CONCLUSIONS AND FUTURE PERSPECTIVES
A soluble factor produced by CD8+ T cells in HIV-infected patients is involved in part in CD8+ cell anti-HIV activity. This implies their significant participation in progressive and non-progressive HIV disease.
The non- cytotoxic activity of CD8+ T cells suppresses transcription of human immunodeficiency virus type 1 (HIV-1) in an antigen-independent and MHC-unrestricted manner. But, the precise cellular and molecular factors or the biochemical constituents mediating this CD8+ T cell effector function remain obscure. While the CTL activity mediated by CD8+ T cells is protective against HIV infection, it is highly variable between different groups of HIV patients. In contrast, the antiviral arm of the CD8+ T cells is more stable and a strong predictor of HIV disease stages. This activity comprises of potent antiviral soluble factors, the actual biochemical definition of which remains poorly understood. Once characterized, these soluble factors can be used as potential markers to predict the progression and non-progression of HIV disease. In addition, these soluble factors could be important candidates, which can be used in predicting the success and failure of HAART therapy in HIV patients. Further, it is likely that a subset of CD8+ T cells mediate these antiviral soluble factors and a detailed analysis of various subsets of CD8+ T cells in vivo and their modulation during HIV infection will yield valuable insights to mechanisms governing the infectious process in the host. With the advent of whole human genome microarray technologies, gene expression analysis of transcriptomes of various CD8+ T cell subsets may shed greater light on how HIV subverts and manipulates the host gene machinery at the level of genes encoding these soluble antiviral factors in minor, yet physiologically and biologically important CD8+ T cell subsets.REFERENCES
[1] Saksena NK, Wu JQ, Potter SJ, Wilkinson J, Wang B.
Human immunodeficiency virus interactions with CD8+ T lymphocytes. Curr HIV Res. 2008;6(1):1-9.[2] Walker CM, Moody DJ, Stites DP, Levy JA. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science. 1986;234(4783):1563-1566.
[3] Bagasra O, Pomerantz RJ. The role of CD8-positive lymphocytes in the control of HIV-1 infection of peripheral blood mononuclear cells. Immunol Lett. 1993;35(2):83-92.
[4] De Maria A, Pantaleo G, Schnittman SM, Greenhouse JJ, Baseler M, Orenstein JM, et al. Infection of CD8+ T lymphocytes with HIV. Requirement for interaction with infected CD4+ cells and induction of infectious virus from chronically infected CD8+ cells. J Immunol. 1991;146(7):2220-2226.
[5] De Rossi A, Franchini G, Aldovini A, Del Mistro A, Chieco-Bianchi L, Gallo RC, et al. Differential response to the cytopathic effects of human T-cell lymphotropic virus type III (HTLV-III) superinfection in T4+ (helper) and T8+ (suppressor) T-cell clones transformed by HTLV-I. Proc Natl Acad Sci USA. 1986;83(12):4297-4301.
[6] Mercure L, Phaneuf D, Wainberg MA. Detection of unintegrated human immunodeficiency virus type 1 DNA in persistently infected CD8+ cells. J Gen Virol. 1993;74 ( Pt 10):2077-2083.
[7] Wang B, Dyer WB, Zaunders JJ, Mikhail M, Sullivan JS, Williams L, et al. Comprehensive analyses of a unique HIV-1-infected nonprogressor reveal a complex association of immunobiological mechanisms in the context of replication-incompetent infection. Virology. 2002;304(2):246-264.
[8] Livingstone WJ, Moore M, Innes D, Bell JE, Simmonds P. Frequent infection of peripheral blood CD8-positive T- lymphocytes with HIV-1. Edinburgh Heterosexual Transmission Study Group. Lancet. 1996;348(9028):649-654.
[9] Imlach S, McBreen S, Shirafuji T, Leen C, Bell JE, Simmonds P. Activated peripheral CD8 lymphocytes express CD4 in vivo and are targets for infection by human immunodeficiency virus type 1. J Virol. 2001;75(23):11555-11564.
[10] Semenzato G, Agostini C, Ometto L, Zambello R, Trentin L, Chieco-Bianchi L, et al.
