Over the years, a number of small studies have been published suggesting that there might be benefits associated with probiotic and/or prebiotic supplementation in people with HIV infection. Probiotics typically comprise live microbes that play a key role in maintaining gut health—commonly known as “good bacteria”—while prebiotics are food ingredients intended to stimulate the expansion and activity of these bacteria. The past decade has seen a renewed interest in gut health in HIV infection due to evidence that the virus severely depletes CD4 T cells in the GI tract, leading to diminished immune surveillance, compromised gut-wall integrity, and microbial translocation (the leakage of gut bacteria into the systemic circulation). Additionally, suppression of HIV replication by antiretroviral therapy (ART) does not necessarily restore gut CD4 T-cell numbers, and markers of microbial translocation have been associated with poor immune reconstitution despite ART.
To try to address the question of whether a combination of probiotics and prebiotics (referred to as synbiotic treatment) might serve as a useful adjunct to ART, Nichole Klatt and colleagues conducted a study in the animal model of SIV-infected pigtailed macaques. The results are published in the February issue of the Journal of Clinical Investigation. The researchers report that, compared to ART alone, adjunctive synbiotic treatment (the specific products used were VSL#3 and Culturelle) had positive effects on gut CD4 T cells and antigen-presenting cells, and also reduced fibrosis in local lymph tissue. The results appear encouraging, and were discussed in further detail at the recent CROI by senior author Jason Brenchley (the third talk in the symposium entitled Is Something Bugging You?).
Something that isn’t mentioned in the JCI paper, or addressed directly in Brenchley’s talk, is that previous work from this research group has shown that gut integrity in pigtailed macaques is unusually compromised even in uninfected animals; in a separate new paper published in the March 15 issue of the Journal of Immunology, they show that this correlates with the faster progression to AIDS that occurs in this monkey species. On the one hand, this may make pigtailed macaques a useful worst-case scenario in terms of modeling the contribution of microbial translocation to HIV pathogenesis and studying interventions like probiotics, but, on the other hand, the extent to which findings from this extreme situation can be extrapolated to humans is as yet unclear.
Available published data on synbiotic treatment in people with HIV appear limited, either involving individuals not on ART or on very short-term follow-up. As far as I can discern from a PubMed search, no trials have used the specific combination of VSL#3 and Culturelle. Currently, clinicaltrials.gov lists one open clinical trial of the probiotic Biola that is enrolling individuals both on and off ART; study sites are limited to Oslo, Norway, and Stockholm, Sweden. According to U.S.-based researchers, there are plans afoot to conduct a randomized, controlled clinical trial to assess whether the promising results from the Brenchley laboratory can be translated to humans with HIV infection.
Published in Volume 123, Issue 2 (February 1, 2013)
J Clin Invest. 2013;123(2):903–907. doi:10.1172/JCI66227.
Nichole R. Klatt1, Lauren A. Canary1, Xiaoyong Sun2, Carol L. Vinton1, Nicholas T. Funderburg3, David R. Morcock4, Mariam Quiñones1, Clayton B. Deming5, Molly Perkins1, Daria J. Hazuda6, Michael D. Miller7, Michael M. Lederman3, Julie A. Segre5, Jeffrey D. Lifson4, Elias K. Haddad2, Jacob D. Estes4 and Jason M. Brenchley1
1National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2VGTI-Florida, Port St. Lucie, Florida, USA.
3Division of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio, USA.
4SAIC Frederick Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
5National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.
6Merck Research Labs, West Point, Pennsylvania, USA.
7Gilead Sciences Inc., Foster City, California, USA.
HIV infection results in gastrointestinal (GI) tract damage, microbial translocation, and immune activation, which are not completely ameliorated with suppression of viremia by antiretroviral (ARV) therapy. Furthermore, increased morbidity and mortality of ARV-treated HIV-infected individuals is associated with these dysfunctions. Thus, to enhance GI tract physiology, we treated SIV-infected pigtail macaques with ARVs, probiotics, and prebiotics or with ARVs alone. This synbiotic treatment resulted in increased frequency and functionality of GI tract APCs, enhanced reconstitution and functionality of CD4+ T cells, and reduced fibrosis of lymphoid follicles in the colon. Thus, ARV synbiotic supplementation in HIV-infected individuals may improve GI tract immunity and thereby mitigate inflammatory sequelae, ultimately improving prognosis.
The Journal of Immunology, March 15, 2013, vol. 190 no. 6 2959-2965
Lauren A. Canary*, Carol L. Vinton*, David R. Morcock†, Jordan B. Pierce*, Jacob D. Estes†, Jason M. Brenchley* and Nichole R. Klatt*,‡
*Laboratory of Molecular Microbiology, Program in Barrier Immunity and Repair, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
†AIDS and Cancer and Virus Program, Science Applications International Corporation-Frederick, Frederick National Laboratory for Cancer Research, Frederick, MD 21702; and
‡Department of Pharmaceutics, Washington National Primate Research Center, University of Washington, Seattle, WA 98121
During HIV/SIV infection, mucosal immune system dysfunction and systemic immune activation are associated with progression to AIDS; however, it is unclear to what extent pre-existing gastrointestinal damage relates to disease progression postinfection. Pigtail macaques (PTM) are an excellent model in which to assess mucosal dysfunction in relation to HIV/SIV pathogenesis, as the majority of these animals have high levels of gastrointestinal damage, immune activation, and microbial translocation prior to infection, and rapidly progress to AIDS upon SIV infection. In this study, we characterized the mucosal immune environment prior to and throughout SIV infection in 13 uninfected PTM and 9 SIV-infected PTM, of which 3 were slow progressors. This small subset of slow progressors had limited innate immune activation in mucosal tissues in the periphery, which was associated with a more intact colonic epithelial barrier. Furthermore, we found that preinfection levels of microbial translocation, as measured by LPS-binding protein, in PTM correlated with the rate of progression to AIDS. These data suggest that pre-existing levels of microbial translocation and gastrointestinal tract dysfunction may influence the rate of HIV disease progression.