NK细胞在HIV感染中的作用:进展和展望
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摘要
NK细胞作为免疫系统的一个重要组成部分,在免疫防御和免疫监视的过程中起着关键作用。NK细胞是重要的抗病毒免疫细胞,识别被感染细胞后,能快速分泌颗粒酶和穿孔素裂解细胞,并分泌促炎症因子如IFN-γ、TNF-α引起更广泛的免疫应答,控制机体病毒的数量。目前研究表明,HIV感染可以引起NK细胞亚群数量及功能的改变,NK细胞也能控制HIV及感染细胞,有助于病毒的清除与控制。抗反转录病毒治疗能在一定程度上恢复HIV感染者CD4+T细胞的数量,将病毒载量控制在低水平,但病毒储存库的存在仍然是HIV治疗所面临的一个巨大的挑战。最近对猴免疫缺陷病毒感染的猕猴和HIV感染者的研究发现,存在于B细胞滤泡中的NK细胞可抑制病毒复制、清除储存库,为病毒储存库的清除提供新的研究方向。随着对NK细胞研究的深入,其在HIV感染中发挥的作用也越来越受到重视。本文对NK细胞的表型、功能及其在HIV感染中的改变与作用进行介绍,为今后的研究提供思路。
NK cells, occupying a significant niche in the immune system, play a critical role in the immune defense and surveillance. NK cells are important antiviral immune cells, which can rapidly secrete granzyme and perforin as well as pro-inflammatory factors such as IFN-γ, TNF-α to induce a broader immune response and control viruses after recognizing infected cells. The present study demonstrates that HIV infection leads to changes in the number and function of NK cell subsets, while NK cells also control HIV and infected cells, which is conductive to the viral clearance and control. Antiretroviral therapy has been able to restore the number of CD4~+ T cells in HIV-infected patients to some extent and controls the viral load at a low level, but the viral reservoirs remain a huge challenge for HIV treatment. Recent studies on simian immunodeficiency virus-infected macaques and HIV-infected individuals have found that NK cells in B-cell follicles can inhibit viral replication, clear viral reservoirs and provide a new direction for the clearance of viral reservoirs. With recent advances in our understanding of NK cells, the role of NK cells playing in HIV infection becomes increasingly important. This article introduces NK cells phenotype, function, changes and effects in HIV infection and provides ideas for future research.
NK cells, occupying a significant niche in the immune system, play a critical role in the immune defense and surveillance. NK cells are important antiviral immune cells, which can rapidly secrete granzyme and perforin as well as pro-inflammatory factors such as IFN-γ, TNF-α to induce a broader immune response and control viruses after recognizing infected cells. The present study demonstrates that HIV infection leads to changes in the number and function of NK cell subsets, while NK cells also control HIV and infected cells, which is conductive to the viral clearance and control. Antiretroviral therapy has been able to restore the number of CD4~+ T cells in HIV-infected patients to some extent and controls the viral load at a low level, but the viral reservoirs remain a huge challenge for HIV treatment. Recent studies on simian immunodeficiency virus-infected macaques and HIV-infected individuals have found that NK cells in B-cell follicles can inhibit viral replication, clear viral reservoirs and provide a new direction for the clearance of viral reservoirs. With recent advances in our understanding of NK cells, the role of NK cells playing in HIV infection becomes increasingly important. This article introduces NK cells phenotype, function, changes and effects in HIV infection and provides ideas for future research.
引文
[1]曹雪涛.免疫学前沿进展[M].北京:人民卫生出版社,2009:26,27-28.
[2]Di Santo, James P. Natural killer cells:diversity in search of a niche[J]. Nat Immunol, 2008, 9(5):473-475.
[3]Iannello A, Debbeche O, Samarani S, et al. Antiviral NK cell responses in HIV infection:II. viral strategies for evasion and lessons for immunotherapy and vaccination[J]. J Leukoc Biol, 2008, 84(1):27-49.
