Introduction to iCRL and HIVDR

The role of innate immunity in the pathogenesis of Serious Non-AIDS Events

Suzanne CroweAssociate Director, Burnet InstituteConsultant Infectious Diseases Physician, The Alfred HospitalMelbourne1Todays presentationHIV, LPS trigger inflammationContribution of monocyte activationPro-inflammatory cytokinesInvolvement of innate immune pathways inFibrosisAtherosclerotic plaque formationPro-coagulant activityMetabolic dysregulationImmune senescenceSerious non-AIDS EventsHow HIV & inflammation are linkedHow breaches in gut mucosa trigger inflammationLinks between monocytemetabolism &inflammationHow monocyte activationImpacts these pathwaysInnate immune senescence& risk of events---Today I have been asked to talk about the contribution of one aspect of the immune system, innate immunity, to the development of serious non-AIDS events

Ill cover how HIV and inflammation are linkedHow HIV disrupts the gut mucosa and triggers the production of pro inflammatory cytokines that predict SNAEs

How monocyte activation contributes to these innate immune, pathwaysIncluding links between altered metabolism in monocytes and inflammation

And lastly Ill mention the contribution of innate immune senescence, to SNAEs. .But note that these arrows are only dotted

2Todays presentationHIV, LPS trigger inflammationContribution of monocyte activationPro-inflammatory cytokinesInvolvement of innate immune pathways inFibrosisAtherosclerotic plaque formationPro-coagulant activityMetabolic dysregulationImmune senescenceSerious non-AIDS EventsAnd there are huge gaps in what we know about how these pathways loop back and intersect

3Chronic inflammation and immune activationChronic immune activation & inflammation is central to HIV pathogenesisIn both treated and untreated individuals Starts during seroconversion

Pro-inflammatory pathways triggered byHIV replication and viremiaCo-infection eg with CMVMicrobial translocation across the gut mucosa

Chronic immune activation and inflammation are central to HIV pathogenesis, both playing a pivotal role in both untreated and treated individuals.

This starts very early, in fact during seroconversion

4 Stacey et al J Virol 2009 83:3719-3733Intense cytokine storm in acute HIV infection prior to peak viremiaCytokine response in acute HIV Stacey 2009

Changes in plasma cytokine levels Time since HIV infection (days)When there is an intense cytokine storm, with high plasma levels of a range of proinflammatory cytokines including IL12, IL18 and TNFaccompanied by intense T cell activation

5T cell immune activation declines during suppressive ART

Hunt et al, JID, 2003; PLoS One, 2011T cell activation, shown here on CD8+ T cells, declines dramatically in patients on suppressive ART

6But T cell activation remains elevated during suppressive ART

Hunt et al, JID, 2003; PLoS One, 2011But remains still significantly higher that in uninfected controls7What about Innate immunity and pro-inflammatory pathways?

8What is meant by pro-inflammatory pathways?

Activation of cells eg monocytes & m that produce pro-inflammatory cytokines

Pro-inflammatory cytokines include IL-6, TNF-alpha

Chronic inflammation leads to fibrosis and end-organ diseaseR Medzhitov Cell 2010; 140:771When we talk about pro-inflammatory pathways we are referring to monocyte activation in particular that produces cytokines capable of promoting inflammation such as IL-6 and TNF. Uncontrolled chronic inflammation leads to fibrosis and organ damage.

9Differing pathogenetic roles of T cells & monocytes in HIV infectionT cell activation Main effect: Central role in T cell decline

Monocyte activationMain effect: Central role in chronic inflammation

Important in pathogenesis of longer-term, non-AIDS morbidity

CD16+ pro-inflammatory monocytes increased in HIV & only partly normalized by cART

Westhorpe C et al Immunol & Cell Biol 2014;92:1338; 2.Tenorio AR et al J Infect Dis 2014; 3. Lederman MM et al Adv Immunol 2013; 11951; 4. Sandler &Sereti Curr Opin HIV AIDS 2014;9:72T cell activation is most relevant to HIV pathogenesis in untreated patients where it is tightly linked with T cell death and decline

Monocytes contribute more to the pathogenesis of longer term non-AIDS complications that are associated with chronic inflammation

The proportion of CD16+ monocytes increases in the blood with HIV and is only partly restored to normal levels with ART

CD11b and CX3CR1 independently predicted cIMT in HIV+, after controlling for Framingham risk score: imporrtant role for monocyte activaoin in CVD oathogenesis

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increase with inflammation [pro-inflammatory] CD16-positive monocytesclassical CD14++CD16- monocytesCD14+CD16++ non-classicalCD14++CD16+ intermediate

7-10%5-8%85%monocyte subsets are classified based on their expression of CD16 and CD14

CD16+ monocytes are a minor monocyte population, generally considered to be pro-inflammatoryThey are further subdivided into non classical and intermediate subsets11

Traditional Inflammatory Patrolling 1. Funderburg NT et al Blood 2012 120: 45992. Krishnan S et al J Infect Dis 2014; 209:931CD16+ monocyte subsets are increased in uncontrolled viremia & may normalize with ARTCD14++CD16-

ClassicalCD14++ CD16+

IntermediateCD14+CD16++

Non classicalHIV infection increases the proportions of CD16+ monocytes in blood

cART restores the proportions of monocytes in blood1

CD16+ monocytes remain elevated in elite controllers2HIV- HIV+ VL400HIV increases the proportion of CD16+ monocytes in the blood (shown in green)

In this study from the Lederman lab ART restored the proportions of monocytes

However patient populations differ

For example CD16+ monocytes remain elevated in elite controllers.

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Hearps, A, Angelovich T et al unpublished data 2014; Lichtfuss G et al., J Immunol 2012;189:149 ; Hearps A et al AIDS 2012;24:843; Martin G et al PLoSOne 2013;8:e55279l Pro-inflammatory CD14++CD16+ monocytes remain expanded despite cART & virologic suppressionHIV-HIV+And further, Data from our lab at Burnet suggest that the proinflammatory monocytes can remain expanded despite ART and virologic suppression 13

IntermediateNon-ClassicalClassicalAngelovich T et al 2014 unpublished data 2014Elevated levels of intracellular proinflammatory cytokines IL-6 & TNF in monocytes from HIV+ ptsIL-6TNFHIV- HIV+ VL