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Coagulation and Morbidity in Treated HIV Infection
Michael M. Lederman, MD Scott R. Inkley Professor of Medicine
Case Western Reserve University
Although survival has improved, predicted life expectancy still seems shorter in the HIV+ population
Adapted from Lohse N, et al. Ann Intern Med 2007;146:87–95
Prob
abilit
y of S
urviv
al
Pre-HAART (1995–1996)
Early HAART (1997–1999)
Survival from Age 25 Years N= 3,990 1
0.75
0.5
0.25
0
25 30 35 40 45 50 55 60 65 70
Age, years
Late HAART (2000–2005)
Population controls
Many Age-associated Diseases Are More Common in Treated HIV Disease Than In Age-matched Uninfected Persons
• Cardiovascular disease
• Cancer (non-AIDS) • Bone fractures/osteopenia
• Left ventricular dysfunction • Lung Disease • Liver failure • Kidney failure
• Cognitive decline
• Frailty
Multiple factors likely explain this increased risk, including co-morbid conditions, other exposures, ARV drug toxicity
S. Deeks
Inflammation/coagulation predicts morbidity/mortality in HIV infection
in “SMART” • Interleukin-6 • D-dimers • C-reactive protein
• Kuller et al PLOS Medicine ‘08
NWCS 329 • Nested case control study within the ACTG ALLRT cohort • Cases (n=143): Virologically suppressed (VL < 400 copies/ml) ART-
treated subjects with: – Non-accidental death – Non-AIDS morbidity
• Myocardial infarction • Stroke • Malignancy • Serious bacterial infections
• Controls: 2 virologically suppressed subjects matched for: – Age – Gender and sex – Baseline CD4+ T-cells (within 50 cells/mm3) – ART regimen at week 48 (PI- or ABC-containing or not) – Parent study
NWCS 329 in treated HIV Infection, pre-Event Soluble Markers relate to Outcome
IL6Unadjusted <.0012.58 (1.91-3.48)Adjusted* <.0012.48 (1.83-3.35)
IP-10Unadjusted 0.0021.49 (1.16-1.91)Adjusted* 0.0071.42 (1.10-1.84)
sTNFr-IUnadjusted <.0011.99 (1.49-2.66)Adjusted* <.0011.94 (1.45-2.60)
sTNFr-IIUnadjusted <.0011.88 (1.44-2.46)Adjusted* <.0011.81 (1.38-2.38)
Soluble CD14Unadjusted <.0011.74 (1.29-2.35)Adjusted* <.0011.67 (1.23-2.27)
D-DimerUnadjusted <.0012.41 (1.78-3.27)Adjusted* <.0012.38 (1.75-3.25)
CD8+ %DR+38+Unadjusted 0.5161.06 (0.88-1.28)Adjusted* 0.8630.98 (0.80-1.20)
0.50 1.00 4.00
Pre-event Marker P ValueOdds Ratio per 1 IQR increase
*Adjusted by CD4 count
OR for: Death CA MI/Stroke
20.9** 3.1** 2.2** 19.9** 2.9** 2.1**
1.9 1.7* 1.7* 1.8 1.5 1.7*
3.3** 2.3** 2.1**
3.3* 2.2** 2.1**
2.6** 2.1** 1.9**
2.9** 1.9* 2*
2.7* 1.5 1.7 2.8* 1.4 1.7
8.4** 3.2** 2.6** 8.1** 3.1** 2.6**
1.4 1 1
0.8 0.9 0.9
** **
** **
** **
** **
** **
** **
Tenorio J Inf Dis ‘14 Similar findings by Hunt et al JID ‘14
Arteries are inflamed in treated HIV infection
Subramanian et al JAMA ‘12
FSC
SSC
mIg
G1
mIgG2b
CD16
CD14
Monocyte subsets can be identified by expression of CD14 and CD16
HIV- HIV+ Traditional Monocytes
Inflammatory Monocytes
Patrolling Monocytes
Funderburg et al Blood 2012
Proportions of inflammatory and patrolling monocytes are increased in HIV disease
Traditional Inflammatory Patrolling
Funderburg et al Blood 2012
Medium alone LPS Pam3CSK4
IL-8 IL-1B IL-6 IL-10 TNF-a
Monocytes elaborate inflammatory mediators (IL-6, TNF, IL-18, IL-1b, IL-10)
in response to microbial elements
Nick Funderburg
Tissue Factor – a cell surface protein that activates the Extrinsic Coagulation Pathway
Goodsell The Oncologist 2006
Cell surface
Microbial Products may drive coagulation via induction of the procoagulant Tissue Factor on
Monocytes
57.7 10.1
2336 1194 331
78.1
TF MFI
Tissue Factor
No Stim LPS 20ng Flagellin 1ug
Funderburg et al Blood ‘10
HIV- HIV+ <400c/mL HIV+ >400c/mL Cardio CTRLs ACS Patients
%TF
+
Inflammatory and Patrolling monocytes are enriched for the procoagulant Tissue Factor in HIV infection
and in uninfected persons with Acute Coronary Syndromes