[4]Bansal GP, Malaspina A, Flores J. Future paths for HIV vaccine research:exploiting results from recent clinical trials and current scientific advances[J]. Curr Opin Mol Ther, 2010, 12(1):39-46.
[5]Caligiuri MA. Human natural killer cells[J]. Blood, 2008, 112(3):461-469.
[6]Alter G, Suscovich TJ, Kleyman M, et al. Low perforin and elevated SHIP-1 expression is associated with functional anergy of natural killer cells in chronic HIV-1 infection[J]. AIDS, 2006, 20(11):1549-1551.
[7]Bj?rkstr?m NK, Ljunggren HG, Sandberg JK. CD56 negative NK cells:origin, function, and role in chronic viral disease[J]. Trends Immunol, 2010, 31(11):401-406.
[8]Yokoyama WM. Mistaken notions about natural killer cells[J]. Nat Immunol, 2008, 9(5):481-485.
[9]Montaldo E, Zotto GD, Chiesa MD, et al. Human NK cell receptors/markers:a tool to analyze NK cell development, subsets and function[J]. Cytometry A, 2013, 83(8):702-713.
[10]Lanier LL. Up on the tightrope:natural killer cell activation and inhibition[J]. Nat Immunol, 2008, 9(5):495-502.
[11]Smyth MJ, Cretney E, Kelly JM, et al. Activation of NK cell cytotoxicity[J]. Mol Immunol, 2005, 42:501-510.
[12]Bashirova AA, Thomas R, Carrington M. HLA/KIR restraint of HIV:surviving the fittest[J]. Annu Rev Immunol, 2011, 29:295-317.
[13]Huth TK, Brenu EW, Ashton KJ, et al. Natural killer cell cytotoxic activity:measurement of the apoptotic inducing mechanisms[J]. Clin Exp Med Sci, 2013, 1(8):373-386.
[14]Wang W, Erbe AK, Hank JA, et al. NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy[J]. Front Immunol, 2015, 6:368.
[15]Wherry EJ. T cell exhaustion[J]. Nat Immunol, 2011, 12(6):492-499.
[16]Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion[J]. Nat Rev Immunol, 2015, 15(8):486-499.
[17]Angelosanto JM, Wherry EJ. Transcription factor regulation of CD8+T-cell memory and exhaustion[J]. Immunol Rev, 2010, 236(1):167-175.
[18]Pesce S, Greppi M, Tabellini G, et al. Identification of a subset of human natural killer cells expressing high levels of programmed death 1:a phenotypic and functional characterization[J]. J Allergy Clin Immunol, 2017, 139(1):335-346.
[19]Beldi-Ferchiou A, Lambert M, Dogniaux S, et al. PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma[J]. Oncotarget, 2016, 7(45):72961-72977.
[20]Wiesmayr S, Webber SA, Macedo C, et al. Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD[J]. Eur J Immunol, 2012, 42(2):541-550.
[21]MacFarlane AW, Jillab M, Plimack ER, et al. PD-1 expression on peripheral blood cells increases with stage in renal cell carcinoma patients and is rapidly reduced after surgical tumor resection[J]. Cancer Immunol Res, 2014, 2(4):320-331.
[22]Zhang Q, Bi J, Zheng X, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity[J]. Nat Immunol, 2018, 19(7):723-732..
[23]Sun C, Xu J, Huang Q, et al. High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer[J]. Oncoimmunology, 2017, 6(1):e1264562.
[24]da Silva IP, Gallois A, Baranda SJ, et al. Reversal of NK cell exhaustion in advanced melanoma by Tim-3 blockade[J]. Cancer Immunol Res, 2014, 2(5):410-422.
[25]Gallois A, Silva I, Osman I, et al. Reversal of natural killer cell exhaustion by TIM-3 blockade[J]. Oncoimmunology, 2014, 3(12):e946365.
