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Immune Activation, HIV
Persistence, and the Cure
Daniel C. Douek, MD, PhD
Bethesda, Maryland
From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
IAS–USA
Slide 2 of 10
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
From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 3 of 10
Consequences of HIV Infection in GI Tract
Loss of tight junctions
Mucus
CD4 T cell loss
Microbial products
Enterocyte apoptosis
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
HIV-Infected Gut
•Massive loss of CD4 T cells
•Enteropathy
•2-10x increased permeability
•Translocation of microbial products
•Systemic immune activation
From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 4 of 10
immune deficiency
gut
CD4 depletion
enteropathy
ART
HIV
Tem Tem
immune
activation
Tcm
Tem Tcm
low thymic output
LT fibrosis
T/B cell dysfunction
inflammation
non-AIDS morbidity
tissue damage
and
mortality
coagulopathy
From DC Douek, MD, at Atlanta, GA: April 10,
2013, IAS-USA.
CMV
???
Slide 5 of 10
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
• 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
From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 6 of 10
HIV-Specific Immunity and HIV Persistence
Immune activation adversely affects HIVspecific 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?
From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 7 of 10
CD8
1.0
r = - 0.56, P = 0.01
0.5
0.0
0
1
2
% Gag-specific IFNg+ IL2+
CD4+ T cells (GALT)
% Gag-specific IFNg+ IL2+
CD8+ T cells (GALT)
HIV-Specific Immunity and HIV Persistence
CD4
6
r = - 0.37, P = 0.12
5
4
3
2
1
0
0
log10 Proviral DNA
(per mil PBMC)
1
2
log10 Proviral DNA
(per mil PBMC)
Hatano JID 2011
On suppressive ART, strong HIV specific T cell responses in the
gut mucosa are associated with lower levels of PBMC viral DNA
From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 8 of 10
target cell generation
infected cell proliferation
virus transcription
virus production
low thymic output
immune
activation
new infection events
From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
lymphoid fibrosis
poor CD4 T cell renewal
T/B cell dysfunction
mucosal damage
Slide 9 of 10
Therapeutic Interventions in Development
• Chemokine receptor inhibitors: • Anti-inflammatory drugs:
– 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
–
–
–
–
–
–
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
From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 10 of 10
In The Context of The Cure
• 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
Combination therapy may be necessary
From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.