Programmed Death 1 Expression on HIV-Specific CD4+ T Cells Is Driven by Viral Replication and Associated with T Cell Dysfunction

Journal of Immunology - Tập 179 Số 3 - Trang 1979-1987 - 2007
Michelle D’Souza1, Andrew P. Fontenot1,2, Doug G. Mack1, Catherine Lozupone3, Stephanie M. Dillon1, Amie L. Meditz1, Cara C. Wilson1,2, Elizabeth Connick1, Brent E. Palmer1
1Department of Medicine and
2†Department of Immunology, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262; and
3‡Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Boulder, CO 80309

Tóm tắt

Abstract Functional impairment of HIV-specific CD4+ T cells during chronic HIV infection is closely linked to viral replication and thought to be due to T cell exhaustion. Programmed death 1 (PD-1) has been linked to T cell dysfunction in chronic viral infections, and blockade of the PD-1 pathway restores HIV-specific CD4+ and CD8+ T cell function in HIV infection. This study extends those findings by directly examining PD-1 expression on virus-specific CD4+ T cells. To investigate the role of PD-1 in HIV-associated CD4+ T cell dysfunction, we measured PD-1 expression on blood and lymph node T cells from HIV-infected subjects with chronic disease. PD-1 expression was significantly higher on IFN-γ-producing HIV-specific CD4+ T cells compared with total or CMV-specific CD4+ T cells in untreated HIV-infected subjects (p = 0.0001 and p < 0.0001, respectively). PD-1 expression on HIV-specific CD4+ T cells from subjects receiving antiretroviral therapy was significantly reduced (p = 0.007), and there was a direct correlation between PD-1 expression on HIV-specific CD4+ T cells and plasma viral load (r = 0.71; p = 0.005). PD-1 expression was significantly higher on HIV-specific T cells in the lymph node, the main site of HIV replication, compared with those in the blood (p = 0.0078). Thus, PD-1 expression on HIV-specific CD4+ T cells is driven by persistent HIV replication, providing a potential target for enhancing the functional capacity of HIV-specific CD4+ T cells.

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Tài liệu tham khảo

Palmer, B. E., N. Blyveis, A. P. Fontenot, C. C. Wilson. 2005. Functional and phenotypic characterization of CD57+CD4+ T cells and their association with HIV-1-induced T cell dysfunction. J. Immunol. 175: 8415-8423.

Palmer, B. E., E. Boritz, C. C. Wilson. 2004. Effects of sustained HIV-1 plasma viremia on HIV-1 Gag-specific CD4+ T cell maturation and function. J. Immunol. 172: 3337-3347.

Younes, S. A., B. Yassine-Diab, A. R. Dumont, M. R. Boulassel, Z. Grossman, J. P. Routy, R. P. Sekaly. 2003. HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity. J. Exp. Med. 198: 1909-1922.

Iyasere, C., J. C. Tilton, A. J. Johnson, S. Younes, B. Yassine-Diab, R. P. Sekaly, W. W. Kwok, S. A. Migueles, A. C. Laborico, W. L. Shupert, et al 2003. Diminished proliferation of human immunodeficiency virus-specific CD4+ T cells is associated with diminished interleukin-2 (IL-2) production and is recovered by exogenous IL-2. J. Virol. 77: 10900-10909.

Rosenberg, E. S., J. M. Billingsley, A. M. Caliendo, S. L. Boswell, P. E. Sax, S. A. Kalams, B. D. Walker. 1997. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278: 1447-1450.

Pontesilli, O., P. Carotenuto, S. R. Kerkhof-Garde, M. T. Roos, I. P. Keet, R. A. Coutinho, J. Goudsmit, F. Miedema. 1999. Lymphoproliferative response to HIV type 1 p24 in long-term survivors of HIV type 1 infection is predictive of persistent AIDS-free infection. AIDS Res. Hum. Retroviruses 15: 973-981.

Wilson, J. D., N. Imami, A. Watkins, J. Gill, P. Hay, B. Gazzard, M. Westby, F. M. Gotch. 2000. Loss of CD4+ T cell proliferative ability but not loss of human immunodeficiency virus type 1 specificity equates with progression to disease. J. Infect. Dis. 182: 792-798.

Boaz, M. J., A. Waters, S. Murad, P. J. Easterbrook, A. Vyakarnam. 2002. Presence of HIV-1 Gag-specific IFN-γ+IL-2+ and CD28+IL-2+ CD4 T cell responses is associated with nonprogression in HIV-1 infection. J. Immunol. 169: 6376-6385.

Harari, A., G. P. Rizzardi, K. Ellefsen, D. Ciuffreda, P. Champagne, P. A. Bart, D. Kaufmann, A. Telenti, R. Sahli, G. Tambussi, et al 2002. Analysis of HIV-1- and CMV-specific memory CD4 T-cell responses during primary and chronic infection. Blood 100: 1381-1387.

Ishida, Y., Y. Agata, K. Shibahara, T. Honjo. 1992. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11: 3887-3895.

Sharpe, A. H., G. J. Freeman. 2002. The B7-CD28 superfamily. Nat. Rev. Immunol. 2: 116-126.

Latchman, Y., C. R. Wood, T. Chernova, D. Chaudhary, M. Borde, I. Chernova, Y. Iwai, A. J. Long, J. A. Brown, R. Nunes, et al 2001. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2: 261-268.