[26]Li YH, Zhou WH, Tao Y, et al. The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal–fetal interface in early pregnancy[J]. Cell Mol Immunol, 2016, 13(1):73-81.
[27]Ju Y, Hou N, Meng J, et al. T cell immunoglobulin-and mucin-domain-containing molecule-3(Tim-3)mediates natural killer cell suppression in chronic hepatitis B[J]. J Hepatol, 2010, 52(3):322-329.
[28]Hodge G, Barnawi J, Jurisevic C, et al. Lung cancer is associated with decreased expression of perforin, granzyme B and interferon(IFN)‐γby infiltrating lung tissue T cells, natural killer(NK)T‐like and NK cells[J]. Clin Exp Immunol, 2014, 178(1):79-85.
[29]Sun C, Fu B, Gao Y, et al. TGF-β1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence[J]. PLoS Pathog, 2012, 8(3):e1002594.
[30]Shifrin N, Raulet DH, Ardolino M. NK cell self tolerance, responsiveness and missing self recognition[J]. Semin Immunol, 2014, 26(2):138-144.
[31]Scully E, Alter G. NK cells in HIV disease[J]. Curr HIV/AIDS Rep, 2016, 13(2):85-94.
[32]Mavilio D, Lombardo G, Kinter A, et al. Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection[J]. J Exp Med, 2006, 203(10):2339-2350.
[33]Scott-Algara D, Truong LX, Versmisse P, et al.Cutting edge:increased NK cell activity in HIV-1-exposed but uninfected Vietnamese intravascular drug users[J]. J Immunol, 2003, 171(11):5663-5667.
[34]Perera SS, Saksena NK. Innate, adaptive and intrinsic immunity in human immunodeficiency virus infection[J]. Am J Infect Dis, 2012, 8(3):132.
[35]刘贝贝,赵敏. HIV感染者Siglec-7+NK细胞数量和功能的研究[J].中国艾滋病性病,2017,23(7):587-591.
[36]Kuri-Cervantes L, de Oca GS, Avila-Ríos S, et al. Activation of NK cells is associated with HIV-1 disease progression[J]. J Leukoc Biol, 2014, 96(1):7-16.
[37]Gonzalez VD, Falconer K, Bj?rkstr?m NK, et al. Expansion of functionally skewed CD56-negative NK cells in chronic hepatitis C virus infection:correlation with outcome of pegylated IFN-αand ribavirin treatment[J]. J Immunol, 2009, 183(10):6612-6218.
[38]Gonzalez VD, Falconer K, Micha?lsson J, et al. Expansion of CD56-NK cells in chronic HCV/HIV-1 co-infection:reversion by antiviral treatment with pegylated IFNαand ribavirin[J]. Clin Immunol, 2008, 128(1):46-56.
[39]Tiemessen CT, Shalekoff S, Meddows-Taylor S, et al. Natural killer cells that respond to human immunodeficiency virus type 1(HIV-1)peptides are associated with control of HIV-1 infection[J]. J Infect Dis,2010, 202(9):1444-1453.
[40]Martin MP, Gao X, Lee JH, et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS[J]. Nat Genet, 2002, 31(4):429-434.
[41]Alter G, Martin MP, Teigen N, et al. Differential natural killer cell–mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes[J]. J Exp Med,2007, 204(12):3027-3036.
[42]Alter G, Rihn S, Walter K, et al. HLA class I subtype-dependent expansion of KIR3DS1+and KIR3DL1+NK cells during acute human immunodeficiency virus type 1 infection[J]. J Virol, 2009, 83(13):6798-6805.
[43]Zhang X, Lu X, Moog C, et al. KIR3DL1-negative CD8 T cells and KIR3DL1-negative natural killer cells contribute to the advantageous control of early human immunodeficiency virus type 1 infection in HLA-B Bw4 homozygous individuals[J]. Front Immunol, 2018, 9:1855.
