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

HIV & Immune Activation 2HIV Research Catalyst Forum, April

HIV & Immune Activation 3 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

Correlation between viral load and levels of CD8 T cells expressing CD38. Chun T et al. PNAS 2004;101: ©2004 by National Academy of Sciences 4HIV Research Catalyst Forum, April

Immune Activation Linked to Inflammation 5 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

6 Priscilla Hsue, CROI 2010

Inflammatory Markers Linked to Poor Health Outcomes 7 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) HIV Research Catalyst Forum, April

Antiretroviral Therapy Does Not Always Lower Inflammation to Background Levels 8 Steve Deeks, IBT Workshop 2/20/2010 HIV Research Catalyst Forum, April

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 9HIV Research Catalyst Forum, April

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 10HIV Research Catalyst Forum, April

“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) 11HIV Research Catalyst Forum, April

12HIV Research Catalyst Forum, April

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) 13HIV Research Catalyst Forum, April

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? 14HIV Research Catalyst Forum, April

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 15HIV Research Catalyst Forum, April Steve Deeks, IBT Workshop 2/20/2010