CD8+ T lymphocytes in the lung of acquired immunodeficiency syndrome patients harbor human immunodeficiency virus type 1. Blood. 1995;85(9):2308-2314.[11] McBreen S, Imlach S, Shirafuji T, Scott GR, Leen C, Bell JE, et al. Infection of the CD45RA+ (naive) subset of peripheral CD8+ lymphocytes by human immunodeficiency virus type 1 in vivo. J Virol. 2001;75(9):4091-4102.
[12] Brooks DG, Kitchen SG, Kitchen CM, Scripture-Adams DD, Zack JA. Generation of HIV latency during thymopoiesis. Nat Med. 2001;7(4):459-464.
[13] Lee S, Goldstein H, Baseler M, Adelsberger J, Golding H. Human immunodeficiency virus type 1 infection of mature CD3hiCD8+ thymocytes. J Virol. 1997;71(9):6671-6676.
[14] Flamand L, Crowley RW, Lusso P, Colombini-Hatch S, Margolis DM, Gallo RC. Activation of CD8+ T lymphocytes through the T cell receptor turns on CD4 gene expression: implications for HIV pathogenesis. Proc Natl Acad Sci USA. 1998;95(6):3111-3116.
[15] Yang LP, Riley JL, Carroll RG, June CH, Hoxie J, Patterson BK, et al. Productive infection of neonatal CD8+ T lymphocytes by HIV-1. J Exp Med. 1998;187(7):1139-1144.
[16] Kitchen SG, LaForge S, Patel VP, Kitchen CM, Miceli MC, Zack JA. Activation of CD8 T cells induces expression of CD4, which functions as a chemotactic receptor. Blood. 2002;99(1):207-212.
[17] Kitchen SG, Jones NR, LaForge S, Whitmire JK, Vu BA, Galic Z, et al. CD4 on CD8(+) T cells directly enhances effector function and is a target for HIV infection. Proc Natl Acad Sci USA. 2004;101(23):8727-8732.
[18] Zloza A, Sullivan YB, Connick E, Landay AL, Al-Harthi L. CD8+ T cells that express CD4 on their surface (CD4dimCD8bright T cells) recognize an antigen-specific target, are detected in vivo, and can be productively infected by T-tropic HIV. Blood. 2003;102(6):2156-2164.
[19] Saha K, Zhang J, Zerhouni B. Evidence of productively infected CD8+ T cells in patients with AIDS: implications for HIV-1 pathogenesis. J Acquir Immune Defic Syndr. 2001;26(3):199-207.
[20] Zerhouni B, Nelson JA, Saha K. CXCR4-dependent infection of CD8+, but not CD4+, lymphocytes by a primary human immunodeficiency virus type 1 isolate. J Virol. 2004;78(22):12288-12296.
[21] Semenzato G, Agostini C, Chieco-Bianchi L, De Rossi A. HIV load in highly purified CD8+ T cells retrieved from pulmonary and blood compartments. J Leukoc Biol. 1998;64(3):298-301.
[22] Brenchley JM, Hill BJ, Ambrozak DR, Price DA, Guenaga FJ, Casazza JP, et al. T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J Virol. 2004;78(3):1160-1168.
[23] Herbein G, Mahlknecht U, Batliwalla F, Gregersen P, Pappas T, Butler J, et al. Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4. Nature. 1998;395(6698):189-194.
[24] Lewis DE, Tang DS, Adu-Oppong A, Schober W, Rodgers JR. Anergy and apoptosis in CD8+ T cells from HIV- infected persons. J Immunol. 1994;153(1):412-420.
[25] Kalams SA, Walker BD. The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses. J Exp Med. 1998;188(12):2199-2204.
[26] Roederer M. T-cell dynamics of immunodeficiency. Nat Med. 1995;1(7):621-622.
[27] Bohler T, Walcher J, Holzl-Wenig G, Geiss M, Buchholz B, Linde R, et al. Early effects of antiretroviral combination therapy on activation, apoptosis and regeneration of T cells in HIV-1-infected children and adolescents. AIDS. 1999;13(7):779-789.