[44]Ye X, Zhang Z, Jiang Y, et al. Expression of human CD226 on T cells and natural killer cells and of soluble CD226 in plasma of HIV-1-infected Chinese patients[J]. Viral immunol, 2006, 19(3):576-581.
[45]Scott-Algara D, Truong LX, Versmisse P, et al. Cutting edge:increased NK cell activity in HIV-1-exposed but uninfected Vietnamese intravascular drug users[J]. J Immunol, 2003, 171(11):5663-5667.
[46]Alsahafi N, Richard J, Prévost J, et al. Impaired downregulation of NKG2D ligands by Nef protein from elite controllers sensitizes HIV-1-infected cells to ADCC[J]. J Virol, 2017, 91(16):pii:e00109-17.
[47]Tomescu C, Tebas P, Montaner LJ. IFN-αaugments natural killer-mediated antibody-dependent cellular cytotoxicity of HIV-1-infected autologous CD4+T cells regardless of major histocompatibility complex class 1 downregulation[J]. AIDS, 2017, 31(5):613-622.
[48]Mavilio D, Lombardo G, Kinter A, et al. Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection[J]. J Exp Med, 2006, 203(10):2339-2350.
[49]Porichis F, Hart MG, Massa A, et al. Immune checkpoint blockade restores HIV-specific CD4 T cell help for NK cells[J]. J Immunol, 2018, 201(3):971-981.
[50]张和倩,常文仙,焦艳梅,等. HIV病毒库清除策略研究进展[J].传染病信息,2017,30(6):321-326.
[51]Huot N, Jacquelin B, Garcia-Tellez T, et al. Natural killer cells migrate into and control simian immunodeficiency virus replication in lymph node follicles in African green monkeys[J]. 2017, 23(11):1277-1286.
[2]Di Santo, James P. Natural killer cells:diversity in search of a niche[J]. Nat Immunol, 2008, 9(5):473-475.
[3]Iannello A, Debbeche O, Samarani S, et al. Antiviral NK cell responses in HIV infection:II. viral strategies for evasion and lessons for immunotherapy and vaccination[J]. J Leukoc Biol, 2008, 84(1):27-49.
[4]Bansal GP, Malaspina A, Flores J. Future paths for HIV vaccine research:exploiting results from recent clinical trials and current scientific advances[J]. Curr Opin Mol Ther, 2010, 12(1):39-46.
[5]Caligiuri MA. Human natural killer cells[J]. Blood, 2008, 112(3):461-469.
[6]Alter G, Suscovich TJ, Kleyman M, et al. Low perforin and elevated SHIP-1 expression is associated with functional anergy of natural killer cells in chronic HIV-1 infection[J]. AIDS, 2006, 20(11):1549-1551.
[7]Bj?rkstr?m NK, Ljunggren HG, Sandberg JK. CD56 negative NK cells:origin, function, and role in chronic viral disease[J]. Trends Immunol, 2010, 31(11):401-406.
[8]Yokoyama WM. Mistaken notions about natural killer cells[J]. Nat Immunol, 2008, 9(5):481-485.
[9]Montaldo E, Zotto GD, Chiesa MD, et al. Human NK cell receptors/markers:a tool to analyze NK cell development, subsets and function[J]. Cytometry A, 2013, 83(8):702-713.
[10]Lanier LL. Up on the tightrope:natural killer cell activation and inhibition[J]. Nat Immunol, 2008, 9(5):495-502.
[11]Smyth MJ, Cretney E, Kelly JM, et al. Activation of NK cell cytotoxicity[J]. Mol Immunol, 2005, 42:501-510.
[12]Bashirova AA, Thomas R, Carrington M. HLA/KIR restraint of HIV:surviving the fittest[J]. Annu Rev Immunol, 2011, 29:295-317.
