In the December issue of Nature Medicine, Daniel Douek and colleagues publish evidence supporting their theory that HIV’s depletion of gut CD4 T cells causes a phenomenon known as “microbial translocation.” This theory holds that HIV infection damages the integrity of the gut mucosa in a way that allows friendly commensal bacteria to leak from the gut into the circulation; the leaked bacteria then cause the immune activation seen in HIV infection. The researchers support their theory by showing that people with chronic HIV infection have higher levels of lipopolysaccharide (LPS) in their bloodstream than uninfected controls, and that LPS levels correlate with markers of immune activation (CD38 expression on CD8 T cells). LPS is typically a product of gut bacteria although it can also be produced by other sources (such as pathogens). LPS levels are often used as a marker for microbial translocation in other settings (such as inflammatory bowel disease), although recently researchers have also begun using DNA PCR to look directly for bacteria in the bloodstream; Douek's research group plans to evaluate this technology in future studies.
The paper also notes that LPS levels were elevated in 10 out of 11 SIV-infected macaques that the researchers studied at two timepoints (baseline and 100 days post-infection). Two macaques treated with antibiotics showed a transient (2 week) decline in LPS levels and bacteria in their feces, leading the researchers to state that: “These data suggest that the origin of plasma LPS in SIV-infected rhesus macaques and, by inference, in HIV-infected humans is translocation from the gastrointestinal tract.” It is perhaps worth noting that a considerable amount is being inferred from two macaques. The researchers also suggest that LPS levels are not elevated in early HIV infection because of anti-LPS antibodies – when immunodeficiency worsens, they argue, these antibodies wane and levels of LPS therefore increase. They support this argument with data showing an inverse correlation between anti-LPS antibodies and LPS levels. Additionally, the authors found reduced anti-LPS antibody levels in people with acute/early HIV infection compared to uninfected controls and a further reduction in anti-LPS antibody levels in chronic HIV infection versus acute/early infection. These data suggest that HIV-related immunodeficiency impairs the anti-LPS antibody response.
The effects of ART on LPS levels were also investigated. Out of 28 individuals studied, 24 showed a decline in LPS levels after 48 weeks of ART. There was also a significant correlation between the reduction of LPS and the magnitude of CD4 T cell reconstitution, although the researchers note that there was no correlation between LPS levels and CD4 T cells counts prior to the initiation of ART.
The paper concludes by addressing the seemingly confounding data on gut CD4 T cell depletion in SIV-infected Sooty Mangabeys. These animals rarely develop immunodeficiency but, surprisingly, do show evidence of severe CD4 T cell loss from the gut. An investigation of LPS levels in SIV-infected Sooty Mangabeys found no difference compared to uninfected controls, leading the authors to argue that while these animals experience an apparent loss of gut CD4 T cells, they are protected from immune activation because microbial translocation does not occur (although they do not yet have an explanation as to why this might be the case).
Taken together, the results reported in this paper are very interesting and provocative, but additional research will be needed to confirm that microbial translocation occurs and is responsible for immune activation in HIV infection.
Study abstract:
Nat Med. 2006 Dec;12(12):1365-71. Epub 2006 Nov 19.
Microbial translocation is a cause of systemic immune activation in chronic HIV infection.
Brenchley JM,Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG, Douek DC.
Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here we show that circulating microbial products, probably derived from the gastrointestinal tract, are a cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, which we used as an indicator of microbial translocation, was significantly increased in chronically HIV-infected individuals and in simian immunodeficiency virus (SIV)-infected rhesus macaques (P </= 0.002). We show that increased lipopolysaccharide is bioactive in vivo and correlates with measures of innate and adaptive immune activation. Effective antiretroviral therapy seemed to reduce microbial translocation partially. Furthermore, in nonpathogenic SIV infection of sooty mangabeys, microbial translocation did not seem to occur. These data establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide new directions for therapeutic interventions that modify the consequences of acute HIV infection.
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