T-Cell Senescence & Inflammation HIV Research Catalyst Forum, April 21 2010 1

T-Cell Senescence & Inflammation

HIV Research Catalyst Forum, April 21 2010

1HIV Research Catalyst Forum, April 21 2010

HIV & Immune Activation


HIV & Immune Activation

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• 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


Correlation between viral load and levels of CD8 T cells expressing CD38.

Chun T et al. PNAS 2004;101:2464-2469

©2004 by National Academy of Sciences4HIV Research Catalyst Forum, April 21 2010

Immune Activation Linked to Inflammation

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• 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



Priscilla Hsue, CROI 2010

Inflammatory Markers Linked to Poor Health Outcomes

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• 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)


Antiretroviral Therapy Does Not Always Lower Inflammation to Background Levels

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HIV Negative Untreated HAART0

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60

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Steve Deeks, IBT Workshop 2/20/2010


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


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


“Immune Risk Profile”• Described in Swedish cohort studies of HIV-

uninfected 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)



Research Implications• Delineating who is at greatest risk, monitoring tools

(which biomarkers?)• Impact of earlier viral load suppression (START trial)• Anti-inflammatory approaches

– 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)


Research Implications

• Enhancing T cell renewal: growth hormone, IL-7, 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?


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:– 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

Documents

T-Cell Senescence & Inflammation HIV Research Catalyst Forum, April 21 2010 1