[13]Huth TK, Brenu EW, Ashton KJ, et al. Natural killer cell cytotoxic activity:measurement of the apoptotic inducing mechanisms[J]. Clin Exp Med Sci, 2013, 1(8):373-386.
[14]Wang W, Erbe AK, Hank JA, et al. NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy[J]. Front Immunol, 2015, 6:368.
[15]Wherry EJ. T cell exhaustion[J]. Nat Immunol, 2011, 12(6):492-499.
[16]Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion[J]. Nat Rev Immunol, 2015, 15(8):486-499.
[17]Angelosanto JM, Wherry EJ. Transcription factor regulation of CD8+T-cell memory and exhaustion[J]. Immunol Rev, 2010, 236(1):167-175.
[18]Pesce S, Greppi M, Tabellini G, et al. Identification of a subset of human natural killer cells expressing high levels of programmed death 1:a phenotypic and functional characterization[J]. J Allergy Clin Immunol, 2017, 139(1):335-346.
[19]Beldi-Ferchiou A, Lambert M, Dogniaux S, et al. PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma[J]. Oncotarget, 2016, 7(45):72961-72977.
[20]Wiesmayr S, Webber SA, Macedo C, et al. Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD[J]. Eur J Immunol, 2012, 42(2):541-550.
[21]MacFarlane AW, Jillab M, Plimack ER, et al. PD-1 expression on peripheral blood cells increases with stage in renal cell carcinoma patients and is rapidly reduced after surgical tumor resection[J]. Cancer Immunol Res, 2014, 2(4):320-331.
[22]Zhang Q, Bi J, Zheng X, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity[J]. Nat Immunol, 2018, 19(7):723-732..
[23]Sun C, Xu J, Huang Q, et al. High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer[J]. Oncoimmunology, 2017, 6(1):e1264562.
[24]da Silva IP, Gallois A, Baranda SJ, et al. Reversal of NK cell exhaustion in advanced melanoma by Tim-3 blockade[J]. Cancer Immunol Res, 2014, 2(5):410-422.
[25]Gallois A, Silva I, Osman I, et al. Reversal of natural killer cell exhaustion by TIM-3 blockade[J]. Oncoimmunology, 2014, 3(12):e946365.
[26]Li YH, Zhou WH, Tao Y, et al. The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal–fetal interface in early pregnancy[J]. Cell Mol Immunol, 2016, 13(1):73-81.
[27]Ju Y, Hou N, Meng J, et al. T cell immunoglobulin-and mucin-domain-containing molecule-3(Tim-3)mediates natural killer cell suppression in chronic hepatitis B[J]. J Hepatol, 2010, 52(3):322-329.
[28]Hodge G, Barnawi J, Jurisevic C, et al. Lung cancer is associated with decreased expression of perforin, granzyme B and interferon(IFN)‐γby infiltrating lung tissue T cells, natural killer(NK)T‐like and NK cells[J]. Clin Exp Immunol, 2014, 178(1):79-85.
[29]Sun C, Fu B, Gao Y, et al. TGF-β1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence[J]. PLoS Pathog, 2012, 8(3):e1002594.
[30]Shifrin N, Raulet DH, Ardolino M. NK cell self tolerance, responsiveness and missing self recognition[J]. Semin Immunol, 2014, 26(2):138-144.
[31]Scully E, Alter G. NK cells in HIV disease[J]. Curr HIV/AIDS Rep, 2016, 13(2):85-94.
[32]Mavilio D, Lombardo G, Kinter A, et al. Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection[J]. J Exp Med, 2006, 203(10):2339-2350.
[33]Scott-Algara D, Truong LX, Versmisse P, et al.Cutting edge:increased NK cell activity in HIV-1-exposed but uninfected Vietnamese intravascular drug users[J]. J Immunol, 2003, 171(11):5663-5667.
[34]Perera SS, Saksena NK. Innate, adaptive and intrinsic immunity in human immunodeficiency virus infection[J]. Am J Infect Dis, 2012, 8(3):132.
