Abstract
Background: Anti-viral cytokine expressions by cytotoxic T-cells and lower activation rates have been reported to correlate with suppressed HIV replication in long-term non-progressors (LTNP). Immune mechanisms underlying disease non-progression in LTNP might vary with HIV-1 subtype and geographical locations.
Objective: This study evaluates cytokine expression and T-cells activation in relation to disease non-progression in LTNP.
Methods: HIV-1 Subtype C infected LTNP (n=20) and progressors (n=15) were enrolled and flowcytometry assays were performed to study HIV-specific CD8 T-cells expressing IL-2, IFN-γ, TNF-α and MIP-1β against gag and env peptides. CD4+ T-cell activation was evaluated by surface expression of HLADR and CD38.
Results: Proportions of cytokines studied did not differ significantly between LTNP and progressors, while contrasting correlations with disease progression markers were observed in LTNP. CD4+ T-cell activation rates were significantly lower in LTNP compared to progressors which indicate the potential role of T-cell activation rates in disease non-progression in LTNP.
Conclusion: LTNP and progressors showed similar CD8+ T-cell responses, but final conclusions can be drawn only by comparing multiple immune factors in larger LTNP cohort with HIV-1 infected individuals at various levels of disease progression. A possible role of HIV-1 subtype variation and ethnic differences in addition to host-genetic and viral factors cannot be ruled out.
Keywords: HIV LTNP, HIV non-progression, antiviral cytokine response in HIV LTNP, T-cell activation in HIV LTNP, HLADR, CD38.
Graphical Abstract
[1]
Betts MR, Nason MC, West SM, et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 2006; 107(12): 4781-9.
[2]
Bangham CRM. CTL quality and the control of human retroviral infections. Eur J Immunol 2009; 39(7): 1700-12.
[3]
Allen TM, O’Connor DH, Jing P, et al. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 2000; 407(6802): 386-90.
[4]
Nemes E, Bertoncelli L, Lugli E, et al. Cytotoxic granule release dominates gag-specific CD4+ T-cell response in different phases of HIV infection. AIDS 2010; 24(7): 947-57.
[5]
Davenport MP, Ribeiro RM, Perelson AS. Kinetics of virus-specific CD8+ T cells and the control of human immunodeficiency virus infection. J Virol 2004; 78(18): 10096-103.
[6]
Daucher M, Price DA, Brenchley JM, et al. Virological outcome after structured interruption of antiretroviral therapy for human immunodeficiency virus infection is associated with the functional profile of virus-specific CD8+ T cells. J Virol 2008; 82(8): 4102-14.
[7]
Almeida JR, Price DA, Papagno L, et al. Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J Exp Med 2007; 204(10): 2473-85.
[8]
Seder RA, Darrah PA, Roederer M. T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol 2008; 8(4): 247-58.
[9]
López M, Soriano V, Lozano S, et al. no major differences in the functional profile of hiv gag and nef-specific cd8+ reponses between long-term nonprogressors and typical progressors. AIDS Res Hum Retroviruses 2008; 24(9): 1185-95.
[10]
Madec Y, Boufassa F, Avettand-Fenoel V, et al. Early control of HIV-1 infection in long-term nonprogressors followed since diagnosis in the ANRS SEROCO/HEMOCO cohort. J Acquir Immune Defic Syndr 1999 2009; 50(1): 19-26.
[11]
Rodés B, Toro C, Paxinos E, et al. Differences in disease progression in a cohort of long-term non-progressors after more than 16 years of HIV-1 infection. AIDS Lond Engl 2004; 18(8): 1109-16.
[12]
Goudsmit J, Bogaards JA, Jurriaans S, et al. Naturally HIV-1 seroconverters with lowest viral load have best prognosis, but in time lose control of viraemia. AIDS Lond Engl 2002; 16(5): 791-3.
[13]
Okulicz JF, Lambotte O. Epidemiology and clinical characteristics of elite controllers. Curr Opin HIV AIDS 2011; May; 6(3): 163-8.
[14]
Boaz MJ, Waters A, Murad S, Easterbrook PJ, Vyakarnam A. 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 2002; 169(11): 6376-85.
