Immune Activation, HIV Persistence, and the Cure
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Transcript of 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