Freeman, G. J., A. J. Long, Y. Iwai, K. Bourque, T. Chernova, H. Nishimura, L. J. Fitz, N. Malenkovich, T. Okazaki, M. C. Byrne, et al 2000. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192: 1027-1034.

Parry, R. V., J. M. Chemnitz, K. A. Frauwirth, A. R. Lanfranco, I. Braunstein, S. V. Kobayashi, P. S. Linsley, C. B. Thompson, J. L. Riley. 2005. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25: 9543-9553.

Trautmann, L., L. Janbazian, N. Chomont, E. A. Said, G. Wang, S. Gimmig, B. Bessette, M. R. Boulassel, E. Delwart, H. Sepulveda, et al 2006. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12: 1124-1125.

Day, C. L., D. E. Kaufmann, P. Kiepiela, J. A. Brown, E. S. Moodley, S. Reddy, E. W. Mackey, J. D. Miller, A. J. Leslie, C. Depierres, et al 2006. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443: 282-283.

Barber, D. L., E. J. Wherry, D. Masopust, B. Zhu, J. P. Allison, A. H. Sharpe, G. J. Freeman, R. Ahmed. 2006. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439: 682-687.

Palmer, B. E., E. Boritz, N. Blyveis, C. C. Wilson. 2002. Discordance between frequency of human immunodeficiency virus type 1 (HIV-1)-specific γ interferon-producing CD4+ T cells and HIV-1-specific lymphoproliferation in HIV-1-infected subjects with active viral replication. J. Virol. 76: 5925-5936.

McNeil, A. C., W. L. Shupert, C. A. Iyasere, C. W. Hallahan, J. A. Mican, R. T. Davey, Jr, M. Connors. 2001. High-level HIV-1 viremia suppresses viral antigen-specific CD4+ T cell proliferation. Proc. Natl. Acad. Sci. USA 98: 13878-13883.

Pantaleo, G., C. Graziosi, J. F. Demarest, L. Butini, M. Montroni, C. H. Fox, J. M. Orenstein, D. P. Kotler, A. S. Fauci. 1993. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362: 355-358.

Pantaleo, G., C. Graziosi, L. Butini, P. A. Pizzo, S. M. Schnittman, D. P. Kotler, A. S. Fauci. 1991. Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc. Natl. Acad. Sci. USA. 88: 9838-9842.

Embretson, J., M. Zupancic, J. L. Ribas, A. Burke, P. Racz, K. Tenner-Racz, A. T. Haase. 1993. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 362: 359-362.

Betts, M. R., D. R. Ambrozak, D. C. Douek, S. Bonhoeffer, J. M. Brenchley, J. P. Casazza, R. A. Koup, L. J. Picker. 2001. Analysis of total human immunodeficiency virus (HIV)-specific CD4+ and CD8+ T-cell responses: relationship to viral load in untreated HIV infection. J. Virol. 75: 11983-11991.

Bennett, F., D. Luxenberg, V. Ling, I. M. Wang, K. Marquette, D. Lowe, N. Khan, G. Veldman, K. A. Jacobs, V. E. Valge-Archer, M. Collins, B. M. Carreno. 2003. Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses. J. Immunol. 170: 711-718.

Carter, L., L. A. Fouser, J. Jussif, L. Fitz, B. Deng, C. R. Wood, M. Collins, T. Honjo, G. J. Freeman, B. M. Carreno. 2002. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2. Eur. J. Immunol. 32: 634-643.

Ellefsen, K., A. Harari, P. Champagne, P. A. Bart, R. P. Sekaly, G. Pantaleo. 2002. Distribution and functional analysis of memory antiviral CD8 T cell responses in HIV-1 and cytomegalovirus infections. Eur. J. Immunol. 32: 3756-3764.

Ratto-Kim, S., K. V. Sitz, A. M. Scherer, J. H. Kim, D. W. Anderson, M. E. Nau, D. L. Mann, P. N. Akolkar, B. Gulwani-Akolkar, J. Silver, D. L. Birx. 1997. Comparison of HIV-1 envelope-specific CD4+ T cell lines simultaneously established from peripheral blood mononuclear cells and lymph node biopsy in HIV-1-infected individuals. J. Immunol. 159: 5162-5167.

Kuroda, M. J., J. E. Schmitz, W. A. Charini, C. E. Nickerson, C. I. Lord, M. A. Forman, N. L. Letvin. 1999. Comparative analysis of cytotoxic T lymphocytes in lymph nodes and peripheral blood of simian immunodeficiency virus-infected rhesus monkeys. J. Virol. 73: 1573-1579.

Petrovas, C., J. P. Casazza, J. M. Brenchley, D. A. Price, E. Gostick, W. C. Adams, M. L. Precopio, T. Schacker, M. Roederer, D. C. Douek, R. A. Koup. 2006. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J. Exp. Med. 203: 2281-2292.

Drew, W. L.. 1988. Cytomegalovirus infection in patients with AIDS. J. Infect. Dis. 158: 449-456.

Erice, A., C. Tierney, M. Hirsch, A. M. Caliendo, A. Weinberg, M. A. Kendall, B. Polsky. 2003. Cytomegalovirus (CMV) and human immunodeficiency virus (HIV) burden, CMV end-organ disease, and survival in subjects with advanced HIV infection (AIDS Clinical Trials Group Protocol 360). Clin. Infect. Dis. 37: 567-578.

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Journal of Immunology

Tập 179 Số 3

1979-1987

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