Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Microbial translocation in HIV infection: causes, consequences and treatment opportunities

Key Points

  • Individuals with HIV infection have increased translocation of commensal microbial products, such as lipopolysaccharide (LPS), from the intestinal lumen into the systemic circulation.

  • Increased translocation of pro-inflammatory microbial products in HIV infection may be caused by enterocyte death, loss of tight junctions between enterocytes, decreased intestinal lumen immunoglobulin A (IgA), loss of CD4+ T cells (especially T helper 17 cells) from gut-associated lymphoid tissue, alterations in intestinal flora and decreased clearance of microbial products by the liver and other mechanisms.

  • Rhesus macaques infected with SIV (a virus similar to HIV) show persistent intestinal damage, increased microbial translocation and increased immune activation, and the infection eventually progresses to AIDS. Conversely, sooty mangabees infected with SIV do not show persistent intestinal damage, increased microbial translocation or increased immune activation, and they do not develop AIDS.

  • In individuals infected with HIV, increased levels of LPS and/or soluble CD14 (sCD14), which reflects LPS-induced monocyte activation, correlate with numerous markers of immune activation, such as type I interferons and activated CD8+ T cells (the latter being one of the strongest predictors of disease progression in HIV infection). Microbial translocation has also been associated with lymphoid tissue fibrosis, which may impair CD4+ T cell recovery in patients on antiretroviral therapy.

  • An increase in sCD14 levels is a predictor of dementia, hypertension, low CD4+ T cell recovery on antiretroviral therapy and, most notably, mortality.

  • Numerous therapeutic options for decreasing microbial translocation and its downstream effects are currently under investigation.

Abstract

Systemic immune activation is increased in HIV-infected individuals, even in the setting of virus suppression with antiretroviral therapy. Although numerous factors may contribute, microbial products have recently emerged as potential drivers of this immune activation. In this Review, we describe the intestinal damage that occurs in HIV infection, the evidence for translocation of microbial products into the systemic circulation and the pathways by which these products activate the immune system. We also discuss novel therapies that disrupt the translocation of microbial products and the downstream effects of microbial translocation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The intestinal epithelium in health and during HIV infection.
Figure 2: Indoleamine 2,3-dioxygenase 1 pathway.
Figure 3: Therapeutic interventions to attenuate microbial translocation-induced immune activation.

Similar content being viewed by others

References

  1. Guaraldi, G. et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin. Infect. Dis. 53, 1120–1126 (2011).

    Article  PubMed  Google Scholar 

  2. Hansson, G. K. & Hermansson, A. The immune system in atherosclerosis. Nature Immunol. 12, 204–212 (2011).

    Article  CAS  Google Scholar 

  3. Mantovani, A., Cassatella, M. A., Costantini, C. & Jaillon, S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nature Rev. Immunol. 11, 519–531 (2011).

    Article  CAS  Google Scholar 

  4. Pacifici, R. The immune system and bone. Arch. Biochem. Biophys. 503, 41–53 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hellerstein, M. et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nature Med. 5, 83–89 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Hazenberg, M. D. et al. T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). Blood 95, 249–255 (2000).

    CAS  PubMed  Google Scholar 

  7. Kuller, L. H. et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 5, e203 (2008). A study showing that increased levels of markers of inflammation and coagulation, specifically IL-6, CRP and D-dimer, are associated with an increased risk of all-cause mortality in HIV-infected individuals.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sandler, N. G. et al. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J. Infect. Dis. 203, 780–790 (2011). This study demonstrates that increased sCD14 levels, reflecting increased LPS-induced monocyte activation, predict an increased risk of all-cause mortality in HIV-infected individuals independently of other markers of inflammation, CD4+ T cell counts and HIV RNA levels.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lederman, M. M. et al. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J. Infect. Dis. 204, 1217–1226 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hunt, P. W. et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J. Infect. Dis. 187, 1534–1543 (2003). This study shows that, among individuals on ART with suppressed HIV RNA levels, a higher frequency of activated CD8+ T cells is associated with lower CD4+ T cell recovery after a median of 21 months of therapy.

