Microbial translocation and T cell dysfunction in HIV

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  • Absorption from lumen increased (work of George Griffin)
  • Raised plasma LPS levels correlate with monocyte hyporesponsiveness to in vitro LPS stimulation Raised plasma sCD14 indicates chronic in vivo stimulation of monocyte/macrophages by LPS Plasma LPS levels correlate with degree of CD8 T cell activation Plasma LPS levels correlate with pDC stimulation LPS is an indicator of translocation of other microbial products

Transcript

  • 1. Microbial translocation and T cell dysfunction in HIV Jason Brenchley Human Immunology Section Vaccine Research Center, NIH
  • 2. The Acute Phase
    • During acute infection, the primary target for HIV is the majority of the CD4 T cell compartment
    • The majority of CD4 T cells are mucosal
    • The majority of all CD4 T cells are lost during the acute phase
    • Depletion of gut CD4 T cells persists into chronic phase
    • Frequency of infection is very high in gut CD4 T cells in acute AND chronic phases of HIV infection and can explain depletion
  • 3. Question
    • What are the manifestations of gastrointestinal depletion?
      • Why no opportunistic infections until PB CD4+ T cell counts fall?
        • Hrm…..
  • 4. 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
  • 5. Hypothesis
    • Mayhem that occurs to mucosal surfaces after acute infection damages immunological and structural GI barrier allowing intestinal microbial products to cross over to the “other side”
    • Systemic microbes and microbial products stimulate the adaptive and innate immune systems and exacerbate immune activation
      • Microbial translocation
  • 6. Evidence for Increased Gut Permeability Increased gut permeability in HIV + individuals Kotler, D.P., et al. Enteropathy associated with the acquired immunodeficiency syndrome. Ann Intern Med 421-8 1984. Batman, P. A., et al. HIV enteropathy: comparative morphometry of the jejunal mucosa of HIV infected patients resident in the United Kingdom and Uganda. Gut 43:350-5 1998. Griffin, G. E. Malabsorption, malnutrition and HIV disease. Baillieres Clin Gastroenterol 4:361-73 1990. Kapembwa, M. S., et al. Altered small-intestinal permeability associated with diarrhoea in human-immunodeficiency-virus-infected Caucasian and African subjects. Clin Sci (Lond) 81:327-34 1991. Miller, A. R., et al. Jejunal mucosal architecture and fat absorption in male homosexuals infected with human immunodeficiency virus. Q J Med 69:1009-19 1988.
  • 7. Evidence for Microbial Translocation
    • Plasma LPS levels are a quantitative indicator of microbial translocation
    Increased plasma LPS levels in HIV + individuals
  • 8. Evidence for Microbial Translocation
    • Most bacteria contain peptidoglycan in their cell walls
    Increased plasma PPG levels in HIV + individuals
  • 9. Evidence for Microbial Translocation
    • PCR for bacterial 16s DNA in plasma and CSF has been used in the diagnosis of meningococcal infections
    Increased 16S DNA levels in HIV+ individuals
  • 10. Evidence for Microbial Translocation 16s DNA levels correlate with plasma LPS
  • 11. Evidence for Chronic LPS Stimulation
    • LPS-stimulated monocytes secrete sCD14 and shed surface CD14
    Raised plasma sCD14 indicates chronic in vivo stimulation of monocyte/macrophages by LPS
  • 12. Evidence for Chronic LPS Stimulation
    • LPS-stimulated monocytes secrete sCD14 and shed surface CD14
  • 13. The Natural Antibody Response to LPS
    • Naturally occurring neutralizing antibodies against LPS in healthy human plasma
    • In acute microbial translocation EndoCAb bind and clear plasma LPS
    • In chronic microbial translocation EndoCAb increase in response to LPS
    Decreased EndoCAb levels in acute HIV infection Failure to maintain EndoCab response in chronic infection
  • 14. Systemic Immune Activation
    • LPS is an indicator of translocation of other immunostimulatory products
    • Does it correlate with other measures of (non-LPS) immune activation?
    Plasma LPS levels correlate with marker of pDC activation Other immunostimulatory factors apart from LPS Plasma LPS levels correlate with degree of CD8 T cell activation Other factors directly or indirectly stimulating T cells
  • 15. Viral Controllers
    • Some ‘elite controllers’ manifest very low levels of immune activation
    • No obvious immunological association (HLA-B27, 57, 58)
    • Do they have less microbial translocation?
  • 16. Viral Controllers
    • Do viral controllers have evidence of immune activation?
    Elite controllers have higher frequencies of activated T cells compared to uninfected individuals
  • 17. Viral Controllers
    • Are low levels of immune activation detrimental in viral controllers?
    Elite controllers may have slow CD4 T cell depletion that is associated with T cell activation
  • 18. Viral Controllers
    • Is immune activation in controllers associated with microbial translocation?
  • 19. Microbial translocation and HAART HAART results in decreased MT, but it remains significantly elevated compared to unifected individuals
  • 20. Microbial translocation and HAART CD4 reconstitution during HAART is negatively associated with T cell activation
  • 21. Microbial translocation and HAART T cell immune activation is associated with microbial translocation
  • 22. Microbial translocation and HAART CD4 reconstitution during HAART is negatively associated with microbial translocation
  • 23. Microbial Translocation in HIV Infection
    • Massive mucosal CD4 T cell depletion in the acute phase of the infection
    • Increased gut permeability
    • Increased plasma LPS levels indicate microbial translocation
    • Translocated LPS is bioactive in vivo
    • Markers of activation of innate and adaptive immunity correlate with LPS
      • Other bacterial and viral products are likely to be involved
    • Microbial translocation also occurs in elite controllers and this is associated with T cell activation and possibly slow CD4 T cell decline
    • HAART results in slightly reduced microbial translocation and CD4 reconstitution is limited by immune activation which is associated with microbial translocation
    • Microbial translocation is a cause of immune activation in HIV-infected individuals
  • 24. Many Thanks To… VRC Daniel Douek David Price Tedi Asher Srinivas Rao Mario Roederer U. Minn Tim Schacker Ashley Haase CWRU Mike Lederman OHSU Louis Picker UCSF Peter Hunt Steve Deeks U. Penn Guido Silvestri Tulane Cristian Apetrei Ivona Pandreiou H. Bicere Olivier Lambotte