[15]
Poropatich K, Sullivan DJJ. Human immunodeficiency virus type 1 long-term non-progressors: the viral, genetic and immunological basis for disease non-progression. J Gen Virol 2011; 92(Pt 2): 247-68.
[16]
Migueles SA, Laborico AC, Shupert WL, et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 2002; 3(11): 1061-8.
[17]
Gea-Banacloche JC, Migueles SA, Martino L, et al. Maintenance of large numbers of virus-specific CD8+ T cells in HIV-infected progressors and long-term nonprogressors. J Immunol 2000; 165(2): 1082-92.
[18]
Mothe B, Llano A, Ibarrondo J, et al. CTL responses of high functional avidity and broad variant cross-reactivity are associated with HIV control. PLoS One 2012; 7(1): e29717.
[19]
Ndhlovu ZM, Chibnik LB, Proudfoot J, et al. High-dimensional immunomonitoring models of HIV-1-specific CD8 T-cell responses accurately identify subjects achieving spontaneous viral control. Blood 2013; 121(5): 801-11.
[20]
Rehr M, Cahenzli J, Haas A, Price DA, Gostick E, Huber M, et al. Emergence of polyfunctional CD8+ T cells after prolonged suppression of human immunodeficiency virus replication by antiretroviral therapy. J Virol 2008; 82(7): 3391-404.
[21]
Benito JM, López M, Lozano S, et al. Phenotype and functional characteristics of HIV-specific cytotoxic CD8+ T cells in chronically infected patients. J AIDS 2003; 34: 255-66.
[22]
Champagne P, Ogg GS, King AS, et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 2001; 410(6824): 106-11.
[23]
Appay V, Dunbar PR, Callan M, et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 2002; 8(4): 379-85.
[24]
Ghiglione Y, Falivene J, Ruiz MJ, et al. Early skewed distribution of total and hiv-specific cd8+ t-cell memory phenotypes during primary hiv infection is related to reduced antiviral activity and faster disease progression. PLoS One 2014; 9(8): e104235.
[25]
Appay V, Nixon DF, Donahoe SM, et al. HIV-specific CD8+ T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 2000; 192(1): 63-76.
[26]
Kostense S, Vandenberghe K, Joling J, et al. Persistent numbers of tetramer+ CD8+ T cells, but loss of interferon-γ+ HIV-specific T cells during progression to AIDS. Blood 2002; 99(7): 2505-11.
[27]
Choudhary SK, Vrisekoop N, Jansen CA, et al. Low immune activation despite high levels of pathogenic human immunodeficiency virus type 1 results in long-term asymptomatic disease. J Virol 2007; 81(16): 8838-42.
[28]
Deeks SG, Kitchen CMR, Liu L, et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 2004; 104(4): 942-7.
[29]
Kamya P, Tsoukas CM, Boulet S, et al. T cell Activation does not drive CD4 decline in longitudinally followed HIV-infected Elite Controllers. AIDS Res Ther 2011; 8(1): 20.
[30]
Carbone J, Gil J, Benito JM, Fernandez-Cruz E. Decreased expression of activation markers on CD4 T lymphocytes of HIV-infected long-term non-progressors. AIDS 2003; 17(1): 133-4.
[31]
Gaardbo JC, Hartling HJ, Gerstoft J, Nielsen SD. Thirty years with HIV infection—nonprogression is still puzzling: lessons to be learned from controllers and long-term nonprogressors. AIDS Res Treat 2012; 2012.
[32]
Bégaud E, Chartier L, Marechal V, et al. Reduced CD4 T cell activation and in vitro susceptibility to HIV-1 infection in exposed uninfected Central Africans. Retrovirology 2006; 3: 35.
[33]
Broussard SR, Staprans SI, White R, Whitehead EM, Feinberg MB, Allan JS. Simian immunodeficiency virus replicates to high levels in naturally infected African green monkeys without inducing immunologic or neurologic disease. J Virol 2001; 75(5): 2262-75.
[34]
Whittall T, Peters B, Rahman D, Kingsley CI, Vaughan R, Lehner T. Immunogenic and tolerogenic signatures in human immunodeficiency virus (HIV)-infected controllers compared with progressors and a conversion strategy of virus control. Clin Exp Immunol 2011; Nov 166(2): 208-17.