    Article  CAS  PubMed  Google Scholar 

  11. Kelly, C. J., Colgan, S. P. & Frank, D. N. Of microbes and meals: the health consequences of dietary endotoxemia. Nutr. Clin. Pract. 27, 215–225 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Clarke, T. B. et al. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nature Med. 16, 228–231 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Haruta, I. et al. Lipoteichoic acid may affect the pathogenesis of PBC-like bile duct damage and might be involved in systemic multifocal epithelial inflammations in chronic colitis-harboring TCRα−/− xAIM−/− mice. Autoimmunity 40, 372–379 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ziegler, T. R. et al. Detectable serum flagellin and lipopolysaccharide and upregulated anti-flagellin and lipopolysaccharide immunoglobulins in human short bowel syndrome. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R402–R410 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Jiang, W. 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, 1177–1185 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Frances, R. et al. Bacterial DNA in patients with cirrhosis and noninfected ascites mimics the soluble immune response established in patients with spontaneous bacterial peritonitis. Hepatology 47, 978–985 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Grivennikov, S. I. & Karin, M. Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann. Rheum. Dis. 70 (Suppl. 1), i104–i108 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Raisz, L. G. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J. Clin. Invest. 115, 3318–3325 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Brenchley, J. M., Silvestri, G. & Douek, D. C. Nonprogressive and progressive primate immunodeficiency lentivirus infections. Immunity 32, 737–742 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Estes, J. D. et al. Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. PLoS Pathog. 6, e1001052 (2010). This study finds that microbial products are present in distal lymphatic tissues and in the liver in SIV-infected rhesus macaques but not in sooty mangabees. Microbial products colocalize with IFNα in lymphoid tissue, and breaches in the epithelial lining and microbial translocation occur during the late acute stage of SIV infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chege, D. et al. Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy. AIDS 25, 741–749 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Brenchley, J. M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Med. 12, 1365–1371 (2006). This landmark study demonstrates that individuals with HIV infection have increased microbial translocation and that increased LPS levels correlate with immune activation, as quantified by circulating IFNα levels and the frequency of activated CD8+ T cells.

    Article  CAS  PubMed  Google Scholar 

  23. Hunt, P. W. 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. 197, 126–133 (2008).

    Article  PubMed  Google Scholar 

  24. Papasavvas, E. et al. Delayed loss of control of plasma lipopolysaccharide levels after therapy interruption in chronically HIV-1-infected patients. AIDS 23, 369–375 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Sun, B. et al. Peripheral biomarkers do not correlate with cognitive impairment in highly active antiretroviral therapy-treated subjects with human immunodeficiency virus type 1 infection. J. Neurovirol. 16, 115–124 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Troseid, M., Sonnerborg, A. & Nowak, P. High mobility group box protein-1 in HIV-1 infection. Curr. HIV Res. 9, 6–10 (2010).

    Article  Google Scholar 

  27. Wallet, M. A. et al. Microbial translocation induces persistent macrophage activation unrelated to HIV-1 levels or T-cell activation following therapy. AIDS 24, 1281–1290 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Burdo, T. H. et al. Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients. J. Infect. Dis. 204, 1227–1236 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rajasuriar, R. et al. Biological determinants of immune reconstitution in HIV-infected patients receiving antiretroviral therapy: the role of interleukin 7 and interleukin 7 receptor α and microbial translocation. J. Infect. Dis. 202, 1254–1264 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Nowroozalizadeh, S. et al. Microbial translocation correlates with the severity of both HIV-1 and HIV-2 infections. J. Infect. Dis. 201, 1150–1154 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Anselmi, A. et al. Immune reconstitution in human immunodeficiency virus type 1-infected children with different virological responses to anti-retroviral therapy. Clin. Exp. Immunol. 150, 442–450 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Papasavvas, E. et al. Increased microbial translocation in ≤180 days old perinatally human immunodeficiency virus-positive infants as compared with human immunodeficiency virus-exposed uninfected infants of similar age. Pediatr. Infect. Dis. J. 30, 877–882 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ancuta, P. et al. Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS ONE 3, e2516 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. d'Ettorre, G. et al. HIV persistence in the gut mucosa of HIV-infected subjects undergoing antiretroviral therapy correlates with immune activation and increased levels of LPS. Curr. HIV Res. 9, 148–153 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Cassol, E. et al. Persistent microbial translocation and immune activation in HIV-1-infected South Africans receiving combination antiretroviral therapy. J. Infect. Dis. 202, 723–733 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Lester, R. T. et al. HIV-1 RNA dysregulates the natural TLR response to subclinical endotoxemia in Kenyan female sex-workers. PLoS ONE 4, e5644 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mavigner, M. et al. Altered CD4+ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals. J. Clin. Invest. 122, 62–69 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Redd, A. D. et al. Microbial translocation, the innate cytokine response, and HIV-1 disease progression in Africa. Proc. Natl Acad. Sci. USA 106, 6718–6723 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Ciccone, E. J. et al. Cycling of gut mucosal CD4+ T cells decreases after prolonged anti-retroviral therapy and is associated with plasma LPS levels. Mucosal Immunol. 3, 172–181 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Bukh, A. R. et al. Endotoxemia is associated with altered innate and adaptive immune responses in untreated HIV-1 infected individuals. PLoS ONE 6, e21275 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ketchum, P. A. & Novitsky, T. J. Assay of endotoxin by limulus amebocyte lysate. Methods Mol. Med. 36, 3–12 (2000).

