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Microbial translocation is a cause of systemic immune activation in chronic HIV infection

Nature Medicine volume 12, pages 1365–1371 (2006)Cite this article

Abstract

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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Figure 1: Gastrointestinal tract damage and microbial translocation in HIV infection.
Figure 2: Chronic LPS stimulation in vivo.
Figure 3: Microbial translocation contributes to chronic innate and adaptive immune activation.
Figure 4: Differences in microbial translocation in nonprogressive HIV infection and nonpathogenic SIV infection.

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Acknowledgements

We would like to thank G. Barclay for information on the origins of EndoCab. The authors would like to acknowledge the Bad Boys of Cleveland (BBC), J. Spritzler, R. Seder and R. Koup for advice and discussion. This study was supported by grants from the US National Institutes of Health (AI 25879, AI 38858 and AI 36219 to M.M.L.; ROI AI052755 and AI066998 to G.S.; and AI052745, AI41531, P30 AI27763, P30 MH62246 and MO1-RR0083-37 to the UCSF cohort study) and the Yerkes Primate Center (RR-00165 to G.S.). O.L. is supported by grants from the French National Agency for Research on Aids and Viral Hepatitis (ANRS) and is a member of the ANRS EP36 study group. D.A.P. is a Senior Clinical Fellow of the Medical Research Council (UK). This research was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health.

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Authors and Affiliations

  1. Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Jason M Brenchley, David A Price, Tedi E Asher, Zachary Kazzaz, Ethan Bornstein & Daniel C Douek

  2. Department of Medicine, University of Minnesota, Minneapolis, 55455, Minnesota, USA

    Timothy W Schacker

  3. Department of Pathology, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Guido Silvestri

  4. Laboratory of Animal Medicine, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Srinivas Rao

  5. University Hospital of Bicêtre, Bicêtre, 94 276, France

    Olivier Lambotte

  6. Department of Infectious Diseases, Hammersmith Hospital, Imperial College London, London, W12 ONN, UK

    Daniel Altmann

  7. Department of Pediatrics, Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Minnesota, Minneapolis, 55455, Minnesota, USA

    Bruce R Blazar

  8. Case Western Reserve University and University Hospitals of Cleveland, Cleveland, 44016, Ohio, USA

    Benigno Rodriguez, Leia Teixeira-Johnson & Michael M Lederman

  9. Department of Immunology and Microbiology, Rush Medical College, Chicago, 60612, Illinois, USA

    Alan Landay

  10. University of California at San Francisco, San Francisco, 90210, California, USA

    Jeffrey N Martin, Frederick M Hecht & Steven G Deeks

  11. Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, 97006, Oregon, USA

    Louis J Picker

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Contributions

J.M.B., D.A.P., T.E.A., Z.K., E.B., D.A. and D.C.D. conducted the in vitro experiments; J.M.B. and D.C.D conducted the data analyses; T.W.S., O.L., B.R., L.T.-J., A.L., J.N.M., F.M.H., M.M.L. and S.G.D. procured samples and recruited subjects for the human clinical studies; G.S., S.R. and L.J.P. led the studies in SIV-infected monkeys. All authors contributed to the project's planning and writing of the manuscript; D.C.D. supervised the project.

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Correspondence to Daniel C Douek.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Plasma LBP and sCD14 levels. (PDF 89 kb)

Supplementary Fig. 2

Stimulation of PBMC from uninfected individuals with plasma from HIV-infected and uninfected individuals. (PDF 176 kb)

Supplementary Fig. 3

EndoCAb and plasma LPS in controllers. (PDF 544 kb)

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Brenchley, J., Price, D., Schacker, T. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12, 1365–1371 (2006). https://doi.org/10.1038/nm1511

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