[28] Potter SJ, Dwyer DE, Saksena NK. Differential cellular distribution of HIV-1 drug resistance in vivo: evidence for infection of CD8+ T cells during HAART. Virology. 2003;305(2):339-352.
[29] Potter SJ, Lemey P, Achaz G, Chew CB, Vandamme AM, Dwyer DE, et al. HIV-1 compartmentalization in diverse leukocyte populations during antiretroviral therapy. J Leukoc Biol. 2004;76(3):562-570.
[30] Potter SJ, Lemey P, Dyer WB, Sullivan JS, Chew CB, Vandamme AM, et al. Genetic analyses reveal structured HIV-1 populations in serially sampled T lymphocytes of patients receiving HAART.
Virology. 2006;348(1):35-46.[31] Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS. Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci USA. 1998;95(15):8869-8873.
[32] Chun TW, Engel D, Mizell SB, Ehler LA, Fauci AS. Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines. J Exp Med. 1998;188(1):83-91.
[33] Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina CA, et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science. 1997;278(5341):1291-1295.
[34] Furtado MR, Callaway DS, Phair JP, Kunstman KJ, Stanton JL, Macken CA, et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N Engl J Med. 1999;340(21):1614-1622.
[35] Wilson JD, Ogg GS, Allen RL, Goulder PJ, Kelleher A, Sewell AK, et al. Oligoclonal expansions of CD8(+) T cells in chronic HIV infection are antigen specific. J Exp Med. 1998;188(4):785-790.
[36] Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science. 1999;283(5403):857-860.
[37] Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, Blanchard J, et al. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med. 1999;189(6):991-998.
[38] Stebbings R, Stott J, Almond N, Hull R, Lines J, Silvera P, et al. Mechanisms of protection induced by attenuated simian immunodeficiency virus. II. Lymphocyte depletion does not abrogate protection. AIDS Res Hum Retroviruses. 1998;14(13):1187-1198.
[39] Matano T, Shibata R, Siemon C, Connors M, Lane HC, Martin MA. Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques.
J Virol. 1998;72(1):164-169.[40] Cao J, McNevin J, Malhotra U, McElrath MJ. Evolution of CD8+ T cell immunity and viral escape following acute HIV-1 infection. J Immunol. 2003;171(7):3837-3846.
[41] Pantaleo G, Demarest JF, Soudeyns H, Graziosi C, Denis F, Adelsberger JW, et al. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature. 1994;370(6489):463-467.
[42] Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol. 1994;68(7):4650-4655.
[43] Yang OO, Kalams SA, Trocha A, Cao H, Luster A, Johnson RP, et al. Suppression of human immunodeficiency virus type 1 replication by CD8+ cells: evidence for HLA class I-restricted triggering of cytolytic and noncytolytic mechanisms. J Virol. 1997;71(4):3120-3128.
[44] Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science. 1997;278(5342):1447-1450.
[45] Zaunders JJ, Dyer WB, Wang B, Munier ML, Miranda-Saksena M, Newton R, et al. Identification of circulating antigen-specific CD4+ T lymphocytes with a CCR5+, cytotoxic phenotype in an HIV-1 long-term nonprogressor and in CMV infection. Blood. 2004;103(6):2238-2247.
[46] Draenert R, Verrill CL, Tang Y, Allen TM, Wurcel AG, Boczanowski M, et al. Persistent recognition of autologous virus by high-avidity CD8 T cells in chronic, progressive human immunodeficiency virus type 1 infection. J Virol. 2004;78(2):630-641.
[47] Migueles SA, Laborico AC, Shupert WL, Sabbaghian MS, Rabin R, Hallahan CW, et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol. 2002;3(11):1061-1068.
[48] Lieberman J, Shankar P, Manjunath N, Andersson J. Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection. Blood. 2001;98(6):1667-1677.
[49] Barouch DH, Kunstman J, Kuroda MJ, Schmitz JE, Santra S, Peyerl FW, et al. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature. 2002;415(6869):335-339.
[50] Lange CG, Lederman MM, Madero JS, Medvik K, Asaad R, Pacheko C, et al. Impact of suppression of viral replication by highly active antiretroviral therapy on immune function and phenotype in chronic HIV-1 infection. J Acquir Immune Defic Syndr. 2002;30(1):33-40.