    CAS  PubMed  Google Scholar 

  42. Eichbaum, E. B., Harris, H. W., Kane, J. P. & Rapp, J. H. Chylomicrons can inhibit endotoxin activity in vitro. J. Surg. Res. 51, 413–416 (1991).

    Article  CAS  PubMed  Google Scholar 

  43. Landmann, R. et al. Human monocyte CD14 is upregulated by lipopolysaccharide. Infect. Immun. 64, 1762–1769 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Hiki, N. et al. Endotoxin binding and elimination by monocytes: secretion of soluble CD14 represents an inducible mechanism counteracting reduced expression of membrane CD14 in patients with sepsis and in a patient with paroxysmal nocturnal hemoglobinuria. Infect. Immun. 66, 1135–1141 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Nockher, W. A., Bergmann, L. & Scherberich, J. E. Increased soluble CD14 serum levels and altered CD14 expression of peripheral blood monocytes in HIV-infected patients. Clin. Exp. Immunol. 98, 369–374 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Eller, M. A. et al. Innate and adaptive immune responses both contribute to pathological CD4 T cell activation in HIV-1 infected Ugandans. PLoS ONE 6, e18779 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Merlini, E. et al. Evidence for polymicrobic flora translocating in peripheral blood of HIV-infected patients with poor immune response to antiretroviral therapy. PLoS ONE 6, e18580 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Burdo, T. H. et al. Soluble CD163 made by monocyte/macrophages is a novel marker of HIV activity in early and chronic infection prior to and after anti-retroviral therapy. J. Infect. Dis. 204, 154–163 (2011). In this study, levels of sCD163 are shown to be increased in HIV-infected individuals, to correlate with the frequency of activated CD8+ T cells and to decrease with ART.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mayne, E. et al. Increased platelet and microparticle activation in HIV infection: upregulation of P-selectin and tissue factor expression. J. Acquir. Immune Defic. Syndr. 59, 340–346 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Byakwaga, H. et al. Intensification of antiretroviral therapy with raltegravir or addition of hyperimmune bovine colostrum in HIV-infected patients with suboptimal CD4+ T-cell response: a randomized controlled trial. J. Infect. Dis. 204, 1532–1540 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Funderburg, N. T. et al. Delayed reduction in CD4 T cell turnover following viral control correlates with markers of microbial translocation in treatment-naïve patients receiving RAL-based ART: preliminary results from ACTG A5248. In 18th Conf. on Retroviruses and Opportunistic Infections (Boston, Massachusetts, USA; 27 Feb–2 Mar 2011) Poster 318 (2011).

    Google Scholar 

  52. Meiler, C. et al. Different effects of a CD14 gene polymorphism on disease outcome in patients with alcoholic liver disease and chronic hepatitis C infection. World J. Gastroenterol. 11, 6031–6037 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Alhawi, M., Stewart, J., Erridge, C., Patrick, S. & Poxton, I. R. Bacteroides fragilis signals through Toll-like receptor (TLR) 2 and not through TLR4. J. Med. Microbiol. 58, 1015–1022 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Kramski, M. et al. Novel sensitive real-time PCR for quantification of bacterial 16S rRNA genes in plasma of HIV-infected patients as a marker for microbial translocation. J. Clin. Microbiol. 49, 3691–3693 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bottger, E. C. Frequent contamination of Taq polymerase with DNA. Clin. Chem. 36, 1258–1259 (1990).

    CAS  PubMed  Google Scholar 

  56. Nowak, P., Abdurahman, S., Lindkvist, A., Troseid, M. & Sonnerborg, A. Impact of HMGB1/TLR ligand complexes on HIV-1 replication: possible role for flagellin during HIV-1 infection. Int. J. Microbiol. 2012, 263836 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ellis, C. L. 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. 57, 363–370 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kotler, D. P., Gaetz, H. P., Lange, M., Klein, E. B. & Holt, P. R. Enteropathy associated with the acquired immunodeficiency syndrome. Ann. Intern. Med. 101, 421–428 (1984).

    Article  CAS  PubMed  Google Scholar 

  59. Kapembwa, M. S. et al. Altered small-intestinal permeability associated with diarrhoea in human-immunodeficiency-virus-infected Caucasian and African subjects. Clin. Sci. (Lond.). 81, 327–334 (1991).

    Article  CAS  PubMed  Google Scholar 

  60. Zeitz, M. et al. HIV/SIV enteropathy. Ann. NY Acad. Sci. 859, 139–148 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Moir, S., Chun, T. W. & Fauci, A. S. Pathogenic mechanisms of HIV disease. Annu. Rev. Pathol. 6, 223–248 (2009).

    Article  CAS  Google Scholar 

  62. Budhraja, M., Levendoglu, H., Kocka, F., Mangkornkanok, M. & Sherer, R. Duodenal mucosal T cell subpopulation and bacterial cultures in acquired immune deficiency syndrome. Am. J. Gastroenterol. 82, 427–431 (1987).