[35]
Vieillard V, Fausther-Bovendo H, Samri A, Debré P. French Asymptomatiques à Long Terme (ALT) ANRS-CO15 Study Group. Specific phenotypic and functional features of natural killer cells from HIV-infected long-term nonprogressors and HIV controllers. J Acquir Immune Defic Syndr 1999 2010; 53(5): 564-73.
[36]
Okulicz JF, Marconi VC, Landrum ML, et al. Clinical outcomes of elite controllers, viremic controllers, and long-term nonprogressors in the us department of defense hiv natural history study. J Infect Dis 2009; 200(11): 1714-23.
[37]
Chevalier MF, Jülg B, Pyo A, et al. HIV-1-Specific interleukin-21+ cd4+ t cell responses contribute to durable viral control through the modulation of hiv-specific cd8+ t cell function. J Virol 2011; 85(2): 733-41.
[39]
Migueles SA, Tilton JC, Connors M. Advances in understanding immunologic control of HIV infection. Curr HIV/AIDS Rep 2004; 1(1): 12-7.
[40]
Koup RA, Safrit JT, Cao Y, 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): 4650-5.
[41]
Saez-Cirion A, Jacquelin B, Barré-Sinoussi F, Müller-Trutwin M. Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure? Philos Trans R Soc Lond B Biol Sci 2014; 369(1645): 20130436.
[42]
Kiepiela P, Ngumbela K, Thobakgale C, et al. CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med 2007; 13(1): 46-53.
[43]
Levy JA. HIV pathogenesis: 25 years of progress and persistent challenges. AIDS 2009; 23(2): 147-60.
[44]
Okoye A, Park H, Rohankhedkar M, et al. Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis. J Exp Med 2009; 206(7): 1575-88.
[45]
Schmitz JE, Simon MA, Kuroda MJ, et al. A nonhuman primate model for the selective elimination of CD8+ lymphocytes using a mouse-human chimeric monoclonal antibody. Am J Pathol 1999; 154(6): 1923-32.
[46]
Jin X, Bauer DE, Tuttleton SE, et al. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 1999; 189(6): 991-8.
[47]
Migueles SA, Connors M. Long-term nonprogressive disease among untreated HIV-infected individuals: clinical implications of understanding immune control of HIV. JAMA J Am Med Assoc 2010; 304(2): 194-201.
[48]
Demers KR, Reuter MA, Betts MR. CD8+ T-cell effector function and transcriptional regulation during HIV pathogenesis. Immunol Rev 2013; 254(1): 190-206.
[49]
Geldmacher C, Currier JR, Herrmann E, et al. CD8 T-cell recognition of multiple epitopes within specific Gag regions is associated with maintenance of a low steady-state viremia in human immunodeficiency virus type 1-seropositive patients. J Virol 2007; 81(5): 2440-8.
[50]
Emu B, Sinclair E, Hatano H, et al. HLA class I-restricted T-cell responses may contribute to the control of human immunodeficiency virus infection, but such responses are not always necessary for long-term virus control. J Virol 2008; 82(11): 5398-407.
[51]
Altfeld M, Addo MM, Kreuzer KA, et al. T (H) 1 to T (H) 2 shift of cytokines in peripheral blood of HIV-infected patients is detectable by reverse transcriptase polymerase chain reaction but not by enzyme-linked immunosorbent assay under nonstimulated conditions. J Acquir Immune Defic Syndr 1999 2000; 23(4): 287-94.
[52]
Pasquereau S, Kumar A, Herbein G. Targeting TNF and TNF receptor pathway in hiv-1 infection: from immune activation to viral reservoirs. Viruses 2017; 9(4): pii E64.
[53]
Cummins NW, Badley AD. Mechanisms of HIV-associated lymphocyte apoptosis: 2010. Cell Death Dis 2010; 1(11): e99.
[54]
Zimmerli SC, Harari A, Cellerai C, Vallelian F, Bart P-A, Pantaleo G. HIV-1-specific IFN-γ/IL-2-secreting CD8 T cells support CD4-independent proliferation of HIV-1-specific CD8 T cells. Proc Natl Acad Sci USA 2005; 102(20): 7239-44.
