Continuing debate over the role of microbial translocation in HIV infection
1 April 2011. Related: Basic science and immunology.
Richard Jefferys, TAG
Several years ago, researchers led by Jason Brenchley and Daniel Douek at the National Institute of Allergy & Infectious Diseases published data suggesting an important role for microbial translocation in HIV pathogenesis. [1]
Microbial translocation is the leaking of normally friendly commensal bacteria from the gut where they are usually contained into the systemic circulation. Brenchley and colleagues proposed that this phenomenon contributes to immune activation in people with HIV, and thus plays a causative role in the progression of the disease.
Several subsequent studies have confirmed an association between markers of microbial translocation found in the bloodstream (e.g. the bacterial component LPS and bacterial DNA) and immune deficiency in people with HIV, including people with poor immune reconstitution on antiretroviral therapy (ART). [2]
However, these results have not ruled out the possibility that microbial translocation occurs as a result of HIV-induced immune deficiency, rather than playing a key role in causing it.
To try and gain a better understanding of the importance of microbial translocation in the pathogenesis of HIV infection, Daniel Douek has collaborated with researchers from the INSIGHT network to analyse samples from the Strategic Management of AntiRetroviral Therapy (SMART) trial. [3]
This trial randomised 5,472 people with HIV to either continuous or intermittent, CD4-guided ART, and the results showed that intermittent ART was associated with a doubling of the risk of illness and death compared to continuous treatment. [4]
During the study, 85 participants died, 142 developed major cardiovascular disease events, and 100 developed AIDS-defining events. Of these participants, 74, 120, and 81, respectively, had samples available.
Douek and colleagues used a case control study design to evaluate whether any of a suite of different markers of microbial translocation showed associations with these clinical outcomes. The same case control study design has previously been used to analyse the data from SMART, revealing a highly significant association between levels of inflammatory biomarkers and mortality. [5]
The biological markers assessed in the new study were: intestinal fatty acid binding protein (a marker of damage to cells of the gut wall called enterocytes), the bacterial product lipopolysaccharide (LPS), bacterial DNA (16S rDNA), anti-LPS antibodies (endotoxin core IgM antibody or EndoCAb) and soluble CD14 (sCD14). CD14 is a molecule expressed on monocytes that is known to be shed as a result of simulation by LPS.
The only marker that showed a correlation with a clinical outcome was sCD14; higher levels were significantly associated with an increased risk of mortality. Levels of sCD14 also correlated with the inflammatory biomarkers that have previously been associated with mortality risk in SMART. The study authors offer a variety of possible reasons why other markers of microbial translocation were not associated with clinical outcomes, and argue strongly that elevated levels of sCD14 represent a consequence of microbial translocation (even though the other markers did not correlate with sCD14). There are, however, alternate possibilities that might explain elevated sCD14 levels that are not discussed in the paper. Specifically, alpha interferon has been reported to increase levels of sCD14, and levels of this cytokine are increased in HIV infection. [6]
Furthermore, a study published last year that looked for evidence of monocyte stimulation by LPS in HIV found that the gene expression patterns of these cells were more consistent with stimulation by alpha interferon, not LPS. [7]
So while Douek and colleagues write: these observations are consistent with a model in which HIV infection causes ongoing damage to the gut mucosa, leading to increased microbial translocation, increased systemic inflammation, and increased mortality, this interpretation of the data seems debatable, as the elevated levels of sCD14 may not necessarily be explained solely by microbial translocation.
Coincidentally, the current issue of the Journal of Infectious Diseases includes a letter from several researchers (Andrew Redd, Ronald Gray and Thomas Quinn) highlighting the uncertainty regarding whether microbial translocation is a cause or consequence of HIV pathogenesis. They argue that the current evidence favors the view that increased microbial translocation and LPS levels are a consequence of advanced HIV-1 disease and AIDS. The letter closes by stressing the need for additional longitudinal studies to fully resolve the issue. [9]
Source: TAG Basic Science Blog (08 Feb 2011).
http://tagbasicscienceproject.typepad.com
References:
- Brenchley JM et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006 Dec;12(12):1365-71. Epub 2006 Nov 19.
http://www.ncbi.nlm.nih.gov/pubmed/17115046?dopt=AbstractPlus - 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(15):2035-2038, October 1, 2008. Research Letter.
http://journals.lww.com/aidsonline/pages/articleviewer.aspx?year=2008&issue=10010&article=00016&type=abstract
See:
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2008/09/microbial-trans.html - Sandler NG et al. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis. 2011 Jan 20. [Epub ahead of print] doi: 10.1093/infdis/jiq118.
http://jid.oxfordjournals.org/content/early/2011/01/20/infdis.jiq118.abstract - SMART Group. CD4+ countguided interruption of antiretroviral treatment. N Engl J Med 2006; 355:2283-2296 (November 2006)
http://www.nejm.org/doi/full/10.1056/NEJMoa062360 - Kuller LH et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Medicine Vol. 5, No. 10, e203 doi:10.1371/journal.pmed.0050203.
http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050203
See:
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2008/10/inflammatory-an.html - Carotenuto P et al. Antiviral treatment with alpha interferon up-regulates CD14 on liver macrophages and its soluble form in patients with chronic hepatitis B. Antimicrobial Agents and Chem. February 2005, p. 590-599, Vol. 49, No. 2.
http://aac.asm.org/cgi/content/full/49/2/590 - Rempel H et al. Interferon-alpha drives monocyte gene expression in chronic unsuppressed HIV-1 infection. AIDS. 2010 Jun 19;24(10):1415-23.
http://journals.lww.com/aidsonline/Abstract/2010/06190/Interferon__alpha__drives_monocyte_gene_expression.3.aspx - Redd AD et al. Is Microbial Translocation a Cause or Consequence of HIV Disease Progression? J Infect Dis. (2011) 203 (5): 744-745. doi: 10.1093/infdis/jiq107.
http://jid.oxfordjournals.org/content/203/5/744.extract