    CAS  PubMed  Google Scholar 

  63. Lauritano, E. C. et al. Small intestinal bacterial overgrowth and intestinal permeability. Scand. J. Gastroenterol. 45, 1131–1132 (2010).

    Article  PubMed  Google Scholar 

  64. Crenn, P. et al. Plasma citrulline is a biomarker of enterocyte mass and an indicator of parenteral nutrition in HIV-infected patients. Am. J. Clin. Nutr. 90, 587–594 (2009). This study establishes plasma citrulline as a marker of functional enterocyte mass, thus showing that citrulline levels can be used to quantify intestinal damage in HIV-infected individuals.

    Article  CAS  PubMed  Google Scholar 

  65. Heise, C. et al. Human immunodeficiency virus infection of enterocytes and mononuclear cells in human jejunal mucosa. Gastroenterology 100, 1521–1527 (1991).

    Article  CAS  PubMed  Google Scholar 

  66. Papadia, C. et al. Plasma citrulline as a quantitative biomarker of HIV-associated villous atrophy in a tropical enteropathy population. Clin. Nutr. 29, 795–800 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Maresca, M. et al. The virotoxin model of HIV-1 enteropathy: involvement of GPR15/Bob and galactosylceramide in the cytopathic effects induced by HIV-1 gp120 in the HT-29-D4 intestinal cell line. J. Biomed. Sci. 10, 156–166 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Yu, L. C., Turner, J. R. & Buret, A. G. LPS/CD14 activation triggers SGLT-1-mediated glucose uptake and cell rescue in intestinal epithelial cells via early apoptotic signals upstream of caspase-3. Exp. Cell Res. 312, 3276–3286 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Epple, H. J. et al. Acute HIV infection induces mucosal infiltration with CD4+ and CD8+ T cells, epithelial apoptosis, and a mucosal barrier defect. Gastroenterology 139, 1289–1300 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Asmuth, D. M., Hammer, S. M. & Wanke, C. A. Physiological effects of HIV infection on human intestinal epithelial cells: an in vitro model for HIV enteropathy. AIDS 8, 205–211 (1994).

    Article  CAS  PubMed  Google Scholar 

  71. Nazli, A. et al. Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PLoS Pathog. 6, e1000852 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Canani, R. B. et al. Inhibitory effect of HIV-1 Tat protein on the sodium-D-glucose symporter of human intestinal epithelial cells. AIDS 20, 5–10 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Di Sabatino, A. et al. Intraepithelial and lamina propria lymphocytes show distinct patterns of apoptosis whereas both populations are active in Fas based cytotoxicity in coeliac disease. Gut 49, 380–386 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. MacDonald, T. T. & Spencer, J. The role of activated T cells in transformed intestinal mucosa. Digestion 46 (Suppl. 2), 290–296 (1990).

    Article  PubMed  Google Scholar 

  75. Ciccocioppo, R. et al. Increased enterocyte apoptosis and Fas-Fas ligand system in celiac disease. Am. J. Clin. Pathol. 115, 494–503 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Kam, L. Y. & Targan, S. R. Cytokine-based therapies in inflammatory bowel disease. Curr. Opin. Gastroenterol. 15, 302–307 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Crenn, P., Coudray-Lucas, C., Thuillier, F., Cynober, L. & Messing, B. Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. Gastroenterology 119, 1496–1505 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Sankaran, S. et al. Rapid onset of intestinal epithelial barrier dysfunction in primary human immunodeficiency virus infection is driven by an imbalance between immune response and mucosal repair and regeneration. J. Virol. 82, 538–545 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Smith, A. J., Schacker, T. W., Reilly, C. S. & Haase, A. T. A role for syndecan-1 and claudin-2 in microbial translocation during HIV-1 infection. J. Acquir. Immune Defic. Syndr. 55, 306–315 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kotler, D. P., Reka, S. & Clayton, F. Intestinal mucosal inflammation associated with human immunodeficiency virus infection. Dig. Dis. Sci. 38, 1119–1127 (1993).

    Article  CAS  PubMed  Google Scholar 

  81. Clayton, F., Snow, G., Reka, S. & Kotler, D. P. Selective depletion of rectal lamina propria rather than lymphoid aggregate CD4 lymphocytes in HIV infection. Clin. Exp. Immunol. 107, 288–292 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Schneider, T. et al. Loss of CD4 T lymphocytes in patients infected with human immunodeficiency virus type 1 is more pronounced in the duodenal mucosa than in the peripheral blood. Berlin Diarrhea/Wasting Syndrome Study Group. Gut 37, 524–529 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Smit-McBride, Z., Mattapallil, J. J., 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. 72, 6646–6656 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Brenchley, J. M. et al. Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 112, 2826–2835 (2008). This study demonstrates that T H 17 cells are preferentially lost in the gastrointestinal tract but not in the blood of HIV-infected individuals, but they are maintained in SIV-infected sooty mangabees.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Mattapallil, J. J. et al. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 434, 1093–1097 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Gordon, S. N. et al. Disruption of intestinal CD4+ T cell homeostasis is a key marker of systemic CD4+ T cell activation in HIV-infected individuals. J. Immunol. 185, 5169–5179 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Deng, H. et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 381, 661–666 (1996).