[51] Walker CM, Levy JA. A diffusible lymphokine produced by CD8+ T lymphocytes suppresses HIV replication. Immunology. 1989;66(4):628-630.
[52] Mackewicz CE, Blackbourn DJ, Levy JA. CD8+ T cells suppress human immunodeficiency virus replication by inhibiting viral transcription. Proc Natl Acad Sci USA. 1995;92(6):2308-2312.
[53] Mackewicz CE, Patterson BK, Lee SA, Levy JA. CD8(+) cell noncytotoxic anti-human immunodeficiency virus response inhibits expression of viral RNA but not reverse transcription or provirus integration. J Gen Virol. 2000;81(Pt 5):1261-1264.
[54] Chang TL, Mosoian A, Pine R, Klotman ME, Moore JP. A soluble factor(s) secreted from CD8(+) T lymphocytes inhibits human immunodeficiency virus type 1 replication through STAT1 activation. J Virol. 2002;76(2):569-581.
[55] Tumne A, Prasad VS, Chen Y, Stolz DB, Saha K, Ratner DM, et al. Noncytotoxic Suppression of HIV- 1Transcription by Exosomes Secreted from CD8+ T Cells. J Virol. 2009.
[56] Wada M, Wada NA, Shirono H, Taniguchi K, Tsuchie H, Koga J. Amino-terminal fragment of urokinase-type plasminogen activator inhibits HIV-1 replication. Biochem Biophys Res Commun. 2001;284(2):346-351.
[57] Alfano M, Mariani SA, Elia C, Pardi R, Blasi F, Poli G. Ligand-engaged urokinase-type plasminogen activator receptor and activation of the CD11b/CD18 integrin inhibit late events of HIV expression in monocytic cells. Blood. 2009;113(8):1699-1709.
[58] Mackewicz CE, Craik CS, Levy JA. The CD8+ cell noncytotoxic anti-HIV response can be blocked by protease inhibitors. Proc Natl Acad Sci USA. 2003;100(6):3433-3438.
[59] Alfano M, Sidenius N, Panzeri B, Blasi F, Poli G. Urokinase-urokinase receptor interaction mediates an inhibitory signal for HIV-1 replication. Proc Natl Acad Sci USA. 2002;99(13):8862-8867.
[60] Chang TL, Francois F, Mosoian A, Klotman ME. CAF-mediated human immunodeficiency virus (HIV) type 1 transcriptional inhibition is distinct from alpha-defensin-1 HIV inhibition. J Virol. 2003;77(12):6777-6784.
[61] Furci L, Sironi F, Tolazzi M, Vassena L, Lusso P. Alpha-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4. Blood. 2007;109(7):2928-2935.
[62] Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science. 1995;270(5243):1811-1815.
[63] Brinchmann JE, Gaudernack G, Vartdal F. CD8+ T cells inhibit HIV replication in naturally infected CD4+ T cells. Evidence for a soluble inhibitor. J Immunol. 1990;144(8):2961-2966.
[64] Le Borgne S, Fevrier M, Callebaut C, Lee SP, Riviere Y. CD8(+)-Cell antiviral factor activity is not restricted to human immunodeficiency virus (HIV)-specific T cells and can block HIV replication after initiation of reverse transcription. J Virol. 2000;74(10):4456-4464.
[65] Geiben-Lynn R, Kursar M, Brown NV, Kerr EL, Luster AD, Walker BD. Noncytolytic inhibition of X4 virus by bulk CD8(+) cells from human immunodeficiency virus type 1 (HIV-1)-infected persons and HIV-1-specific cytotoxic T lymphocytes is not mediated by beta-chemokines. J Virol. 2001;75(17):8306-8316.
[66] Steinman RM, Granelli-Piperno A, Pope M, Trumpfheller C, Ignatius R, Arrode G, et al. The interaction of immunodeficiency viruses with dendritic cells. Curr Top Microbiol Immunol. 2003;276:1-30.
