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

BackgroundEarly 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-1BaL or 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.ResultsThe 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.ConclusionsGram-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.

[1]  A. Keshavarzian,et al.  A Compositional Look at the Human Gastrointestinal Microbiome and Immune Activation Parameters in HIV Infected Subjects , 2014, PLoS pathogens.

[2]  R P Johnson,et al.  Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. , 1998, Science.

[3]  G. Silvestri,et al.  Microbial Translocation in the Pathogenesis of HIV Infection and AIDS , 2013, Clinical Microbiology Reviews.

[4]  M. Paiardini Th17 cells in natural SIV hosts , 2010, Current opinion in HIV and AIDS.

[5]  W. Greene,et al.  Abortive HIV Infection Mediates CD4 T Cell Depletion and Inflammation in Human Lymphoid Tissue , 2010, Cell.

[6]  A. Kane,et al.  Intestinal microbiota, microbial translocation, and systemic inflammation in chronic HIV infection. , 2015, The Journal of infectious diseases.

[7]  S. Rhee,et al.  Human immunodeficiency virus type 1 Nef-induced down-modulation of CD4 is due to rapid internalization and degradation of surface CD4 , 1994, Journal of Virology.

[8]  A. Gettie,et al.  The Frequency of &agr;4&bgr;7high Memory CD4+ T Cells Correlates With Susceptibility to Rectal Simian Immunodeficiency Virus Infection , 2013, Journal of acquired immune deficiency syndromes.

[9]  Xin Geng,et al.  Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection , 2013, Nature.

[10]  J. García,et al.  Impact of highly active antiretroviral therapy initiation on CD4+ T-cell repopulation in duodenal and rectal mucosa , 2013, AIDS.

[11]  S. Gianella,et al.  An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia , 2014, Mucosal Immunology.

[12]  Elmar Pruesse,et al.  SINA: Accurate high-throughput multiple sequence alignment of ribosomal RNA genes , 2012, Bioinform..

[13]  S. Nielsen,et al.  Incomplete Immune Recovery in HIV Infection: Mechanisms, Relevance for Clinical Care, and Possible Solutions , 2012, Clinical & developmental immunology.

[14]  M. Lederman,et al.  Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. , 2014, The Journal of infectious diseases.

[15]  Handan Wand,et al.  Plasma levels of soluble CD14 independently predict mortality in HIV infection. , 2011, The Journal of infectious diseases.

[16]  K. Mansfield,et al.  Dynamics of CCR5 Expression by CD4+ T Cells in Lymphoid Tissues during Simian Immunodeficiency Virus Infection , 2000, Journal of Virology.

[17]  Mario Roederer,et al.  Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection , 2005, Nature.

[18]  M. Herzberg,et al.  Porphyromonas gingivalis Selectively Up-Regulates the HIV-1 Coreceptor CCR5 in Oral Keratinocytes1 , 2007, The Journal of Immunology.

[19]  V. Piguet,et al.  The role of human dendritic cells in HIV-1 infection. , 2015, The Journal of investigative dermatology.

[20]  C. Mackay,et al.  Enhanced levels of functional HIV-1 co-receptors on human mucosal T cells demonstrated using intestinal biopsy tissue , 2000, AIDS.

[21]  M. Markowitz,et al.  Erratum: Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection (PloS Medicine 3,12 DOI:10.1371/journal.pmed. 0030484) , 2006 .

[22]  A. Latorre,et al.  Altered metabolism of gut microbiota contributes to chronic immune activation in HIV-infected individuals , 2014, Mucosal Immunology.

[23]  M. Bocchino,et al.  Expansion of CCR5+ CD4+ T-lymphocytes in the course of active pulmonary tuberculosis , 2004, European Respiratory Journal.

[24]  Ryan D. Hernandez,et al.  Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism , 2013, Science Translational Medicine.

[25]  T. van der Poll,et al.  Patients with active tuberculosis have increased expression of HIV coreceptors CXCR4 and CCR5 on CD4(+) T cells. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[26]  M. Herzberg,et al.  Plausibility of HIV-1 Infection of Oral Mucosal Epithelial Cells , 2011, Advances in dental research.

[27]  M. McCarter,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 , 2010, The Journal of Immunology.

[28]  I. Chen,et al.  A Preponderance of CCR5+CXCR4+ Mononuclear Cells Enhances Gastrointestinal Mucosal Susceptibility to Human Immunodeficiency Virus Type 1 Infection , 2001, Journal of Virology.

[29]  Natalie J Torok,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 , 2011, Journal of acquired immune deficiency syndromes.

[30]  M. Lederman,et al.  Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. , 2014, The Journal of infectious diseases.

[31]  S. Bixler,et al.  Loss and Dysregulation of Th17 Cells during HIV Infection , 2013, Clinical & developmental immunology.