    Article  CAS  PubMed  Google Scholar 

  88. Veazey, R. S. et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280, 427–431 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Guadalupe, M. et al. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J. Virol. 77, 11708–11717 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Cecchinato, V. et al. Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques. Mucosal Immunol. 1, 279–288 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. El Hed, A. et al. Susceptibility of human Th17 cells to human immunodeficiency virus and their perturbation during infection. J. Infect. Dis. 201, 843–854 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Bettelli, E., Korn, T., Oukka, M. & Kuchroo, V. K. Induction and effector functions of TH17 cells. Nature 453, 1051–1057 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Liu, J. Z., Pezeshki, M. & Raffatellu, M. Th17 cytokines and host-pathogen interactions at the mucosa: dichotomies of help and harm. Cytokine 48, 156–160 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Favre, D. 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, 32ra36 (2010). In this study, induction of IDO1 is associated with a relative loss of T H 17 cells and gain of T Reg cells and may thereby perpetuate increased microbial translocation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Giorgi, J. V. et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J. Infect. Dis. 179, 859–870 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Simonetta, F. et al. Early and long-lasting alteration of effector CD45RAFoxp3high regulatory T-cell homeostasis during HIV infection. J. Infect. Dis. 205, 1510–1519 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Mendez-Lagares, G. et al. Severe immune dysregulation affects CD4+CD25hiFoxP3+ regulatory T cells in HIV-infected patients with low-level CD4 T-cell repopulation despite suppressive highly active antiretroviral therapy. J. Infect. Dis. 205, 1501–1509 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Reeves, R. K. et al. Gut inflammation and indoleamine deoxygenase inhibit IL-17 production and promote cytotoxic potential in NKp44+ mucosal NK cells during SIV infection. Blood 118, 3321–3330 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Feldman, M., Friedman, L. S. & Brandt, L. J. Sleisenger and Fordtran's Gastrointestinal and Liver Disease 9th edn (Saunders, 2010).

    Google Scholar 

  100. Jirillo, E. et al. The role of the liver in the response to LPS: experimental and clinical findings. J. Endotoxin Res. 8, 319–327 (2002).

    CAS  PubMed  Google Scholar 

  101. Balagopal, A. et al. Kupffer cells are depleted with HIV immunodeficiency and partially recovered with antiretroviral immune reconstitution. AIDS 23, 2397–2404 (2009). This study finds that Kupffer cells are depleted in HIV and hepatitis C virus co-infection, suggesting another mechanism, namely decreased LPS clearance, by which increased microbial translocation can occur in these individuals.

    Article  CAS  PubMed  Google Scholar 

  102. Sandler, N. G. et al. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology 141, 1220–1230, 1230.e1–1230.e3 (2011).

    Article  PubMed  Google Scholar 

  103. Fukui, H., Brauner, B., Bode, J. C. & Bode, C. Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay. J. Hepatol. 12, 162–169 (1991).

    Article  CAS  PubMed  Google Scholar 

  104. Vispo, E., Morello, J., Rodriguez-Novoa, S. & Soriano, V. Noncirrhotic portal hypertension in HIV infection. Curr. Opin. Infect. Dis. 24, 12–18 (2011).

    Article  PubMed  Google Scholar 

  105. Cesari, M. et al. Noncirrhotic portal hypertension in HIV-infected patients: a case control evaluation and review of the literature. AIDS Patient Care STDS 24, 697–703 (2010).

    Article  PubMed  Google Scholar 

  106. Stabinski, L. et al. High prevalence of liver fibrosis associated with HIV infection: a study in rural Rakai, Uganda. Antivir. Ther. 16, 405–411 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Kedzierska, K. et al. Defective phagocytosis by human monocyte/macrophages following HIV-1 infection: underlying mechanisms and modulation by adjunctive cytokine therapy. J. Clin. Virol. 26, 247–263 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. da Silva, B., Singer, W., Fong, I. W. & Ottaway, C. A. In vivo cytokine and neuroendocrine responses to endotoxin in human immunodeficiency virus-infected subjects. J. Infect. Dis. 180, 106–115 (1999).

