Article information
Resumen
La infección por el VIH-1 se caracteriza por la eliminación de linfocitos T CD4+, particularmente en la mucosa gastrointestinal, que favorece la traslocación microbiana y la hiperactivación inmunitaria, principal mecanismo patogénico en esta infección.
Las células Th17 son una subpoblación proinflamatoria de linfocitos CD4+, que producen IL-17, IL-21 e IL-22, y son importantes en la respuesta antimicrobiana, principalmente en el sistema gastrointestinal, donde promueven la restauración de la mucosa. Aunque su eliminación se ha asociado con progresión de la infección por el VIH-1 y por el virus de la inmunodeficiencia de los simios, y han sido descritas como deletérea en autoinmunidad. Su papel en la patogenia de la infección por el VIH-1 no está claramente establecido.
Considerando su capacidad funcional, las células Th17 podrían tener un impacto dual, dependiendo de la fase de la infección en que se encuentre el individuo. Actualmente, hay más información que sugiere que estas células tienen un papel benéfico al promover la recuperación de la mucosa intestinal y disminuir la traslocación microbiana, así como la hiperactivación inmunitaria. Sin embargo, su papel patogénico, particularmente promoviendo la replicación viral mediante la producción de citocinas proinflamatorias, no debe descartarse.
En esta revisión, se presentan los datos científicos disponibles del efecto de las células Th17 en la patogenia de la infección por el VIH-1.
Palabras clave:
VIH-1
Th17
tejido linfoide asociado a mucosa gastrointestinal (GALT)
hiperactivación inmunológica
traslocación bacteriana
Abstract
HIV-1 infection is characterized by a gradual decrease of the immunological competence and a massive depletion of CD4+ T cells, particularly in gut-associated lymphoid tissue, which leads to microbial translocation, contributing to immune hyperactivation, the main pathogenic mechanism during HIV-1 infection.
Th17 cells are a proinflammatory CD4+ T cell subset, which produce IL-17, IL-21 and IL-22 and play a pivotal role in host defense, mainly in the gastrointestinal tissue, where they promote antimicrobial responses and gut mucosa restoration. Although Th17 depletion is a hallmark of the progression of the simian and human immunodeficiency viral infections and they have been involved in the pathogenic process in some autoimmune diseases, the role of these cells during HIV-1 infection is not completely understood.
Considering their functional potential, Th17 cells could have a dual role, depending on the stage of HIV infection a patient has reached. Currently, most evidence suggests that Th17 cells have a beneficial role by promoting gut mucosa recovery, preventing microbial translocation and decreasing immune hyperactivation. However, the pathogenic role of these cells, particularly, increasing viral replication through the production of inflammatory cytokines should not be ruled out.
In this review, scientific evidence regarding the role of Th17 on the pathogenesis of HIV infection is discussed.
Key words:
HIV-1
Th17
gut-associated lymphoid tissue (GALT)
immune hyperactivation
bacterial translocation
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Referencias
[1.]
UNAIDS. AIDS epidemic update. 2010. Disponible: http://www.unaids.org/documents/20101123_GlobalReport_Foreword_em.pdf.
[2.]
J.M. Brenchley, T.W. Schacker, L.E. Ruff, D.A. Price, J.H. Taylor, G.J. Beilman, et al.
CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract.
J Exp Med., 200 (2004), pp. 749-759
[3.]
H. Groux, G. Torpier, D. Monte, Y. Mouton, A. Capron, J.C. Ameisen.
Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals.
J Exp Med., 175 (1992), pp. 331-340
[4.]
Z. Liu, W.G. Cumberland, L.E. Hultin, H.E. Prince, R. Detels, J.V. Giorgi.
Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression.
J Acquir Immune Defic Syndr Hum Retrovirol., 16 (1997), pp. 83-92
[5.]
L.E. Harrington, R.D. Hatton, P.R. Mangan, H. Turner, T.L. Murphy, K.M. Murphy, et al.
Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
Nat Immunol., 6 (2005), pp. 1123-1132
[6.]
H. Ishigame, S. Kakuta, T. Nagai, M. Kadoki, A. Nambu, Y. Komiyama, et al.
Differential roles of interleukin-17A and-17F in host defense against mucoepithelial bacterial infection and allergic responses.
Immunity., 30 (2009), pp. 108-119
[7.]
