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Microbial Translocation and HIV/SIV Infections

Microbial Translocation and HIV/SIV Infections. Jason Brenchley LMM NIAID, NIH. Immune Activation in Chronic Progressive Infection. Polyclonal B cell activation Increased turnover of T cells Higher frequency of “activated” phenotype T cells

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Microbial Translocation and HIV/SIV Infections

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  1. Microbial Translocation and HIV/SIV Infections Jason Brenchley LMM NIAID, NIH

  2. Immune Activation in Chronic Progressive Infection • Polyclonal B cell activation • Increased turnover of T cells • Higher frequency of “activated” phenotype T cells • Increased levels of circulating cytokines, chemokines and other proinflammatory mediators Strongest predictor of disease progression

  3. What Causes Immune Activation in HIV Infection? • The virus must be involved because HAART reduces immune activation • HIV-specific immune response? • Only a fraction of activated/effector T cells are HIV-specific • Cytokine-induced activation? • Cytokines are the result of immune activation, not the cause • Virus-induced innate immune activation? • Correlation not great, natural SIV infection

  4. The Gut and Immune Activation in HIV Infection “Microbial Translocation” — translocation of gut-derived microbes and/or microbial products to systemic circulation without overt bacteremia — occurs in HIV-infection and correlates with the degree of systemic immune activation It can be measured by plasma lipopolysacharide, and bacterial DNA

  5. Increased plasma LPS levels in HIV+ individuals Evidence for Microbial Translocation • Plasma LPS levels are a quantitative indicator of microbial translocation

  6. Increased 16S DNA levels in HIV+ individuals Evidence for Microbial Translocation • PCR for bacterial 16s DNA in plasma and CSF has been used in the diagnosis of meningococcal infections

  7. Evidence for Microbial Translocation 16s DNA levels correlate with plasma LPS

  8. 10x 20x 40x The Source of LPS LPS Core Chronically SIV-infected rhesus macaque colon

  9. The Source of LPS LPS Core Chronically SIV-infected rhesus macaque colon

  10. Rhesus Macaques: SIV Infection Day 7 Day 14 6 Months Day 1 LPS Apoptosis

  11. The Source of LPS Chronically SIV-infected animals have LPS in the lamina propria

  12. The Source of LPS MesLN I.T.C. LPS Core AxLN 40x

  13. The Source of LPS

  14. Translocation and immune activation Chronically SIV-infected rhesus macaque jejunum

  15. Translocation and immune activation

  16. Assessing damage to the tight epithelial barrier SIV-uninfected rhesus Chronically SIV-infected rhesus

  17. Assessing damage to the tight epithelial barrier

  18. Localization of LPS and breaches

  19. IHC can be used to quantify LPS in lamina propria • Chronically SIV-infected RM have lots of it! • LPS can also be found in draining and peripheral lymph nodes of chronically SIV-infected rhesus macaques • The mechanism underlying translocation appears to involve breakdown of the tight epithelial barrier • Infiltration of microbial products associated with local immune activation • Microbial translocation is a cause of immune activation in HIV infection Summary

  20. Many Thanks To… LMM Levelle Harris Nichole Klatt UCDavis Chris Miller NCI Jake Estes Jeff Lifson VRC Danny Douek UMinn Ashley Haase

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