    Article  CAS  PubMed  Google Scholar 

  109. Mureith, M. W., Chang, J. J., Lifson, J. D., Ndung'u, T. & Altfeld, M. Exposure to HIV-1-encoded Toll-like receptor 8 ligands enhances monocyte response to microbial encoded Toll-like receptor 2/4 ligands. AIDS 24, 1841–1848 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Ebert, L. M. & McColl, S. R. Up-regulation of CCR5 and CCR6 on distinct subpopulations of antigen-activated CD4+ T lymphocytes. J. Immunol. 168, 65–72 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Juffermans, N. P. et al. Up-regulation of HIV coreceptors CXCR4 and CCR5 on CD4+ T cells during human endotoxemia and after stimulation with (myco) bacterial antigens: the role of cytokines. Blood 96, 2649–2654 (2000).

    CAS  PubMed  Google Scholar 

  112. Munsaka, S. M. et al. Characteristics of activated monocyte phenotype support R5-tropic human immunodeficiency virus. Immunol. Immunogenet. Insights 1, 15–20 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Fernandez, S. et al. CD4+ T-cell deficiency in HIV patients responding to antiretroviral therapy is associated with increased expression of interferon-stimulated genes in CD4+ T cells. J. Infect. Dis. 204, 1927–1935 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. Combadere, B. et al. CD4+Ki67+ lymphocytes in HIV-infected patients are effector T cells accumulated in the G1 phase of the cell cycle. Eur. J. Immunol. 30, 3598–3603 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. Kieper, W. C. et al. Recent immune status determines the source of antigens that drive homeostatic T cell expansion. J. Immunol. 174, 3158–3163 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Piconi, S. et al. Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy. AIDS 24, 1991–2000 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Lim, A. et al. Antibody and B-cell responses may control circulating lipopolysaccharide in patients with HIV infection. AIDS 25, 1379–1383 (2011).

    Article  CAS  PubMed  Google Scholar 

  118. Marchetti, G. et al. Microbial translocation predicts disease progression of HIV-infected antiretroviral-naive patients with high CD4+ cell count. AIDS 25, 1385–1394 (2011). This study demonstrates that immunologic non-responders have increased microbial translocation, and among these individuals LPS levels correlated with the number of activated CD4+ and CD8+ T cells.

    Article  CAS  PubMed  Google Scholar 

  119. Baroncelli, S. et al. Microbial translocation is associated with residual viral replication in HAART-treated HIV+ subjects with <50 copies/ml HIV-1 RNA. J. Clin. Virol. 46, 367–370 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Lien, E. et al. Elevated levels of serum-soluble CD14 in human immunodeficiency virus type 1 (HIV-1) infection: correlation to disease progression and clinical events. Blood 92, 2084–2092 (1998).

    CAS  PubMed  Google Scholar 

  121. Marchetti, G. 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 22, 2035–2038 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Massanella, M. et al. CD4 T-cell hyperactivation and susceptibility to cell death determine poor CD4 T-cell recovery during suppressive HAART. AIDS 24, 959–968 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Marchetti, G. et al. Comparative analysis of T-cell turnover and homeostatic parameters in HIV-infected patients with discordant immune-virological responses to HAART. AIDS 20, 1727–1736 (2006).

    Article  PubMed  Google Scholar 

  124. Hofer, U. & Speck, R. F. Disturbance of the gut-associated lymphoid tissue is associated with disease progression in chronic HIV infection. Semin. Immunopathol. 31, 257–266 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Schacker, T. W. et al. Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis. J. Clin. Invest. 110, 1133–1139 (2002). This study demonstrates increased collagen deposition in lymphatic tissues of HIV-infected individuals. Individuals with more collagen deposition had a lower CD4+ T cell density in the lymphoid tissue and less CD4+ T cell recovery after starting ART.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Estes, J. et al. Collagen deposition limits immune reconstitution in the gut. J. Infect. Dis. 198, 456–464 (2008).

    Article  PubMed  Google Scholar 

  127. Estes, J. D. et al. Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection. J. Infect. Dis. 193, 703–712 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Estes, J. D. et al. Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor β1-positive regulatory T cells and begins in early infection. J. Infect. Dis. 195, 551–561 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Hunt, P. et al. Gut-associated lymphoid tissue fibrosis is associated with CD4+ T cell activation and poor HIV-specific CD8+ T cell responses during suppressive ART. In 18th Conf. on Retroviruses and Opportunistic Infections (Boston, Massachusetts, USA; 27 Feb–2 Mar 2011) Poster 319 (2011).

    Google Scholar 

  130. Zeng, M., Haase, A. T. & Schacker, T. W. Lymphoid tissue structure and HIV-1 infection: life or death for T cells. Trends Immunol. 33, 306–314 (2012).

