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Review
. 2013 Jan;26(1):2-18.
doi: 10.1128/CMR.00050-12.

Microbial translocation in the pathogenesis of HIV infection and AIDS

Giulia Marchetti  1 , Camilla Tincati, Guido Silvestri
Affiliations
Review

Microbial translocation in the pathogenesis of HIV infection and AIDS

Giulia Marchetti et al. Clin Microbiol Rev. 2013 Jan.

Abstract

In pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections, the translocation of microbial products from the gastrointestinal (GI) tract to portal and systemic circulation has been proposed as a major driver of the chronic immune activation that is associated with disease progression. Consistently, microbial translocation is not present in nonpathogenic SIV infections of natural host species. In vivo studies demonstrated that HIV/SIV-associated microbial translocation results from a series of immunopathological events occurring at the GI mucosa: (i) early and severe mucosal CD4(+) depletion, (ii) mucosal immune hyperactivation/persistent inflammation; (iii) damage to the integrity of the intestinal epithelium with enterocyte apoptosis and tight junction disruption; and (iv) subverted the gut microbiome, with a predominance of opportunistic bacteria. Direct in situ evidence of microbial translocation has been provided for SIV-infected rhesus macaques showing translocated microbial products in the intestinal lamina propria and distant sites. While the mechanisms by which microbial translocation causes immune activation remain controversial, a key pathogenic event appears to be innate immunity activation via Toll-like receptors and other pathogen recognition receptors. Accumulating clinical observations suggest that microbial translocation might affect HIV disease progression, response to therapy, and non-AIDS comorbidities. Given its detrimental effect on overall immunity, several interventions to prevent/block microbial translocation are currently under investigation as novel therapeutic agents for HIV/AIDS.

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Figures

Fig 1
Fig 1
Pathogenesis of microbial translocation in HIV-infected patients. (A) In healthy, HIV-negative subjects, the anatomical and functional integrity of the gastrointestinal (GI) mucosal barrier contains the passage of gut bacteria from the intestinal lumen to the lamina propria, thus resulting in physiological levels of mucosal immune activation and very limited if any microbial translocation in peripheral blood. (B) On the contrary, HIV accounts for a breach in the intestinal epithelial barrier with a loss of tight junctions, enterocyte apoptosis, local immune activation, and the depletion of CD4+ Th17 cells. This results in the passage of pathogenic bacteria and microbial products from the gut lumen to the lamina propria and from the lamina propria to the systemic circulation. At these sites, microbes and bacterial fragments further exacerbate local immune activation. Microbial translocation may be antagonized through different strategies: (i) modification of the GI microbiome by antibiotics, probiotics, and prebiotics; (ii) clearance of microbial bioproducts translocated from the gut (e.g., sevelamer); and (iii) interventions to reduce mucosal immune activation, such as IL-7, IL-17, and IL-22. IL, interleukin; HAART, highly active antiretroviral therapy.
Fig 2
Fig 2
Immunological and clinical consequences of microbial translocation in HIV-infected patients. Gut-derived bacteria translocate from the lamina propria to the systemic circulation, leading to peripheral immune activation, which may be an underlying cause of HIV disease progression, poor immunological responses to HAART, and noninfectious comorbidities, such as neurological impairment and cardiovascular, liver, and bone diseases. Microbial translocation may be antagonized through different strategies: (i) modification of the GI microbiome by antibiotics, probiotics, and prebiotics; (ii) clearance of microbial bioproducts translocated from the gut (e.g., sevelamer); and (iii) interventions to reduce mucosal immune activation, such as IL-7, IL-17, and IL-22. IL, interleukin; HAART, highly active antiretroviral therapy.
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