T-Cell Senescence &
Inflammation
HIV Research Catalyst Forum, April 21
2010
HIV Research Catalyst Forum, April 21 2010
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HIV & Immune Activation
HIV Research Catalyst Forum, April 21 2010
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HIV & Immune Activation
• Multiple components of the immune system
battle HIV, as with other infections
• After acute HIV infection, immune system
remains persistently activated in most people
• The T10 marker is now called CD38 and is used to
measure immune activation
• Levels of CD38 measured on immune cells called
CD8 T cells correlate with pace of disease
progression & viral load
HIV Research Catalyst Forum, April 21 2010
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Correlation between viral load and levels of CD8 T cells expressing CD38.
Chun T et al. PNAS 2004;101:2464-2469
HIV Research Catalyst Forum, April 21 2010
©2004 by National Academy of Sciences
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Immune Activation Linked to Inflammation
• Ongoing activation of immune cells causes
release of inflammation-promoting cytokines e.g.
interleukin-6, tumor necrosis factor (TNF)-alpha,
type 1 interferons
• Inflammatory damage to lymph nodes (fibrosis)
• Additional biological markers of inflammation
such as C-reactive protein (CRP), fibrinogen and
D-dimer can be elevated
HIV Research Catalyst Forum, April 21 2010
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Priscilla Hsue, CROI 2010
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Inflammatory Markers Linked to Poor
Health Outcomes
• IL-6, D-dimer & CRP associated with illness, frailty &
mortality in the elderly (“inflammaging”)
• IL-6 & D-dimer levels strongly associated with mortality
in the Strategies for the Management of AntiRetroviral
Therapy (SMART) Trial (Kuller PLoS Med 2008)
• IL-6 & CRP strongly associated with opportunistic disease
in SMART (Rodger J Infect Dis. 2009)
• Elevated levels of fibrinogen and CRP strong independent
predictors or mortality in the FRAM study (922 HIV+ men
& women from 16 US centers) (Tien CROI 2010)
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Antiretroviral Therapy Does Not Always
Lower Inflammation to Background Levels
Inflammation
100
80
60
40
20
0
HIV Negative
Untreated
HAART
Steve Deeks, IBT Workshop 2/20/2010
HIV Research Catalyst Forum, April 21 2010
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Factors Associated with Persistent
Inflammation on ART
• Low CD4 T cell nadir
• Leakage of normally “friendly” gut bacteria
into the systemic circulation (microbial
translocation)
• Persistent HIV replication
• Co-infections (CMV, hepatitis)
• Senescent (worn-out) T cells
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Senescent T cells
• Every time a cell divides protective caps on the end of
chromosomes called telomeres get shorter (frequent
analogy is to protective caps on the ends of shoelaces)
• Both CD4 & CD8 T cells can reach a division limit called
replicative senescence associated with shortened
telomeres, loss of expression of a surface molecule called
CD28
• CD28- CD8 T cells are resistant to cell death (apoptosis)
and produce high levels of pro-inflammatory cytokines
• Higher levels of CD28- CD8 T cells are associated with
illness & mortality in the very elderly
HIV Research Catalyst Forum, April 21 2010
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“Immune Risk Profile”
• Described in Swedish cohort studies of HIVuninfected individuals over 80 years old
• Inverted CD4/CD8 T cell ratio
• Reduced naïve T cell numbers
• Reduced T cell proliferation and IL-2 production
• Increased proportion of CD28- CD8 T cells
• CMV+, increased numbers of CMV-specific CD8 T
cells
• Increased pro-inflammatory cytokines (IL-6)
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HIV Research Catalyst Forum, April 21 2010
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Research Implications
• Delineating who is at greatest risk, monitoring tools
(which biomarkers?)
• Impact of earlier viral load suppression (START trial)
• Anti-inflammatory approaches
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Chloroquine
CCR5 inhibitors
NSAIDs (COX-2 inhibitors)
Microbial translocation (sevelamer, colostrum)
Residual HIV replication (ART intensification)
Statins
Anti-fibrosis treatments
Aspirin, pentoxifylline (impact on arterial health & inflammation)
HIV Research Catalyst Forum, April 21 2010
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Research Implications
• Enhancing T cell renewal: growth hormone, IL7, perfenidone (antifibrotic), lupron, TXA127
• Anti-aging approaches: Caloric restriction,
sirtuin activators (resveratrol), vitamin D,
omega-3 fatty acids, rapamycin
• Dealing with senescent T cells
– Physical removal?
– Telomerase induction to repair telomeres?
HIV Research Catalyst Forum, April 21 2010
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The Vitamin D and Omega-3 Trial (VITAL)
• 20,000 U.S. men and women over the age of 60 (men) or
65 (women) who have not had significant coronary artery
disease (CAD) or cancer
• Randomized to one of four arms:
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Placebo
Vitamin D (~2000 IU)
Omega-3 fatty acids (1 gram)
Vitamin D plus omega-2 fatty acids
• Outcomes: CAD, stroke, cancer
• Study initiation: January 2010
• Duration of follow up: 5-7 years
Steve Deeks, IBT Workshop 2/20/2010
HIV Research Catalyst Forum, April 21 2010
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