[67] Castelli J, Thomas EK, Gilliet M, Liu YJ, Levy JA. Mature dendritic cells can enhance CD8+ cell noncytotoxic anti-HIV responses: the role of IL-15. Blood. 2004;103(7):2699-2704.
[68] Wilkinson J, Zaunders JJ, Carr A, Cooper DA. CD8+ anti-human immunodeficiency virus suppressor activity (CASA) in response to antiretroviral therapy: loss of CASA is associated with loss of viremia. J Infect Dis. 1999;180(1):68-75.
[69] Wilkinson J, Zaunders JJ, Carr A, Guillemin G, Cooper DA. Characterization of the phenotypic and lymphokine profile associated with strong CD8+ anti-HIV-1 suppressor activity (CASA). Clin Exp Immunol. 2002;127(1): 145-150.
[70] Gray CM, Schapiro JM, Winters MA, Merigan TC. Changes in CD4+ and CD8+ T cell subsets in response to highly active antiretroviral therapy in HIV type 1-infected patients with prior protease inhibitor experience. AIDS Res Hum Retroviruses. 1998;14(7):561-569.
[71] Stranford SA, Ong JC, Martinez-Marino B, Busch M, Hecht FM, Kahn J, et al. Reduction in CD8+ cell noncytotoxic anti-HIV activity in individuals receiving highly active antiretroviral therapy during primary infection. Proc Natl Acad Sci USA. 2001;98(2):597-602.
[72] Ogg GS, Jin X, Bonhoeffer S, Dunbar PR, Nowak MA, Monard S, et al. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science. 1998;279(5359):2103-2106.
[73] Torres KJ, Gutierrez F, Espinosa E, Mackewicz C, Regalado J, Reyes-Teran G. CD8+ cell noncytotoxic anti-HIV response: restoration by HAART in the late stage of infection. AIDS Res Hum Retroviruses. 2006;22(2):144-152.
[74] McCune JM. The dynamics of CD4+ T-cell depletion in HIV disease. Nature. 2001;410(6831):974-979.
[75] McCune JM. HIV-1: the infective process in vivo. Cell. 1991;64(2):351-363.
[76] Haase AT. Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu Rev Immunol. 1999;17:625-656.
[77] Imami N, Gotch F. Mechanisms of loss of HIV-1-specific T-cell responses. J HIV Ther. 2002;7(2):30-34.
[78] Bennett SR, Carbone FR, Karamalis F, Miller JF, Heath WR. Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help. J Exp Med. 1997;186(1):65-70.
[79] Keene JA, Forman J. Helper activity is required for the in vivo generation of cytotoxic T lymphocytes. J Exp Med. 1982;155(3):768-782.
[80] Ridge JP, Di Rosa F, Matzinger P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature. 1998;393(6684):474-478.
[81] Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature. 1998;393(6684):480-483.
[82] Spiegel HM, Ogg GS, DeFalcon E, Sheehy ME, Monard S, Haslett PA, et al. Human immunodeficiency virus type 1- and cytomegalovirus-specific cytotoxic T lymphocytes can persist at high frequency for prolonged periods in the absence of circulating peripheral CD4(+) T cells. J Virol. 2000;74(2):1018-1022.
[83] Kalams SA, Buchbinder SP, Rosenberg ES, Billingsley JM, Colbert DS, Jones NG, et al. Association between virus-specific cytotoxic T-lymphocyte and helper responses in human immunodeficiency virus type 1 infection. J Virol. 1999;73(8):6715-6720.
[84] Cardin RD, Brooks JW, Sarawar SR, Doherty PC. Progressive loss of CD8+ T cell-mediated control of a gammaherpesvirus in the absence of CD4+ T cells. J Exp Med. 1996;184(3):863-871.
[85] Bourgeois C, Rocha B, Tanchot C. A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory. Science. 2002;297(5589):2060-2063.
[86] Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature. 2003;421(6925):852-856.
[87] Lichterfeld M, Kaufmann DE, Yu XG, Mui SK, Addo MM, Johnston MN, et al. Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells. J Exp Med. 2004;200(6):701-712.
[88] Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med. 1998;339(1):33-39.
[89] Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol. 1994;68(9):6103-6110.