Funderburg et al Blood 2012
Traditional Inflammatory Patrolling
Like LPS, oxidized LDL (but not LDL) alters inflammatory profiles of blood monocytes
CD16
CD14
No Stim LPS LDL oxLDL
David Zidar, Nick Funderburg , unpublished
Classical (CD14+CD16-)
Inflammatory (CD14+CD16+)
Patrolling (CD14dimCD16+)
LPS LDL oxLDL No Stim LPS LDL oxLDL No
Stim LPS LDL oxLDL No Stim
***
*** *
***
*** ***
% T
issu
e Fa
ctor
Like LPS, oxidized LDL (but not LDL)
increases Tissue factor expression on blood monocytes
David Zidar, Nick Funderburg
Plasma levels of oxLDL are increased in HIV infection
oxLD
L (u
/mL)
HIV- HIV+ <400c/mL HIV+ >400c/mL Cardio CTRLs ACS Patients
Ox LDL - correlated to sCD14, TF levels on patrolling monocytes and Framingham Risk
Zidar, Funderbug et al
CD8 T cell homeostasis in HIV infection • CD8 T cell expansion is characteristic of untreated HIV
infection -and often persists after ART • These are matured effector cells, often senescent and
“exhausted” yet capable of robust inflammatory cytokine expression
• In setting of ART, expanded CD8 T cells are not HIV-reactive – Drivers of persistent CD8 T cell expansion in this setting are
not defined • CD8 T cell expansion and resultant low CD4/CD8 ratios
predict morbid outcomes in treated HIV infection (Serrano-Villar et al PLOS One ’13, Lee et al JID ‘14, Serrano-Villar PLOS Pathogens ‘14)
Mann-Whitney p=<0.0001
Even with complete virologic control and CD4 T cell restoration, CD8 T lymphocytosis persists for many
years
Carey Shive,, JC Mudd unpublished
Do CD8 T cells contribute to the development of atherosclerotic
plaque?
• Activated CD8+ T cell numbers in blood linked to atherosclerotic plaque in treated HIV
infection (Kaplan ‘11 , Longenecker ‘12)
• And are found within them (Grivel ‘11)
Circulating CD8 T cells exclusively express CX3CR1 or CCR7
CX3C
R1
CD3
JC Mudd, unpublished
CD8 T cells expressing CX3CR1 are relatively (and absolutely) expanded in treated HIV
infection
Healthy control
Treated HIV+
Healthy control
Treated HIV+ CX3C
R1
CCR7 JC Mudd, unpublished
CX3CR1+ CD8 T cells are enriched for protease activated receptor (PAR-1) expression and PAR-1+ cells are increased in
treated HIV-infection
CD3+CD8+CCR7+
16.6%
CD3+CD8+CX3CR1+
CX3C
R1
Par-1
52.0%
CCR7+ CX3CR1+
HIV-
Treated HIV+
PAR-1 is cleaved and activated by Thrombin
Coagulation driven by activated monocytes may recruit and activate CX3CR1+ PAR-1+ CD8 T cells at
endothelial surfaces
Summary • Persons with HIV infection are at increased risk
for cardiovascular and other morbidities of aging: this risk is predicted by indices of coagulation and inflammation
• Monocyte subsets are inflammatory and procoagulant in HIV infection; this phenotype may be driven by microbial products translocated from the damaged gut and by inflammatory lipids
• Mature CD8 T cell numbers are expanded in HIV infection, home to endovascular sites and are linked to ART-era cardiovascular morbidities.
• Coagulation and inflammation collaborate to drive increased CVD risk in treated HIV infection.
Dramatis Personae: CWRU: Nick Funderburg Scott Sieg Benigno Rodriguez Carey Shive JC Mudd Marie Ebner Souheil Younes Clifford Harding Chris Longenecker Grace McComsey David Zidar Brian Clagett Ben Kyi Janet Robinson
The NWCS 329 Team: Allan Tenorio Benigno Rodriguez Steven Deeks Alan Landay Ron Bosch Peter Hunt Evelyn Zheng Supriya Krishnan Arjun Seth
The AIDS Clinical Trials Group AI 076174 The Fasenmyer Foundation
A. Landay S. Deeks L. Margolis S. Sieg
G. Silvestri
J. Brenchley
B. Rodriguez
M. Lederman
Z. Grossman
R. Bosch
C. Harding
R. Sekaly D. Douek
G. Hardy
The Bad Boys of Cleveland
T. Schacker
Not shown: I. Sereti N. Sandler M. Carrington N. Klatt W. Jiang
E.Haddad J . Estes
R. Kalayjian
N. Funderburg
P. Hunt
A. Levine
A. Tenorio
M. Paiardini
J Tilton