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

Nature Reviews Microbiology volume 10, pages 655–666 (2012)Cite this article

Subjects

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.

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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.

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Acknowledgements

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

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  1. Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Netanya G. Sandler & Daniel C. Douek

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Correspondence to Daniel C. Douek.

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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.

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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

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