[90] Addo MM, Yu XG, Rathod A, Cohen D, Eldridge RL, Strick D, et al. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J Virol. 2003;77(3):2081-2092.
[91] Betts MR, Ambrozak DR, Douek DC, Bonhoeffer S, Brenchley JM, Casazza JP, et al. Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: relationship to viral load in untreated HIV infection. J Virol. 2001;75(24):11983-11991.
[92] Hazenberg MD, Stuart JW, Otto SA, Borleffs JC, Boucher CA, de Boer RJ, et al. T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). Blood. 2000;95(1):249-255.
[93] Lieberman J, Trimble LA, Friedman RS, Lisziewicz J, Lori F, Shankar P, et al. Expansion of CD57 and CD62L- CD45RA+ CD8 T lymphocytes correlates with reduced viral plasma RNA after primary HIV infection. AIDS. 1999;13(8):891-899.
[94] Trimble LA, Lieberman J. Circulating CD8 T lymphocytes in human immunodeficiency virus-infected individuals have impaired function and downmodulate CD3 zeta, the signaling chain of the T-cell receptor complex. Blood. 1998;91(2):585-594.
[95] Shankar P, Russo M, Harnisch B, Patterson M, Skolnik P, Lieberman J. Impaired function of circulating HIV- specific CD8(+) T cells in chronic human immunodeficiency virus infection. Blood. 2000;96(9):3094-3101.
[96] Shankar P, Xu Z, Lieberman J. Viral-specific cytotoxic T lymphocytes lyse human immunodeficiency virus- infected primary T lymphocytes by the granule exocytosis pathway. Blood. 1999;94(9):3084-3093.
[97] Salerno-Goncalves R, Lu W, Andrieu JM. Quantitative analysis of the antiviral activity of CD8(+) T cells from human immunodeficiency virus-positive asymptomatic patients with different rates of CD4(+) T-cell decrease. J Virol. 2000;74(14):6648-6651.
[98] Dioszeghy V, Benlhassan-Chahour K, Delache B, Dereuddre-Bosquet N, Aubenque C, Gras G, et al. Changes in soluble factor-mediated CD8+ cell-derived antiviral activity in cynomolgus macaques infected with simian immunodeficiency virus SIVmac251: relationship to biological markers of progression. J Virol. 2006;80(1):236-245.
[99] Giri MS, Nebozhyn M, Showe L, Montaner LJ. Microarray data on gene modulation by HIV-1 in immune cells: 2000-2006. J Leukoc Biol. 2006;80(5):1031-1043.
[100] Ryo A, Suzuki Y, Ichiyama K, Wakatsuki T, Kondoh N, Hada A, et al. Serial analysis of gene expression in HIV- 1-infected T cell lines. FEBS Lett. 1999;462(1-2):182-186.
[101] Diaz LS, Stone MR, Mackewicz CE, Levy JA. Differential gene expression in CD8+ cells exhibiting noncytotoxic anti-HIV activity. Virology. 2003;311(2):400-409.
[102] Martinez-Marino B, Foster H, Hao Y, Levy JA. Differential gene expression in CD8(+) cells from HIV-1-infected subjects showing suppression of HIV replication. Virology. 2007;362(1):217-225.
[103] Hyrcza MD, Kovacs C, Loutfy M, Halpenny R, Heisler L, Yang S, et al. Distinct transcriptional profiles in ex vivo CD4+ and CD8+ T cells are established early in human immunodeficiency virus type 1 infection and are characterized by a chronic interferon response as well as extensive transcriptional changes in CD8+ T cells. J Virol. 2007;81(7):3477-3486.
[104] Wu JQ, Wang B, Belov L, Chrisp J, Learmont J, Dyer WB, et al. Antibody microarray analysis of cell surface antigens on CD4+ and CD8+ T cells from HIV+ individuals correlates with disease stages. Retrovirology. 2007;4:83.
[105] Wu JQ, Dwyer DE, Dyer WB, Yang YH, Wang B, Saksena NK. Transcriptional profiles in CD8+ T cells from HIV+ progressors on HAART are characterized by coordinated up-regulation of oxidative phosphorylation enzymes and interferon responses. Virology. 2008;380(1):124-135.