 binding to CXCR4 causes p38-dependent primary T cell death that is facilitated by, but does not require cell-associated CD4. J Immunol 2007, 178:4846-4853.
• [26]Biard-Piechaczyk M, Robert-Hebmann V, Richard V, Roland J, Hipskind RA, Devaux C: Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type 1 envelope glycoprotein (gp120). Virology 2000, 268:329-344.
• [27]Blanco J, Barretina J, Henson G, Bridger G, De Clercq E, Clotet B, Este JA: The CXCR4 antagonist AMD3100 efficiently inhibits cell-surface-expressed human immunodeficiency virus type 1 envelope-induced apoptosis. Antimicrob Agents Chemother 2000, 44:51-56.
• [28]Crotty S: Follicular helper CD4 T cells (TFH). Annu Rev Immunol 2011, 29:621-663.
• [29]Oh SK, Cruikshank WW, Raina J, Blanchard GC, Adler WH, Walker J, Kornfeld H: Identification of HIV-1 envelope glycoprotein in the serum of AIDS and ARC patients. J Acquir Immune Defic Syndr 1992, 5:251-256.
• [30]Cummins NW, Rizza SA, Badley AD: How much gp120 is there? J Infect Dis 2010, 201:1273-1274. author reply 1274–1275
• [31]Pantaleo G, Graziosi C, Demarest JF, Butini L, Montroni M, Fox CH, Orenstein JM, Kotler DP, Fauci AS: HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 1993, 362:355-358.
• [32]Fox CH, Tenner-Racz K, Racz P, Firpo A, Pizzo PA, Fauci AS: Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis 1991, 164:1051-1057.
• [33]Sunila I, Vaccarezza M, Pantaleo G, Fauci AS, Orenstein JM: gp120 is present on the plasma membrane of apoptotic CD4 cells prepared from lymph nodes of HIV-1-infected individuals: an immunoelectron microscopic study. AIDS 1997, 11:27-32.
• [34]Lindqvist M, van Lunzen J, Soghoian DZ, Kuhl BD, Ranasinghe S, Kranias G, Flanders MD, Cutler S, Yudanin N, Muller MI, et al.: Expansion of HIV-specific T follicular helper cells in chronic HIV infection. J Clin Invest 2012, 122:3271-3280.
• [35]Lane HC, Masur H, Edgar LC, Whalen G, Rook AH, Fauci AS: Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 1983, 309:453-458.
• [36]De Milito A, Nilsson A, Titanji K, Thorstensson R, Reizenstein E, Narita M, Grutzmeier S, Sonnerborg A, Chiodi F: Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection. Blood 2004, 103:2180-2186.
• [37]Petrovas C, Yamamoto T, Gerner MY, Boswell KL, Wloka K, Smith EC, Ambrozak DR, Sandler NG, Timmer KJ, Sun X, et al.: CD4 T follicular helper cell dynamics during SIV infection. J Clin Invest 2012, 122:3281-3294.
• [38]Doitsh G, Cavrois M, Lassen KG, Zepeda O, Yang Z, Santiago ML, Hebbeler AM, Greene WC: Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue. Cell 2010, 143:789-801.