Gut bacteria breach the barrier: further confirmation of microbial translocation in HIV infection

Richard Jefferys, TAG

Last October, Guila Marchetti and colleagues reported that DNA from gut bacteria can be detected in the bloodstream of people with HIV, and that elevated bacterial DNA levels correlate with poor immune reconstitution in people on antiretroviral therapy (ART). [1]

The data were concordant with the hypothesis proposed by Daniel Douek, David Price and Jason Brenchley that leaking of gut bacteria into systemic circulation a phenomenon called microbial translocation – contributes to HIV pathogenesis. [2] The Marchetti study was small, however, involving just 47 participants. A paper just published online in the Journal of Infectious Diseases confirms and significantly extends these findings using several larger cohorts of HIV-infected individuals. [3]

The researchers – led by Wei Jiang and Michael Lederman from Case Western Reserve University – first compared levels of bacterial DNA in a group of uninfected individuals to those in people with untreated HIV infection, or treated HIV infection. Study participants on ART were further subdivided into two groups based on whether their HIV viral load was above or below the limit of detection (400 copies/mL). None of the 15 HIV-negative individuals showed detectable levels of bacterial DNA (the lowest level the test used in the study can reliably detect is 5 DNA copies). In contrast, bacterial DNA was found in 18 out of 19 untreated individuals with HIV infection, with median levels of 132.5 copies per microliter. Study participants on ART fell between these two extremes: the median number of bacterial DNA copies was 8.6 among individuals with undetectable viral loads and 22.8 for those with viral loads above the detection limit (this difference was not statistically significant). The researchers also found that there was a significant association between viral load and bacterial DNA levels in the untreated individuals, but there was no such association with total CD4 counts in peripheral blood (naive and memory CD4 T cells were not analyzed separately).

Next, a separate cohort of 114 individuals on long-term ART were studied, in order to gain further insight into the impact of microbial translocation on the response to treatment. Higher levels of bacterial DNA were associated with lower CD4 count gains on ART; for every 100-copy increase in bacterial DNA levels, 11 fewer CD4 T cells were gained (although this could also be looked at the other way around, i.e. larger increases in CD4 T cells were associated with lower levels of bacterial DNA). Bacterial DNA levels also correlated with levels of lipopolysaccharide (LPS), another indicator of microbial translocation, and more weakly – with CD8 T cell activation.

Finally, the researchers used samples from a longitudinal, 54-person study of ART treatment (ACTG 5014) to evaluate changes in bacterial DNA levels over time. Samples were taken before and at 1, 8, and 48 weeks after starting ART. Levels of bacterial DNA declined progressively, and were significantly lower than baseline at the week 8 and 48 timepoints. These changes were independent of changes in HIV viral load, but correlated inversely with CD4 counts after 48 weeks of treatment (the higher the CD4 count, the lower the bacterial DNA level). The study authors note that median bacterial DNA levels were still higher at week 48 (75 copies per microliter) than had been seen in the first cohort analyzed (8.6 copies). Participants in the first cohort had been on ART for a median of over 6 years, suggesting that bacterial DNA levels decline slowly over a protracted period after starting treatment.

In discussing their data, the authors suggest that microbial translocation in HIV infection is driven by viral replication, either via direct effects on mucosal cells that would normally maintain the integrity of the gut wall, or by indirect effects on immune responses that help contain commensal bacteria within the GI tract. Unlike Marchetti and colleagues, these researchers do not cite the basic immunology literature indicating that T cell depletion can contribute to microbial translocation, although they do consider the possibility that in some cases poor CD4 T cell reconstitution might be a cause as well as a consequence of microbial translocation. In arguing against a primary causative role of CD4 T cell depletion, they note the lack of a correlation between CD4 T cell counts and bacterial DNA levels in untreated individuals, and also cite the fact that microbial translocation occurs in conditions such as inflammatory bowel disease that arent associated with loss of CD4 T cells.

While this type of research can seem dauntingly complex, its worth emphasizing that understanding and addressing the causes of poor CD4 T cell reconstitution on ART is critical for improving the care of individuals with HIV infection. As the authors of this paper point out in their introduction, persistently low CD4 T cell counts are associated with signifificant increases in nonAIDS-associated morbidities, including cardiovascular disease, liver disease, cancer, and, perhaps, renal disease. Consequently, there is an urgent need to develop and study therapies that might have the potential to improve CD4 T cell recovery in individuals who remain at risk for clinical illness despite ART-mediated viral suppression. The recent failure of interleukin-2 to provide benefit should not discourage development of approaches with different mechanisms of action, such as enhancement of T cell production by the thymus. Other possible avenues of intervention may include attempting to restore the integrity of the gut wall and/or evaluating anti-inflammatory approaches that aim to reduce the immune activation caused by microbial translocation.

Source: TAG Basic Science Weblog. (06 Mar 2009) http://tagbasicscienceproject.typepad.com

References:

http://tagbasicscienceproject.typepad.com/tags_bas ic_science_vaccin/2008/09/microbial-trans.html
http://www.nature.com/ni/journal/v7/n3/abs/ni1316.html
Jiang W et al. Plasma Levels of Bacterial DNA Correlate with Immune Activation and the Magnitude of Immune Restoration in Persons with Antiretroviral-Treated HIV Infection. JID 2009;199:000000.
http://www.journals.uchicago.edu/doi/abs/10.1086/597476