M. Raffatellu, R.L. Santos, D.E. Verhoeven, M.D. George, R.P. Wilson, S.E. Winter, et al.
Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut.
Nat Med., 14 (2008), pp. 421-428
[8.]
P. Ye, F.H. Rodríguez, S. Kanaly, K.L. Stocking, J. Schurr, P. Schwarzenberger, et al.
Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense.
J Exp Med., 194 (2001), pp. 519-527
[9.]
M.A. Kleinschek, K. Boniface, S. Sadekova, J. Grein, E.E. Murphy, S.P. Turner, et al.
Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation.
J Exp Med., 206 (2009), pp. 525-534
[10.]
I.I. Ivanov, N. Manel.
[Induction of gut mucosal Th17 cells by segmented filamentous bacteria.
Med Sci (Paris)., 26 (2010), pp. 352-355
[11.]
J.M. Brenchley, M. Paiardini, K.S. Knox, A.I. Asher, B. Cervasi, T.E. Asher, et al.
Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections.
Blood., 112 (2008), pp. 2826-2835
[12.]
V. Cecchinato, C.J. Trindade, A. Laurence, J.M. Heraud, J.M. Brenchley, M.G. Ferrari, et al.
Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques.
Mucosal Immunol., 1 (2008), pp. 279-288
[13.]
A. Prendergast, J.G. Prado, Y.H. Kang, F. Chen, L.A. Riddell, G. Luzzi, et al.
HIV-1 infection is characterized by profound depletion of CD161+ Th17 cells and gradual decline in regulatory T cells.
AIDS., 24 (2010), pp. 491-502
[14.]
J. Zhu, W.E. Paul.
CD4 T cells: fates, functions, and faults.
Blood., 112 (2008), pp. 1557-1569
[15.]
S. Trifari, H. Spits.
IL-22-producing CD4+ T cells: middle-men between the immune system and its environment.
Eur J Immunol., 40 (2010), pp. 2369-2371
[16.]
V. Dardalhon, A. Awasthi, H. Kwon, G. Galileos, W. Gao, R.A. Sobel, et al.
IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells.
Nat Immunol., 9 (2008), pp. 1347-1355
[17.]
M. Veldhoen, C. Uyttenhove, J. van Snick, H. Helmby, A. Westendorf, J. Buer, et al.
Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset.
Nat Immunol., 9 (2008), pp. 1341-1346
[18.]
S.J. Szabo, S.T. Kim, G.L. Costa, X. Zhang, C.G. Fathman, L.H. Glimcher.
A novel transcription factor.
T-bet, directs Th1 lineage commitment. Cell., 100 (2000), pp. 655-669
[19.]
W. Zheng, R.A. Flavell.
The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.
Cell., 89 (1997), pp. 587-596
[20.]
Z. Fehervari, S. Sakaguchi.
CD4+ Tregs and immune control.
J Clin Invest., 114 (2004), pp. 1209-1217
[21.]
Z. Yao, Y. Kanno, M. Kerenyi, G. Stephens, L. Durant, W.T. Watford, et al.
Nonredundant roles for Stat5a/b in directly regulating Foxp3.
Blood., 109 (2007), pp. 4368-4375
[22.]
Y. Carrier, J. Yuan, V.K. Kuchroo, H.L. Weiner.
Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice.
J Immunol., 178 (2007), pp. 179-185
[23.]
Y. Chen, V.K. Kuchroo, J. Inobe, D.A. Hafler, H.L. Weiner, T. Regulatory.
cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis.
Science., 265 (1994), pp. 1237-1240
[24.]
H. Groux, A. O’Garra, M. Bigler, M. Rouleau, S. Antonenko, J.E. de Vries, et al.
A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis.
Nature., 389 (1997), pp. 737-742
[25.]
C. Dong.
TH17 cells in development: an updated view of their molecular identity and genetic programming.
Nat Rev Immunol., 8 (2008), pp. 337-348
[26.]
L. Cosmi, R. De Palma, V. Santarlasci, L. Maggi, M. Capone, F. Frosali, et al.
Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor.
J Exp Med., 205 (2008), pp. 1903-1916
[27.]
L. Zhou, I.I. Ivanov, R. Spolski, R. Min, K. Shenderov, T. Egawa, et al.
IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.