[35]刘贝贝,赵敏. HIV感染者Siglec-7+NK细胞数量和功能的研究[J].中国艾滋病性病,2017,23(7):587-591.
[36]Kuri-Cervantes L, de Oca GS, Avila-Ríos S, et al. Activation of NK cells is associated with HIV-1 disease progression[J]. J Leukoc Biol, 2014, 96(1):7-16.
[37]Gonzalez VD, Falconer K, Bj?rkstr?m NK, et al. Expansion of functionally skewed CD56-negative NK cells in chronic hepatitis C virus infection:correlation with outcome of pegylated IFN-αand ribavirin treatment[J]. J Immunol, 2009, 183(10):6612-6218.
[38]Gonzalez VD, Falconer K, Micha?lsson J, et al. Expansion of CD56-NK cells in chronic HCV/HIV-1 co-infection:reversion by antiviral treatment with pegylated IFNαand ribavirin[J]. Clin Immunol, 2008, 128(1):46-56.
[39]Tiemessen CT, Shalekoff S, Meddows-Taylor S, et al. Natural killer cells that respond to human immunodeficiency virus type 1(HIV-1)peptides are associated with control of HIV-1 infection[J]. J Infect Dis,2010, 202(9):1444-1453.
[40]Martin MP, Gao X, Lee JH, et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS[J]. Nat Genet, 2002, 31(4):429-434.
[41]Alter G, Martin MP, Teigen N, et al. Differential natural killer cell–mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes[J]. J Exp Med,2007, 204(12):3027-3036.
[42]Alter G, Rihn S, Walter K, et al. HLA class I subtype-dependent expansion of KIR3DS1+and KIR3DL1+NK cells during acute human immunodeficiency virus type 1 infection[J]. J Virol, 2009, 83(13):6798-6805.
[43]Zhang X, Lu X, Moog C, et al. KIR3DL1-negative CD8 T cells and KIR3DL1-negative natural killer cells contribute to the advantageous control of early human immunodeficiency virus type 1 infection in HLA-B Bw4 homozygous individuals[J]. Front Immunol, 2018, 9:1855.
[44]Ye X, Zhang Z, Jiang Y, et al. Expression of human CD226 on T cells and natural killer cells and of soluble CD226 in plasma of HIV-1-infected Chinese patients[J]. Viral immunol, 2006, 19(3):576-581.
[45]Scott-Algara D, Truong LX, Versmisse P, et al. Cutting edge:increased NK cell activity in HIV-1-exposed but uninfected Vietnamese intravascular drug users[J]. J Immunol, 2003, 171(11):5663-5667.
[46]Alsahafi N, Richard J, Prévost J, et al. Impaired downregulation of NKG2D ligands by Nef protein from elite controllers sensitizes HIV-1-infected cells to ADCC[J]. J Virol, 2017, 91(16):pii:e00109-17.
[47]Tomescu C, Tebas P, Montaner LJ. IFN-αaugments natural killer-mediated antibody-dependent cellular cytotoxicity of HIV-1-infected autologous CD4+T cells regardless of major histocompatibility complex class 1 downregulation[J]. AIDS, 2017, 31(5):613-622.
[48]Mavilio D, Lombardo G, Kinter A, et al. Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection[J]. J Exp Med, 2006, 203(10):2339-2350.
[49]Porichis F, Hart MG, Massa A, et al. Immune checkpoint blockade restores HIV-specific CD4 T cell help for NK cells[J]. J Immunol, 2018, 201(3):971-981.
[50]张和倩,常文仙,焦艳梅,等. HIV病毒库清除策略研究进展[J].传染病信息,2017,30(6):321-326.
[51]Huot N, Jacquelin B, Garcia-Tellez T, et al. Natural killer cells migrate into and control simian immunodeficiency virus replication in lymph node follicles in African green monkeys[J]. 2017, 23(11):1277-1286.