Microbial translocation and T cell

dysfunction in HIV

Jason BrenchleyHuman Immunology SectionVaccine Research Center, NIH

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

Question

• What are the manifestations of gastrointestinal depletion?

– Why no opportunistic infections until PB CD4+ T cell counts fall?

• Hrm…..

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

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

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.

Evidence for Microbial Translocation•Plasma LPS levels are a quantitative indicator of microbial translocation

Increased plasma LPS levels in HIV+ individuals

Increased plasma PPG levels in HIV+ individuals

Evidence for Microbial Translocation•Most bacteria contain peptidoglycan in their cell walls

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

16s DNA levels correlate with plasma LPS

Evidence for Microbial Translocation

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

Evidence for Chronic LPS Stimulation•LPS-stimulated monocytes secrete sCD14 and shed surface CD14

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 infectionFailure to maintain EndoCab response in chronic infection

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 activationOther immunostimulatory factors apart from LPS

Plasma LPS levels correlate with degree of CD8 T cell activationOther factors directly or indirectly stimulating T cells

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?

Viral Controllers•Do viral controllers have evidence of immune activation?

Elite controllers have higher frequencies of activated T cells compared to uninfected individuals

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

Viral Controllers•Is immune activation in controllers associated with microbial

translocation?

Microbial translocation and HAART

HAART results in decreased MT, but it remains significantly elevated compared to unifected individuals

Microbial translocation and HAART

CD4 reconstitution during HAART is negatively associated with T cell activation

Microbial translocation and HAART

T cell immune activation is associated with microbial translocation

Microbial translocation and HAART

CD4 reconstitution during HAART is negatively associated with microbial translocation

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

Many Thanks To…VRCDaniel DouekDavid PriceTedi AsherSrinivas RaoMario Roederer

U. MinnTim SchackerAshley Haase

CWRUMike Lederman

OHSULouis Picker

UCSFPeter HuntSteve Deeks

U. PennGuido Silvestri

TulaneCristian ApetreiIvona PandreiouH. Bicere

Olivier Lambotte