[55]
Khanna R, Burrows SR, Thomson SA, et al. Class I processing-defective Burkitt’s lymphoma cells are recognized efficiently by CD4+ EBV-specific CTLs. J Immunol 1997; 158(8): 3619-25.
[56]
Casazza JP, Betts MR, Price DA, et al. Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation. J Exp Med 2006; 203(13): 2865-77.
[57]
Zhou W, Sharma M, Martinez J, et al. Functional characterization of BK virus-specific CD4+ T cells with cytotoxic potential in seropositive adults. Viral Immunol 2007; 20(3): 379-88.
[58]
Premack BA, Schall TJ. Chemokine receptors: gateways to inflammation and infection. Nat Med 1996; 2(11): 1174-8.
[59]
Adams DH, Rlloyd A. Chemokines: leucocyte recruitment and activation cytokines. The Lancet 1997; 349(9050): 490-5.
[60]
Ullum H, Cozzi Lepri A, Victor J, et al. Production of beta-chemokines in human immunodeficiency virus (HIV) infection: evidence that high levels of macrophage inflammatory protein-1beta are associated with a decreased risk of HIV disease progression. J Infect Dis 1998; 177(2): 331-6.
[61]
Paxton WA, Neumann AU, Kang S, et al. RANTES production from CD4+ lymphocytes correlates with host genotype and rates of human immunodeficiency virus type 1 disease progression. J Infect Dis 2001; 183(11): 1678-81.
[62]
Ferbas J, Giorgi JV, Amini S, et al. Antigen-specific production of RANTES, macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta in vitro is a correlate of reduced human immunodeficiency virus burden in vivo. J Infect Dis 2000; 182(4): 1247-50.
[63]
Cocchi F, DeVico AL, Yarchoan R, et al. Higher macrophage inflammatory protein (MIP)-1α and MIP-1β levels from CD8+ T cells are associated with asymptomatic HIV-1 infection. Proc Natl Acad Sci USA 2000; 97(25): 13812-7.
[64]
Jennes W, Sawadogo S, Koblavi-Dème S, et al. Positive association between beta-chemokine-producing T cells and HIV type 1 viral load in HIV-infected subjects in Abidjan, Côte d’Ivoire. AIDS Res Hum Retroviruses 2002; 18(3): 171-7.
[65]
Ogg GS, Jin X, Bonhoeffer S, et al. Decay kinetics of human immunodeficiency virus-specific effector cytotoxic T lymphocytes after combination antiretroviral therapy. J Virol 1999; 73(1): 797-800.
[66]
Kalams SA, Goulder PJ, Shea AK, et al. Levels of human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy. J Virol 1999; 73(8): 6721-8.
[67]
Casazza JP, Betts MR, Picker LJ, Koup RA. Decay kinetics of human immunodeficiency virus-specific CD8+ T cells in peripheral blood after initiation of highly active antiretroviral therapy. J Virol 2001; 75(14): 6508-16.
[68]
Emu B, Sinclair E, Favre D, et al. Phenotypic, functional, and kinetic parameters associated with apparent T-cell control of human immunodeficiency virus replication in individuals with and without antiretroviral treatment. J Virol 2005; 79(22): 14169-78.
[69]
Sáez-Cirión A, Lacabaratz C, Lambotte O, et al. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci USA 2007; 104(16): 6776-81.
[70]
Owen RE, Heitman JW, Hirschkorn DF, et al. HIV+ elite controllers have low HIV-specific T-cell activation yet maintain strong, polyfunctional T-cell responses. AIDS Lond Engl 2010; 24(8): 1095-105.
[71]
Hunt PW, Brenchley J, Sinclair E, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 2008; 197(1): 126-33.
[72]
Mellors JW, Margolick JB, Phair JP, et al. Prognostic value of HIV-1 RNA, CD4 cell count, and CD4 Cell count slope for progression to AIDS and death in untreated HIV-1 infection. JAMA 2007; 297(21): 2349-50.
[73]
Rodríguez B, Sethi AK, Cheruvu VK, et al. Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. JAMA 2006; 296(12): 1498-506.
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