[32]  F. Chirdo,et al.  Immunomodulatory dendritic cells in intestinal lamina propria , 2005, European journal of immunology.

[33]  Pelin Yilmaz,et al.  The SILVA ribosomal RNA gene database project: improved data processing and web-based tools , 2012, Nucleic Acids Res..

[34]  M. McCarter,et al.  HIV-1 Infection of Human Intestinal Lamina Propria CD4+ T Cells In Vitro Is Enhanced by Exposure to Commensal Escherichia coli , 2012, The Journal of Immunology.

[35]  M. Zeitz,et al.  Rapid mucosal CD4(+) T-cell depletion and enteropathy in simian immunodeficiency virus-infected rhesus macaques. , 1999, Gastroenterology.

[36]  R. Kaul,et al.  The integrin α4β7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1 , 2009, Proceedings of the National Academy of Sciences.

[37]  M. McCarter,et al.  Evidence for dendritic cell-dependent CD4(+) T helper-1 type responses to commensal bacteria in normal human intestinal lamina propria. , 2009, Clinical immunology.

[38]  Desmond J. Martin,et al.  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 , 2001, Journal of Clinical Immunology.

[39]  M. Markowitz,et al.  Mechanisms of Gastrointestinal CD4+ T-Cell Depletion during Acuteand Early Human Immunodeficiency Virus Type 1 Infection , 2006, Journal of Virology.

[40]  R. Kaul,et al.  A role for mucosal IL-22 production and Th22 cells in HIV-associated mucosal immunopathogenesis , 2012, Mucosal Immunology.

[41]  Paul M. Ruegger,et al.  HIV Infection is associated with compositional and functional shifts in the rectal mucosal microbiota , 2013, Microbiome.

[42]  Qingsheng Li,et al.  Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells , 2005, Nature.

[43]  P. Gaulard,et al.  Early initiation of combined antiretroviral therapy preserves immune function in the gut of HIV-infected patients , 2014, Mucosal Immunology.

[44]  M. McCarter,et al.  Gut Dendritic Cell Activation Links an Altered Colonic Microbiome to Mucosal and Systemic T Cell Activation in Untreated HIV-1 infection , 2015, Mucosal Immunology.

[45]  S. Pittaluga,et al.  Damaged Intestinal Epithelial Integrity Linked to Microbial Translocation in Pathogenic Simian Immunodeficiency Virus Infections , 2010, PLoS pathogens.

[46]  M. Lederman,et al.  Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. , 2009, The Journal of infectious diseases.

[47]  F. Belardelli,et al.  Human intestinal lamina propria lymphocytes are naturally permissive to HIV‐1 infection , 1999, European journal of immunology.

[48]  M. Clerici,et al.  Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy , 2010, AIDS.

[49]  M. Lederman,et al.  Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. , 2011, The Journal of infectious diseases.

[50]  M. Markowitz,et al.  Lack of Mucosal Immune Reconstitution during Prolonged Treatment of Acute and Early HIV-1 Infection , 2006, PLoS medicine.

[51]  B. Palmer,et al.  HIV-induced alteration in gut microbiota , 2014, Gut microbes.

[52]  J. Lifson,et al.  α4+β7hiCD4+ memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection , 2009, Mucosal Immunology.

[53]  C. Tincati,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 , 2008, AIDS.

[54]  M. McCarter,et al.  Microbial exposure alters HIV-1-induced mucosal CD4+ T cell death pathways Ex vivo , 2014, Retrovirology.

[55]  K. Mansfield,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 , 2000, Journal of Virology.

[56]  Steven Wolinsky,et al.  Microbial Translocation Is Associated with Increased Monocyte Activation and Dementia in AIDS Patients , 2008, PloS one.

[57]  A. E. Sousa,et al.  Enteric mucosa integrity in the presence of a preserved innate interleukin 22 compartment in HIV type 1-treated individuals. , 2014, The Journal of infectious diseases.

[58]  Matthew J. Gebert,et al.  Alterations in the gut microbiota associated with HIV-1 infection. , 2013, Cell host & microbe.

[59]  S. Dandekar,et al.  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 , 1998, Journal of Virology.

[60]  M. Zeitz,et al.  HIV infection and the intestinal mucosal barrier , 2012, Annals of the New York Academy of Sciences.

[61]  J. Brenchley,et al.  Microbial translocation is a cause of systemic immune activation in chronic HIV infection , 2006, Retrovirology.

[62]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[63]  Z. Klase,et al.  Dysbiotic Bacteria Translocate in Progressive SIV Infection , 2014, Mucosal Immunology.

[64]  A. d’Arminio Monforte,et al.  Evidence for Polymicrobic Flora Translocating in Peripheral Blood of HIV-Infected Patients with Poor Immune Response to Antiretroviral Therapy , 2011, PloS one.