Nat Immunol., 8 (2007), pp. 967-974
[28.]
X.O. Yang, B.P. Pappu, R. Nurieva, A. Akimzhanov, H.S. Kang, Y. Chung, et al.
T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.
Immunity., 28 (2008), pp. 29-39
[29.]
D.V. Jovanovic, J.A. Di Battista, J. Martel-Pelletier, F.C. Jolicoeur, Y. He, M. Zhang, et al.
IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages.
J Immunol., 160 (1998), pp. 3513-3521
[30.]
Y. Zheng, P.A. Valdez, D.M. Danilenko, Y. Hu, S.M. Sa, Q. Gong, et al.
Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens.
Nat Med., 14 (2008), pp. 282-289
[31.]
S. Brand, F. Beigel, T. Olszak, K. Zitzmann, S.T. Eichhorst, J.M. Otte, et al.
IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration.
Am J Physiol Gastrointest Liver Physiol., 290 (2006), pp. G827-G838
[32.]
G. Pickert, C. Neufert, M. Leppkes, Y. Zheng, N. Wittkopf, M. Warntjen, et al.
STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing.
J Exp Med., 206 (2009), pp. 1465-1472
[33.]
T. Kinugasa, T. Sakaguchi, X. Gu, H.C. Reinecker.
Claudins regulate the intestinal barrier in response to immune mediators.
Gastroenterology., 118 (2000), pp. 1001-1011
[34.]
T.A. Moseley, D.R. Haudenschild, L. Rose, A.H. Reddi.
Interleukin-17 family and IL-17 receptors.
Cytokine Growth Factor Rev., 14 (2003), pp. 155-174
[35.]
G. Matsuzaki, M. Umemura.
Interleukin-17 as an effector molecule of innate and acquired immunity against infections.
Microbiol Immunol., 51 (2007), pp. 1139-1147
[36.]
J.P. Herbeuval, J.C. Grivel, A. Boasso, A.W. Hardy, C. Chougnet, M.J. Dolan, et al.
CD4+ T-cell death induced by infectious and noninfectious HIV-1: Role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis.
Blood, 106 (2005), pp. 3524-3531
[37.]
A.Y. Liu, E.P. Miskovsky, P.E. Stanhope, R.F. Siliciano.
Production of transmembrane and secreted forms of tumor necrosis factor (TNF)- alpha by HIV-1-specific CD4+ cytolytic T lymphocyte clones. Evidence for a TNF-alpha-independent cytolytic mechanism.
J Immunol., 148 (1992), pp. 3789-3798
[38.]
J.M. Brenchley, D.A. Price, T.W. Schacker, T.E. Asher, G. Silvestri, S. Rao, et al.
Microbial translocation is a cause of systemic immune activation in chronic HIV infection.
Nat Med., 12 (2006), pp. 1365-1371
[39.]
W. Jiang, M.M. Lederman, P. Hunt, S.F. Sieg, K. Haley, B. Rodriguez, et al.
Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral- treated HIV infection.
J Infect Dis., 199 (2009), pp. 1177-1185
[40.]
C.L. Langrish, Y. Chen, W.M. Blumenschein, J. Mattson, B. Basham, J.D. Sedgwick, et al.
IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
J Exp Med., 201 (2005), pp. 233-240
[41.]
D. Chege, P.M. Sheth, T. Kain, C.J. Kim, C. Kovacs, M. Loutfy, et al.
Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy.
AIDS., 25 (2011), pp. 741-749
[42.]
D. Favre, J. Mold, P.W. Hunt, B. Kanwar, P. Loke, L. Seu, et al.
Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease.
Sci Transl Med., 2 (2010),
[43.]
W. Hou, H.S. Kang, B.S. Kim.
Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection.
J Exp Med., 206 (2009), pp. 313-328
[44.]
A.N.W. Maek, S. Buranapraditkun, J. Klaewsongkram, K. Ruxrungtham.
Increased interleukin-17 production both in helper T cell subset Th17 and CD4-negative T cells in human immunodeficiency virus infection.
Viral Immunol., 20 (2007), pp. 66-75
[45.]
L.C. Ndhlovu, J.M. Chapman, A.R. Jha, J.E. Snyder-Cappione, M. Pagan, F.E. Leal, et al.
Suppression of HIV-1 plasma viral load below detection preserves IL-17 producing T cells in HIV-1 infection.
AIDS., 22 (2008), pp. 990-992
[46.]
M. Salgado, N.I. Rallon, B. Rodes, M. López, V. Soriano, J.M. Benito.
Long-term non-progressors display a greater number of Th17 cells than HIV-infected typical progressors.
Clin Immunol., 139 (2011), pp. 110-114
[47.]
J.M. Baeten, E. Kahle, J.R. Lingappa, R.W. Coombs, S. Delany-Moretlwe, E. Nakku-Joloba, et al.
Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission.
Sci Transl Med., 3 (2011),
[48.]
T.W. Chun, D.C. Nickle, J.S. Justement, J.H. Meyers, G. Roby, C.W. Hallahan, et al.
Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy.
J Infect Dis., 197 (2008), pp. 714-720
[49.]
M. Kader, X. Wang, M. Piatak, J. Lifson, M. Roederer, R. Veazey, et al.
Alpha4(+)beta7(hi)CD4(+) memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection.
Mucosal Immunol., 2 (2009), pp. 439-449
[50.]
A. El Hed, A. Khaitan, L. Kozhaya, N. Manel, D. Daskalakis, W. Borkowsky, et al.
Susceptibility of human Th17 cells to human immunodeficiency virus and their perturbation during infection.
J Infect Dis., 201 (2010), pp. 843-854
[51.]
H.W. Lim, J. Lee, P. Hillsamer, C.H. Kim.
Human Th17 cells share major trafficking receptors with both polarized effector T cells and FOXP3+ regulatory T cells.
J Immunol., 180 (2008), pp. 122-129
[52.]
M.E. Moreno-Fernández, W. Zapata, J.T. Blackard, G. Franchini, C.A. Chougnet.
Human regulatory T cells are targets for human immunodeficiency virus (HIV) infection, and their susceptibility differs depending on the HIV type 1 strain.
J Virol., 83 (2009), pp. 12925-12933
[53.]
J. Nilsson, A. Boasso, P.A. Velilla, R. Zhang, M. Vaccari, G. Franchini, et al.
HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS.
Blood., 108 (2006), pp. 3808-3817
[54.]
L. Brandt, T. Benfield, H. Mens, L.N. Clausen, T.L. Katzenstein, A. Fomsgaard, et al.
Low level of regulatory T cells and maintenance of balance between regulatory T cells and TH17 cells in HIV-1-infected elite controllers.
J Acquir Immune Defic Syndr., 57 (2011), pp. 101-108
[55.]
M.D. Sharma, D.Y. Hou, Y. Liu, P.A. Koni, R. Metz, P. Chandler, et al.
Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes.
Blood., 113 (2009), pp. 6102-6111
[56.]
M.S. Sundrud, S.B. Koralov, M. Feuerer, D.P. Calado, A.E. Kozhaya, A. Rhule-Smith, et al.
Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response.
Science., 324 (2009), pp. 1334-1338
[57.]
D. Favre, S. Lederer, B. Kanwar, Z.M. Ma, S. Proll, Z. Kasakow, et al.
Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection.
PLoS Pathog., 5 (2009), pp. e1000295
[58.]
E. Bettelli, Y. Carrier, W. Gao, T. Korn, T.B. Strom, M. Oukka, et al.
Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
Nature., 441 (2006), pp. 235-238
[59.]
F.Y. Yue, A. Merchant, C.M. Kovacs, M. Loutfy, D. Persad, M.A. Ostrowski.
Virus-specific interleukin-17-producing CD4+ T cells are detectable in early human immunodeficiency virus type 1 infection.
J Virol., 82 (2008), pp. 6767-6771
[60.]
E.J. Ciccone, J.H. Greenwald, P.I. Lee, A. Biancotto, S.W. Read, M.A. Yao, et al.
CD4+ T cells, including Th17 and cycling subsets, are intact in the gut mucosa of HIV-1-infected long-term nonprogressors.
J Virol., 85 (2011), pp. 5880-5888
[61.]
M. Macal, S. Sankaran, T.W. Chun, E. Reay, J. Flamm, T.J. Prindiville, et al.
Effective CD4+ T-cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with enhanced Th17 cells and polyfunctional HIV-specific T-cell responses.
Mucosal Immunol., 1 (2008), pp. 475-488
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