    Article  CAS  PubMed  Google Scholar 

  131. Lyons, J. L. et al. Plasma sCD14 is a biomarker associated with impaired neurocognitive test performance in attention and learning domains in HIV infection. J. Acquir. Immune Defic. Syndr. 57, 371–379 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ryan, L. A. et al. Plasma levels of soluble CD14 and tumor necrosis factor-α type II receptor correlate with cognitive dysfunction during human immunodeficiency virus type 1 infection. J. Infect. Dis. 184, 699–706 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. Persidsky, Y. & Gendelman, H. E. Mononuclear phagocyte immunity and the neuropathogenesis of HIV-1 infection. J. Leukoc. Biol. 74, 691–701 (2003).

    Article  CAS  PubMed  Google Scholar 

  134. Currier, J. S. et al. Epidemiological evidence for cardiovascular disease in HIV-infected patients and relationship to highly active antiretroviral therapy. Circulation 118, e29–e35 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Tabib, A., Leroux, C., Mornex, J. F. & Loire, R. Accelerated coronary atherosclerosis and arteriosclerosis in young human-immunodeficiency-virus-positive patients. Coron. Artery Dis. 11, 41–46 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. Matta, F., Yaekoub, A. Y. & Stein, P. D. Human immunodeficiency virus infection and risk of venous thromboembolism. Am. J. Med. Sci. 336, 402–406 (2008).

    Article  PubMed  Google Scholar 

  137. Funderburg, N. T. et al. Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation. Blood 115, 161–167 (2010). The findings of this study suggest that microbial translocation may drive the procoagulant state observed in HIV-infected individuals.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Marmur, J. D. et al. Identification of active tissue factor in human coronary atheroma. Circulation 94, 1226–1232 (1996).

    Article  CAS  PubMed  Google Scholar 

  139. Davi, G. & Patrono, C. Platelet activation and atherothrombosis. N. Engl. J. Med. 357, 2482–2494 (2007).

    Article  CAS  PubMed  Google Scholar 

  140. Merlini, E. et al. Microbial translocation-induced immune activation associates to atherosclerosis in cART-treated HIV+ patients. In 18th Conf. on Retroviruses and Opportunistic Infections (Boston, Massachusetts, USA; 27 Feb–2 Mar 2011) Poster 309 (2011).

    Google Scholar 

  141. El-Sadr, W. M. et al. CD4+ count-guided interruption of antiretroviral treatment. N. Engl. J. Med. 355, 2283–2296 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. Phillips, A. N. et al. Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial. Antivir. Ther. 13, 177–187 (2008).

    CAS  PubMed  Google Scholar 

  143. Mehandru, S. et al. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J. Exp. Med. 200, 761–770 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Mehandru, S. et al. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection. PLoS Med. 3, e484 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Sun, P. P., Perianayagam, M. C. & Jaber, B. L. Endotoxin-binding affinity of sevelamer: a potential novel anti-inflammatory mechanism. Kidney Int. Suppl. S20–S25 (2009).

  146. Stinghen, A. E. et al. Sevelamer decreases systemic inflammation in parallel to a reduction in endotoxemia. Blood Purif. 29, 352–356 (2010).

    Article  CAS  PubMed  Google Scholar 

  147. Vlachogiannakos, J. et al. Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis. Aliment. Pharmacol. Ther. 29, 992–999 (2009).

    Article  CAS  PubMed  Google Scholar 

  148. Kalambokis, G. N. & Tsianos, E. V. Rifaximin reduces endotoxemia and improves liver function and disease severity in patients with decompensated cirrhosis. Hepatology 55, 655–656 (2012).

    Article  CAS  PubMed  Google Scholar 

  149. Pandrea, I. et al. Administration of rifaximin and sulfasalazine during acute SIV infection decreases microbial translocation and coagulation marker levels and significantly impacts viral replication. In 19th Conf. on Retroviruses and Opportunistic Infections (Seattle, Washington, USA; 5–8 Mar 2012) Paper 162 (2012).

    Google Scholar 

  150. Cani, P. D. et al. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia 50, 2374–2383 (2007).

    Article  CAS  PubMed  Google Scholar 

  151. Gori, A. et al. Specific prebiotics modulate gut microbiota and immune activation in HAART-naive HIV-infected adults: results of the “COPA” pilot randomized trial. Mucosal Immunol. 4, 554–563 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).

    Article  CAS  PubMed  Google Scholar 

  153. Murray, S. M. et al. Reduction of immune activation with chloroquine therapy during chronic HIV infection. J. Virol. 84, 12082–12086 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Piconi, S. et al. Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders. Blood 118, 3263–3272 (2010).

    Article  CAS  Google Scholar 

  155. Lynn, M. et al. Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia. J. Infect. Dis. 187, 631–639 (2003).

    Article  CAS  PubMed  Google Scholar 

  156. Kalil, A. C., LaRosa, S. P., Gogate, J., Lynn, M. & Opal, S. M. Influence of severity of illness on the effects of eritoran tetrasodium (E5564) and on other therapies for severe sepsis. Shock 36, 327–331 (2011).

