immune activation, hiv persistence, and the cure

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From DC Douek, MD, at San Francisco, CA: March 24, 2013, IAS-USA. IAS–USA

Daniel C. Douek, MD, PhDBethesda, Maryland

Immune Activation, HIV Persistence, and the Cure

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From DC Douek, MD, at San Francisco, CA: March 24, 2013, IAS-USA.

What We Talk About When We Talk About Immune Activation

Normal innate response to viral infection in the acute phase of the infection

A.R. Stacey et al JV 2009

Virus loadCytokine

Immune activation occurs early in infection

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• Cells: activated phenotype of Macrophages and Dendritic Cells

• Cytokines, chemokines: TNF, IL-1, IL-6, IL-8, IL-15, IL-10• Acute phase proteins: Serum Amyloid A, C-Reactive Protein

• Coagulation: D-dimers, Tissue Factor

• Fibrosis: Matrix Metalloprotease activation, collagen deposition• Microbial sensors: Lipopolysaccharide Binding Protein, soluble CD14

Innate

As viral load decreases, immune activation persists

• T cells: increased turnover, exhaustion, low thymic output, virus reservoir

• B cells: increased turnover, altered phenotypic profile, hyper-Ig-emia

Frequency of activated T cells is a strong predictor of disease progression

Adaptive

What We Talk About When We Talk About Immune Activation

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Causes Of Chronic Immune Activation• Raised cytokine and chemokine levels are a consequence of

immune activation• HIV-induced activation of innate immune system (N. Bhardwaj)

–When virus load decreases after acute phase, immune activation remains elevated

– Virus load alone is a poor predictor of disease progression (Rodriguez JAMA 2006)

–Measures of immune activation predict disease progression independent of viral load (Giorgi, Deeks...)

– Elite controllers who progress have increased activated CD38+ T cells (Hunt JID 2008)

–When virus load is suppressed with ART immune activation still persists and predicts progression

• Increased antigen load, bacterial overgrowth, herpes viruses (S. Deeks, P. Hunt)

• Translocation of proinflammatory mediators across mucosae

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Consequences of HIV Infection in GI Tract

Healthy Gut•Tight epithelial junctions, mucus•Anti-microbial peptides, Abs, cells•Majority of CD4 T cells in body•Cross-talk between microbes and epithelial cells and immune cells

Mucus

HIV-Infected Gut•Massive loss of CD4 T cells•Enteropathy•2-10x increased permeability•Translocation of microbial products•Systemic immune activation

CD4 T cell loss

Loss of tight junctions

Enterocyte apoptosisMicrobial products

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HIV

immune activation

gut

CD4 depletionenteropathy

Tcm

Tcm

TemTemTem

Tem

gut

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HIV

immune activation

gut


Tcm

Tem

Tem

CMV

low thymic outputLT fibrosis

T/B cell dysfunction

inflammationtissue damagecoagulopathy

non-AIDS morbidity and mortality

immune deficiency

???

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Tcm

Tem

gut

Tcm

Tem

Tem





immune deficiency

CMV

???

HIV


ARTimmune

activation

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T cell activation declines during long-term ART, but remains elevated, even after many years of viral suppression

Hunt, et al. J Infect Dis. 2003, 2008 and unpublished observations

ART and T Cell Immune Activation

HIV –(n=132)

HIV +HAART(n=65)

HIV +Untreated

(n=82)

0

20

40

60

80

% C

D38

+ DR

+ CD

8 T

cells P<0.001

P<0.001

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Hunt, CROI 2012SOCA/SCOPE cohorts

Markers of Inflammation and GI Dysfunction Predict Mortality

Odds of Mortality (4th vs 1st Quartile)

Markers of inflammation and gut barrier dysfunction predict mortality independently of CD4 count and virus load

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ART, Immune Activation and CD4 T Cell Recovery

Reduced CD4 T cell recovery associated with immune activation

Hunt, et al. J Infect Dis. 2003 and unpublished observations

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When Immune Activation Turns To The Dark SideGood

• Anti-viral innate immune response

• Restoration of memory CD4 T cells

Bad

• Target cell generation

• HIV replication

• Thymic dysfunction

• T and B cell exhaustion

• Macrophage/DC activation

• Cytokine/Chemokine secretion

• Lymph node fibrosis

• Generalized tissue fibrosis

• Coagulation cascade activation

• … … …

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P < 0.0001

P = 0.060

P < 0.0001

P = 0.266

P = 0.010

Llibre, Buzón, Massanella et al. Antiv Ther 2011

%C

D38

+ mem

ory

CD

8 T

cells

ControlIntensified

Raltegravir intensification reduces immune activation significantly more than conventional therapy

Raltegravir Intensification

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Raltegravir intensification in 9 subjects resulted in decrease in IUPM and CD8 T cell activation

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No association between plasma measures of viral persistence and T cell activation in blood


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Hunt, Yukl and Wong

Virus and Immune Activation in Tissues

Stronger association between cell-based measures of viral persistence and T cell activation in gut tissues

r = 0.65 P = 0.012

Sheth, Muc Imm 2012

Raltegravir intensification reduces immune activation and HIV RNA levels in gut tissue sites

Virus and Immune Activation in TissuesSlide 17 of 36

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• Evidence against ongoing HIV replication on ART

• Increasing evidence in favor of ongoing replication

• Evidence it is associated with immune activation

• The source of the sample is key (blood vs tissues)

• The assay used to measure virus is critical

Ongoing HIV Replication During ART?

Although complete inhibition of viral replication is unlikely to be curative, all cure strategies are based on first having achieved complete suppression

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Saez-Cirion et al, in press

14 subjects who started therapy very early after infectionThey remained on cART for many years and then therapy was stopped

HIV

-DN

A (lo

g 10 c

opie

s/10

6 PB

MC

)

Acute Chronic cART EliteControllers

Post-Rx Controllers

1

2

3

4

5

6

VISCONTI — Activation and Reservoir

PTC did not rebound when cART was stopped Like elite controllers they had low cell-associated HIV DNABut, in contrast, they had very low T cell activation

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On suppressive ART, strong HIV specific T cell responses in the gut mucosa are associated with lower levels of PBMC viral DNA

0 1 2

0.0

0.5

1.0

log10 Proviral DNA(per mil PBMC)

% G

ag-s

peci

fic IF

Ng+

IL2+

CD

8+ T

cel

ls (G

ALT

)

r = - 0.56, P = 0.01

CD4CD8

r = - 0.37, P = 0.12

Hatano JID 2011

HIV-Specific Immunity and HIV Persistence

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Tcm

Tem

gut

Tcm

Tem

Tem





immune deficiency

CMV

???

ARTTem

immune activation

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immune activation

low thymic outputlymphoid fibrosis

poor CD4 T cell renewalT/B cell dysfunctionmucosal damage

target cell generationinfected cell proliferation

virus transcriptionvirus production

new infection events

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• Chemokine receptor inhibitors:– maraviroc, TB-652

• Anti-infective therapy:– CMV, EBV, HSV, HCV/HBV

• Microbial translocation:– sevelamer, colostrum, rifaximin

• Enhance T cell renewal:– Growth Hormone, IL-7

• Anti-fibrotic drugs:– pirfenidone, ACEi, ARBs, KGF

• Anti-aging:– caloric restriction, sirtuin activators,

vitamin D, omega-3 fatty acids, rapamycin, diet, exercise

• Anti-inflammatory drugs:– Chloroquine, HCQ– Minocycline– NSAIDs (COX-2i, aspirin)– Statins– Methotrexate– Thalidomide, lenalidomide,

pentoxyfylline (weak TNF inhibitors)– Biologics (e.g., TNF inhibitors, IL-6

inhibitors, anti-IFNa, anti-PD1

• Anti-coagulants:- low dose warfarin, dabigatran,

aspirin, clopidogrel

Combination therapy may be necessary

Therapeutic Interventions in Development

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• Multiple mechanisms account for HIV persistence, all of which are being addressed therapeutically

• The unifying theme is to reduce HIV reservoir size– Reduce inflammation– Increase immune function– Early ART and ART intensification– Gene therapy to reduce reservoir size– Stem cell transplants can reduce reservoir size– Drugs with biologic activity against latent virus exist– Vaccines may enhance host-clearance mechanisms

In The Context of The Cure

Combination therapy may be necessary

immune activation, hiv persistence, and the cure

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