Immune Activation, HIV Persistence, and the Cure

Slide 1 of 10

From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA. IAS–USA

Daniel C. Douek, MD, PhDBethesda, Maryland

Immune Activation, HIV Persistence, and the Cure

From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

Slide 2 of 10

From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

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

Slide 3 of 10

From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

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

Slide 4 of 10

From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

Tcm

Tem

gut

Tcm

Tem

Tem

low thymic outputLT fibrosis

T/B cell dysfunction

inflammationtissue damagecoagulopathy

non-AIDS morbidity and mortality

immune deficiency

CMV

???

HIV

CD4 depletionenteropathy

ARTimmune

activation

Slide 5 of 10

From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

• 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

Slide 6 of 10

From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

HIV-Specific Immunity and HIV Persistence

Immune activation adversely affects HIV-specific T cell responses

Immune activation adversely affects CD4 T cell immune reconstitution

What is relationship between HIV-specific T cell immunity and the HIV reservoir?

Slide 7 of 10

From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

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

Slide 8 of 10

From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

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

Slide 9 of 10

From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

• 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

Slide 10 of 10

From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

• 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