Update: Leaking LPS

As this issue went to press, a paper appeared from Daniel Douek and colleagues reporting data which, the authors argue, further supports the model of HIV pathogenesis outlined in their Nature Immunology review. Douek's group had previously speculated that one pathogenic byproduct of HIV's impact on the gut might be to inappropriately allow bacterial byproducts into the bloodstream -- a phenomenon known as "microbial translocation" -- allowing them to stimulate runaway immune activation, ultimately leading to CD4 T cell loss and AIDS.

In the December 2006 issue of Nature Medicine, the researchers report that people with chronic HIV infection and AIDS -- but not acute or early HIV infection -- have higher levels of lipopolysaccharides (LPS) in their bloodstream than uninfected controls, and LPS levels correlate with markers of immune activation (CD38 expression on CD8 T cells). LPS is typically a product of gram negative bacteria, and LPS levels are measured in other settings involving microbial translocation such as inflammatory bowel disease. Elevated LPS alone, however, does not necessarily prove that microbial translocation is occurring, as pathogens can also be source.

The researchers also suggest that LPS levels are not elevated in acute/early HIV infection because of anti-LPS antibodies (known as EndoCAbs). When immunodeficiency worsens, they argue, these antibodies wane and levels of LPS increase. Additionally, they found reduced EndoCAb levels in people with acute/early HIV infection compared to uninfected controls and a further reduction in EndoCAb levels in chronic HIV infection versus acute/early infection. These data suggest that HIV-related immunodeficiency impairs the EndoCAb response.

The effects of antiretroviral therapy on LPS levels were also investigated. Out of 28 individuals studied, 24 showed a decline in LPS levels after 48 weeks of ART, and there was a correlation between the magnitude of the decline and CD4 T cell count increase. However there was no correlation between CD4 T cell counts and LPS levels prior to the initiation of ART.

The paper also addresses the paradox that SIV-infected sooty mangabeys experience CD4 T cell depletion of the gut but do not developed an AIDS-like illness by speculating that the monkeys may have evolved other mechanisms to prevent microbial translocation. In a commentary that accompanies the Douek article, Barton Haynes of Duke University notes unanswered questions regarding the LPS hypothesis, including the observation that immune activation is high during acute phase HIV infection-before there is evidence of LPS elevation.

1. 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.

2. Haynes BF. Gut microbes out of control in HIV infection. Nat Med. 2006 Dec;12(12): 1351-52.