    Article  CAS  PubMed  Google Scholar 

  157. Franklin, B. S. et al. Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria. Proc. Natl Acad. Sci. USA 108, 3689–3694 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunol. 11, 373–384 (2010).

    Article  CAS  Google Scholar 

  159. Kanneganti, T. D., Lamkanfi, M. & Nunez, G. Intracellular NOD-like receptors in host defense and disease. Immunity 27, 549–559 (2007).

    Article  CAS  PubMed  Google Scholar 

  160. Brenchley, J. M. & Douek, D. C. HIV infection and the gastrointestinal immune system. Mucosal Immunol. 1, 23–30 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Pastor Rojo, O. et al. Serum lipopolysaccharide-binding protein in endotoxemic patients with inflammatory bowel disease. Inflamm. Bowel Dis. 13, 269–277 (2007).

    Article  PubMed  Google Scholar 

  162. Gardiner, K. R. et al. Significance of systemic endotoxaemia in inflammatory bowel disease. Gut 36, 897–901 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Cho, J. H. The genetics and immunopathogenesis of inflammatory bowel disease. Nature Rev. Immunol. 8, 458–466 (2008).

    Article  CAS  Google Scholar 

  164. Mandrekar, P. & Szabo, G. Signalling pathways in alcohol-induced liver inflammation. J. Hepatol. 50, 1258–1266 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. van de Weg, C. A. et al. Lipopolysaccharide levels are elevated in dengue virus infected patients and correlate with disease severity. J. Clin. Virol. 53, 38–42 (2011).

    Article  CAS  PubMed  Google Scholar 

  166. Santos-Oliveira, J. R. et al. Evidence that lipopolisaccharide may contribute to the cytokine storm and cellular activation in patients with visceral leishmaniasis. PLoS Negl. Trop. Dis. 5, e1198 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. De Palma, G. et al. Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children. BMC Microbiol. 10, 63 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the members of the Cleveland Immunopathogenesis Consortium (BBC), funded by US National Institutes of Health grant AI-76174, for stimulating discussions.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Daniel C. Douek.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Glossary

Lamina propria

Connective tissue that underlies the epithelium of the mucosa and contains various myeloid and lymphoid cells, including macrophages, dendritic cells, T cells and B cells.

T helper 17 cells

(TH17 cells). A subset of CD4+ T helper cells that produce interleukin-17 and that are thought to be important in inflammatory and autoimmune diseases.

Tight junctions

Connections between individual epithelial cells that form a diffusion barrier between the underlying tissue layer and the extracellular environment.

Villous atrophy

Loss of enterocytes lining the villi that protrude into the small intestinal lumen.

Crypt hyperplasia

Increased proliferation of enterocytes in the crypts of the small intestine.

Citrulline

Metabolite of glutamine and arginine that is synthesized exclusively by small intestine enterocytes.

Coeliac disease

A chronic inflammatory condition of the upper small intestine in humans that is caused by immunological hypersensitivity to gliadin, a component of wheat gluten. It often occurs in infants during the introduction to solid foods. It causes severe villus atrophy, which can lead to malabsorption and malnutrition if gluten-containing foods are not removed from the diet.

C-reactive protein

(CRP). An acute-phase reactant protein produced in the liver. The concentration of CRP in plasma increases during inflammation.

Gut-associated lymphoid tissue

(GALT). Lymphoid structures and aggregates associated with the intestinal mucosa.

Sigmoid

Terminal part of the colon adjacent to the rectum.

Regulatory T cells

(TReg cells). A subset of CD4+ T helper cells that can suppress the responses of other T cells.

Kupffer cells

The macrophages of the liver. These cells are derived from blood monocytes, and they phagocytose particles, including bacteria and lipopolysaccharide, that enter the liver sinusoids.

Nadir CD4+ T cell counts

An individual's nadir CD4+ T cell count is their lowest recorded CD4+ T cell count since their diagnosis with HIV infection.

T cell zone

The region of lymphatic tissue where most CD4+ T cells reside and interact with antigen-presenting cells, growth factors and cytokines.

Carotid intima media thickness

A measurement of the thickness of the two inner layers of the carotid artery, often performed by ultrasound, that is used to quantify atherosclerotic disease.

Prebiotic

Prebiotics are substrates that are preferentially metabolized by a single probiotic genus or species and may thus be used as dietary supplements to promote targeted growth of these microorganisms.

Plasmacytoid dendritic cells

Immature dendritic cells with a plasmacytoid morphology. They produce type I interferons in response to viral infection.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sandler, N., Douek, D. Microbial translocation in HIV infection: causes, consequences and treatment opportunities. Nat Rev Microbiol 10, 655–666 (2012). https://doi.org/10.1038/nrmicro2848

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro2848

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing