Enhancement of HIV-1 infection and intestinal CD4+ T cell depletion ex vivo by gut microbes altered during chronic HIV-1 infection

Retrovirology

Cara C. Wilson³  Mario L. Santiago³  Martin D. McCarter¹  Daniel N. Frank²  Michael S. Harper³  Kejun Guo³  Andrew M. Donovan³  Eric J. Lee³  Stephanie M. Dillon³ 

[1] Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA;University of Colorado Microbiome Research Consortium, Aurora, CO, USA;Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

关键词: Lipopolysaccharide;    Gram-negative bacteria;    Lamina propria CD4 T cells;    Gut;    Microbial translocation;    Microbiome;    Human immunodeficiency virus;   

Others  :  1235477
DOI  :  10.1186/s12977-016-0237-1

 received in 2015-09-30, accepted in 2016-01-04,  发布年份 2016

【 摘 要 】

Background

Early HIV-1 infection is characterized by high levels of HIV-1 replication and substantial CD4 T cell depletion in the intestinal mucosa, intestinal epithelial barrier breakdown, and microbial translocation. HIV-1-induced disruption of intestinal homeostasis has also been associated with changes in the intestinal microbiome that are linked to mucosal and systemic immune activation. In this study, we investigated the impact of representative bacterial species that were altered in the colonic mucosa of viremic HIV-1 infected individuals (HIV-altered mucosal bacteria; HAMB) on intestinal CD4 T cell function, infection by HIV-1, and survival in vitro. Lamina propria (LP) mononuclear cells were infected with CCR5-tropic HIV-1 _BaLor mock infected, exposed to high (3 gram-negative) or low (2 gram-positive) abundance HAMB or control gram-negative Escherichia coli and levels of productive HIV-1 infection and CD4 T cell depletion assessed. HAMB-associated changes in LP CD4 T cell activation, proliferation and HIV-1 co-receptor expression were also evaluated.

Results

The majority of HAMB increased HIV-1 infection and depletion of LP CD4 T cells, but gram-negative HAMB enhanced CD4 T cell infection to a greater degree than gram-positive HAMB. Most gram-negative HAMB enhanced T cell infection to levels similar to that induced by gram-negative E. coli despite lower induction of T cell activation and proliferation by HAMB. Both gram-negative HAMB and E. coli significantly increased expression of HIV-1 co-receptor CCR5 on LP CD4 T cells. Lipopolysaccharide, a gram-negative bacteria cell wall component, up-regulated CCR5 expression on LP CD4 T cells whereas gram-positive cell wall lipoteichoic acid did not. Upregulation of CCR5 by gram-negative HAMB was largely abrogated in CD4 T cell-enriched cultures suggesting an indirect mode of stimulation.

Conclusions

Gram-negative commensal bacteria that are altered in abundance in the colonic mucosa of HIV-1 infected individuals have the capacity to enhance CCR5-tropic HIV-1 productive infection and depletion of LP CD4 T cells in vitro. Enhanced infection appears to be primarily mediated indirectly through increased expression of CCR5 on LP CD4 T cells without concomitant large scale T cell activation. This represents a novel mechanism potentially linking intestinal dysbiosis to HIV-1 mucosal pathogenesis.

【 授权许可】

   
2016 Dillon et al.

【 图 表 】

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【 参考文献 】

• [1]Kewenig S, Schneider T, Hohloch K, Lampe-Dreyer K, Ullrich R, Stolte N et al.. Rapid mucosal CD4(+) T-cell depletion and enteropathy in simian immunodeficiency virus-infected rhesus macaques. Gastroenterology. 1999; 116(5):1115-1123.
• [2]Smit-McBride Z, Mattapallil JJ, McChesney M, Ferrick D, Dandekar S. Gastrointestinal T lymphocytes retain high potential for cytokine responses but have severe CD4(+) T-cell depletion at all stages of simian immunodeficiency virus infection compared to peripheral lymphocytes. J Virol. 1998; 72(8):6646-6656.
• [3]Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL et al.. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science. 1998; 280(5362):427-431.
• [4]Bixler SL, Mattapallil JJ. Loss and dysregulation of Th17 cells during HIV infection. Clin Develop Immunol. 2013; 2013:852418.
• [5]Fernandes SM, Pires AR, Ferreira C, Foxall RB, Rino J, Santos C et al.. Enteric mucosa integrity in the presence of a preserved innate interleukin 22 compartment in HIV type 1-treated individuals. J Infect Dis. 2014; 210(4):630-640.
• [6]Kim CJ, Nazli A, Rojas OL, Chege D, Alidina Z, Huibner S et al.. A role for mucosal IL-22 production and Th22 cells in HIV-associated mucosal immunopathogenesis. Mucosal Immunol. 2012; 5(6):670-680.
• [7]Kok A, Hocqueloux L, Hocini H, Carriere M, Lefrou L, Guguin A et al.. Early initiation of combined antiretroviral therapy preserves immune function in the gut of HIV-infected patients. Mucosal Immunol. 2014; 8(1):127-140.
• [8]Paiardini M. Th17 cells in natural SIV hosts. Curr Opin HIV AIDS. 2010; 5(2):166-172.
• [9]Gaardbo JC, Hartling HJ, Gerstoft J, Nielsen SD. Incomplete immune recovery in HIV infection: mechanisms, relevance for clinical care, and possible solutions. Clin Develop Immunol. 2012; 2012:670957.
• [10]Anton PA, Elliott J, Poles MA, McGowan IM, Matud J, Hultin LE et al.. Enhanced levels of functional HIV-1 co-receptors on human mucosal T cells demonstrated using intestinal biopsy tissue. AIDS. 2000; 14(12):1761-1765.
• [11]Arthos J, Cicala C, Martinelli E, Macleod K, Van Ryk D, Wei D et al.. HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol. 2008; 9(3):301-309.
• [12]Cicala C, Martinelli E, McNally JP, Goode DJ, Gopaul R, Hiatt J et al.. The integrin alpha4beta7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1. Proc Natl Acad Sci USA. 2009; 106(49):20877-20882.
• [13]Hayes TL, Asmuth DM, Critchfield JW, Knight TH, McLaughlin BE, Yotter T et al.. Impact of highly active antiretroviral therapy initiation on CD4(+) T-cell repopulation in duodenal and rectal mucosa. AIDS. 2013; 27(6):867-877.
• [14]Kader M, Wang X, Piatak M, Lifson J, Roederer M, Veazey R et al.. Alpha4(+)beta7(hi)CD4(+) memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection. Mucosal Immunol. 2009; 2(5):439-449.
• [15]Martinelli E, Veglia F, Goode D, Guerra-Perez N, Aravantinou M, Arthos J et al.. The frequency of alpha(4)beta(7)(high) memory CD4(+) T cells correlates with susceptibility to rectal simian immunodeficiency virus infection. J Acquir Immune Defic Syndr. 2013; 64(4):325-331.
• [16]Mehandru S, Poles MA, Tenner-Racz K, Jean-Pierre P, Manuelli V, Lopez P et al.. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection. PLoS Med. 2006; 3(12):e484.
• [17]Mehandru S, Poles MA, Tenner-Racz K, Manuelli V, Jean-Pierre P, Lopez P et al.. Mechanisms of gastrointestinal CD4+ T-cell depletion during acute and early human immunodeficiency virus type 1 infection. J Virol. 2007; 81(2):599-612.
• [18]Poles MA, Elliott J, Taing P, Anton PA, Chen IS. A preponderance of CCR5(+) CXCR4(+) mononuclear cells enhances gastrointestinal mucosal susceptibility to human immunodeficiency virus type 1 infection. J Virol. 2001; 75(18):8390-8399.
• [19]Veazey RS, Mansfield KG, Tham IC, Carville AC, Shvetz DE, Forand AE et al.. Dynamics of CCR5 expression by CD4(+) T cells in lymphoid tissues during simian immunodeficiency virus infection. J Virol. 2000; 74(23):11001-11007.
• [20]Veazey RS, Tham IC, Mansfield KG, DeMaria M, Forand AE, Shvetz DE et al.. Identifying the target cell in primary simian immunodeficiency virus (SIV) infection: highly activated memory CD4(+) T cells are rapidly eliminated in early SIV infection in vivo. J Virol. 2000; 74(1):57-64.
• [21]Li Q, Duan L, Estes JD, Ma ZM, Rourke T, Wang Y et al.. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature. 2005; 434(7037):1148-1152.
• [22]Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature. 2005; 434(7037):1093-1097.
• [23]Steele AK, Lee EJ, Manuzak JA, Dillon SM, Beckham JD, McCarter MD et al.. Microbial exposure alters HIV-1-induced mucosal CD4+ T cell death pathways Ex vivo. Retrovirology. 2014; 11:14. BioMed Central Full Text
• [24]Doitsh G, Cavrois M, Lassen KG, Zepeda O, Yang Z, Santiago ML et al.. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue. Cell. 2010; 143(5):789-801.
• [25]Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O et al.. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature. 2014; 505(7484):509-514.
• [26]Epple HJ, Zeitz M. HIV infection and the intestinal mucosal barrier. Ann N Y Acad Sci. 2012; 1258:19-24.
• [27]Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S et al.. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006; 12(12):1365-1371.
• [28]Marchetti G, Tincati C, Silvestri G. Microbial translocation in the pathogenesis of HIV infection and AIDS. Clin Microbiol Rev. 2013; 26(1):2-18.
• [29]Jiang W, Lederman MM, Hunt P, Sieg SF, Haley K, Rodriguez B 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. 2009; 199(8):1177-1185.
• [30]Ancuta P, Kamat A, Kunstman KJ, Kim EY, Autissier P, Wurcel A et al.. Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS One. 2008; 3(6):e2516.
• [31]Hunt PW, Sinclair E, Rodriguez B, Shive C, Clagett B, Funderburg N et al.. Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. J Infect Dis. 2014; 210(8):1228-1238.
• [32]Lederman MM, Calabrese L, Funderburg NT, Clagett B, Medvik K, Bonilla H et al.. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis. 2011; 204(8):1217-1226.
• [33]Marchetti G, Bellistri GM, Borghi E, Tincati C, Ferramosca S, La Francesca M et al.. Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy. AIDS. 2008; 22(15):2035-2038.
• [34]Merlini E, Bai F, Bellistri GM, Tincati C, d’Arminio Monforte A, Marchetti G. Evidence for polymicrobic flora translocating in peripheral blood of HIV-infected patients with poor immune response to antiretroviral therapy. PloS One. 2011;6(4):e18580.
• [35]Piconi S, Trabattoni D, Gori A, Parisotto S, Magni C, Meraviglia P et al.. Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy. AIDS. 2010; 24(13):1991-2000.
• [36]Sandler NG, Wand H, Roque A, Law M, Nason MC, Nixon DE et al.. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis. 2011; 203(6):780-790.
• [37]Tenorio AR, Zheng Y, Bosch RJ, Krishnan S, Rodriguez B, Hunt PW et al.. Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. J Infect Dis. 2014; 210(8):1248-1259.
• [38]Estes JD, Harris LD, Klatt NR, Tabb B, Pittaluga S, Paiardini M et al.. Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. PLoS Pathog. 2010; 6(8):e1001052.
• [39]Klase Z, Ortiz A, Deleage C, Mudd JC, Quinones M, Schwartzman E et al.. Dysbiotic bacteria translocate in progressive SIV infection. Mucosal Immunol. 2015; 8(5):1009-1020.
• [40]Dillon SM, Lee EJ, Kotter CV, Austin GL, Gianella S, Siewe B, Smith DM, Landay AL, McManus MC, Robertson CE, Frank DN, McCarter MD, Wilson CC. Gut dendritic cell activation links an altered colonic microbiome to mucosal and systemic T cell activation in untreated HIV-1 infection. Mucosal Immunol. 2015.
• [41]Dillon SM, Lee EJ, Kotter CV, Austin GL, Dong Z, Hecht DK et al.. An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol. 2014; 7(4):983-994.
• [42]Dinh DM, Volpe GE, Duffalo C, Bhalchandra S, Tai AK, Kane AV et al.. intestinal microbiota, microbial translocation, and systemic inflammation in chronic HIV infection. J Infect Dis. 2015; 211(1):19-27.
• [43]Ellis CL, Ma ZM, Mann SK, Li CS, Wu J, Knight TH et al.. Molecular characterization of stool microbiota in HIV-infected subjects by panbacterial and order-level 16S ribosomal DNA (rDNA) quantification and correlations with immune activation. J Acquir Immune Defic Syndr. 2011; 57(5):363-370.
• [44]Lozupone CA, Li M, Campbell TB, Flores SC, Linderman D, Gebert MJ et al.. Alterations in the gut microbiota associated with HIV-1 infection. Cell Host Microbe. 2013; 14(3):329-339.
• [45]Lozupone CA, Rhodes ME, Neff CP, Fontenot AP, Campbell TB, Palmer BE. HIV-induced alteration in gut microbiota: driving factors, consequences, and effects of antiretroviral therapy. Gut Microbes. 2014; 5(4):562-570.
• [46]McHardy IH, Li X, Tong M, Ruegger P, Jacobs J, Borneman J et al.. HIV infection is associated with compositional and functional shifts in the rectal mucosal microbiota. Microbiome. 2013; 1:26. BioMed Central Full Text
• [47]Mutlu EA, Keshavarzian A, Losurdo J, Swanson G, Siewe B, Forsyth C et al.. A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects. PLoS Pathog. 2014; 10(2):e1003829.
• [48]Vujkovic-Cvijin I, Dunham RM, Iwai S, Maher MC, Albright RG, Broadhurst MJ et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med. 2013;5(193):193ra91.
• [49]Dillon SM, Manuzak JA, Leone AK, Lee EJ, Rogers LM, McCarter MD et al.. HIV-1 infection of human intestinal lamina propria CD4+ T cells in vitro is enhanced by exposure to commensal Escherichia coli. J Immunol. 2012; 189(2):885-896.
• [50]Howe R, Dillon S, Rogers L, McCarter M, Kelly C, Gonzalez R et al.. Evidence for dendritic cell-dependent CD4(+) T helper-1 type responses to commensal bacteria in normal human intestinal lamina propria. Clin Immunol. 2009; 131(2):317-332.
• [51]Vazquez-Castellanos JF, Serrano-Villar S, Latorre A, Artacho A, Ferrus ML, Madrid N et al.. Altered metabolism of gut microbiota contributes to chronic immune activation in HIV-infected individuals. Mucosal Immunol. 2015; 8(4):760-772.
• [52]Lapenta C, Boirivant M, Marini M, Santini SM, Logozzi M, Viora M et al.. Human intestinal lamina propria lymphocytes are naturally permissive to HIV-1 infection. Eur J Immunol. 1999; 29(4):1202-1208.
• [53]Juffermans NP, Speelman P, Verbon A, Veenstra J, Jie C, van Deventer SJ et al.. Patients with active tuberculosis have increased expression of HIV coreceptors CXCR4 and CCR5 on CD4(+) T cells. Clin Infect Dis Off Publ Infect Dis Soc Am. 2001; 32(4):650-652.
• [54]Santucci MB, Bocchino M, Garg SK, Marruchella A, Colizzi V, Saltini C et al.. Expansion of CCR5+ CD4+ T-lymphocytes in the course of active pulmonary tuberculosis. Euro Resp J. 2004; 24(4):638-643.
• [55]Shalekoff S, Pendle S, Johnson D, Martin DJ, Tiemessen CT. Distribution of the human immunodeficiency virus coreceptors CXCR4 and CCR5 on leukocytes of persons with human immunodeficiency virus type 1 infection and pulmonary tuberculosis: implications for pathogenesis. J Clin Immunol. 2001; 21(6):390-401.
• [56]Giacaman RA, Nobbs AH, Ross KF, Herzberg MC. Porphyromonas gingivalis selectively up-regulates the HIV-1 coreceptor CCR5 in oral keratinocytes. J Immunol. 2007; 179(4):2542-2550.
• [57]Herzberg MC, Vacharaksa A, Gebhard KH, Giacaman RA, Ross KF. Plausibility of HIV-1 infection of oral mucosal epithelial cells. Adv Dental Res. 2011; 23(1):38-44.
• [58]Chirdo FG, Millington OR, Beacock-Sharp H, Mowat AM. Immunomodulatory dendritic cells in intestinal lamina propria. Eur J Immunol. 2005; 35(6):1831-1840.
• [59]Ahmed Z, Kawamura T, Shimada S, Piguet V. The role of human dendritic cells in HIV-1 infection. J Invest Dermatol. 2015; 135(5):1225-1233.
• [60]Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990; 215(3):403-410.
• [61]Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 2013;41(Database issue):D590-6.
• [62]Pruesse E, Peplies J, Glockner FO. SINA: accurate high-throughput multiple sequence alignment of ribosomal RNA genes. Bioinformatics. 2012; 28(14):1823-1829.
• [63]Dillon SM, Rogers LM, Howe R, Hostetler LA, Buhrman J, McCarter MD et al.. Human intestinal lamina propria CD1c+ dendritic cells display an activated phenotype at steady state and produce IL-23 in response to TLR7/8 stimulation. J Immunol. 2010; 184(12):6612-6621.
• [64]Rhee SS, Marsh JW. Human immunodeficiency virus type 1 Nef-induced down-modulation of CD4 is due to rapid internalization and degradation of surface CD4. J Virol. 1994; 68(8):5156-5163.