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M228 Biology of HIV: Cytokines and HIV
Winter Quarter, 2012
Liz Crabb Breen, Ph.D.
“kinos”
“cyto”
“cyto”
From Breen, E.C. 2002. Pro- and anti-inflammatory cytokines in HIV Infection and AIDS.
Pharmacology and Therapeutics 95:295-304.
STEP 1:
CYTOKINES
STEP 2:
RECEPTORS
STEP 3:
SIGNALING
STEP 4:
GENE
EXPRESSION
cytokines
TABLE 7.1 (from Decker, 2000, Introduction to Immunology, pg 90)
Modified TABLE 7.1 (from Decker)
INFLAMMATORY CYTOKINES
CYTOKINES IN ADAPTIVE/SPECIFIC RESPONSES
REGULATORY CYTOKINES
INFLAMMATORY CYTOKINES
Macrophage
IL1
TNFa
IL6
INFLAMMATORY CYTOKINES
Modified Table 7.1 (from Decker)
INFLAMMATORY CYTOKINES
Macrophage
IL1
TNFa
IL17
IL6
17
Adapted from Weaver & Hatton,
9:883-889, 2009
CYTOKINES IN ACQUIRED/SPECIFIC RESPONSES
IL2
IL2
IL2
CYTOKINES IN ACQUIRED/SPECIFIC RESPONSES
IL1
IL2
IL12 Co-stim
IL2
IL2
CYTOKINES IN ACQUIRED/SPECIFIC RESPONSES
IL2
IL2
IL2
IL4
IL5
IL6
IL10
IL21
CYTOKINES IN ACQUIRED/SPECIFIC RESPONSES
Modified Table 7.1 (from Decker)
REGULATORY CYTOKINES
Macrophage
Monocyte
IL10
IL12
NK
IFNg
REGULATORY CYTOKINES
Th1
IL12
Th2
IL4
IL6
IL10
IL2
IFNg
CELL-MEDIATED
IMMUNE RESPONSES
m activation
X
X
ANTIBODY-MEDIATED
IMMUNE RESPONSES
cell
B cellBactivation
activation
cytotoxic T cell
activation
= cytokine production and/or stimulatory effects
= inhibitory effects
From Breen, E.C. 2002. Pro- and anti-inflammatory cytokines in HIV Infection and AIDS.
Pharmacology and Therapeutics 95:295-304.
Th1/Th2 cells
Cell-mediated
Humoral
Adapted from Weaver et al, Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties, 2006,
Immunity 24, 677–688
Cross-regulation of Th1/Th2 cells
Cell-mediated
Humoral
Adapted from Weaver et al, Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties, 2006,
Immunity 24, 677–688
Diversification of CD4 T Cell Lineages
Cell-mediated
Humoral
Inflammatory
Adapted from Weaver et al, Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties, 2006,
Immunity 24, 677–688
Th1/Th2/Th17 cells
Cell-mediated
Humoral
Inflammatory
Adapted from Weaver et al, Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties, 2006,
Immunity 24, 677–688
Possible contributions by human Th17 cells
From Afzali et al, The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ
transplantation and autoimmune disease, 2007, Clinical and Experimental Immunology 148: 32-46
Generation of CD4 T Regulatory Cells
Adapted from Weaver et al, Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties, 2006,
Immunity 24, 677–688
TREG
TREG
TREG
TREG
IL-10
TGF-b
TREG
2008
FEBRUARY
4
Monday
Dr. Breen
CYTOKINES IN ACQUIRED/SPECIFIC RESPONSES
IL2
IL2
IL2
CYTOKINES IN ACQUIRED/SPECIFIC RESPONSES
IL2
IL2
IL2
HIV
progression
GOOD
BAD
“Th1 to Th2 Shift”
Adapted from Mandell & Mildvan (Eds.). 1997. Atlas of Infectious Diseases, Volume I-AIDS.
From Mosmann, TR, Sad, S. 1996. The expanding universe of T-cell subsets.
Immunol Today 17:138-146.
Prediction of Th1/Th2 shift:
 GOOD (IFNg)
BAD (IL4)
From Aziz et al. 1998.
Level of Cytokines and
Immune Activation
Markers in Plasma in
HIV Infection: QC
Procedures. Clin.
Diagn. Lab. Immunol.
5:755-761.
HIV- HIV+ HIV+ HIV+ HIV+
>500 350- 200- <200
499 349
HIV- HIV+ HIV+ HIV+ HIV+
>500 350- 200- <200
499 349
INFLAMMATORY CYTOKINES
Macrophage
IL1
TNFa
IL17
IL6
17
From:
Viral Immunology 20:66-75, 2007
↑ TH17 cells in unstimulated
peripheral blood cells
From: ELHED and UNUTMAZ, Curr Opin HIV AIDS 5:146-150, 2010
Possible contributions of cytokines to HIV/AIDS
pathogenesis
• Immune system dysfunction/activation
“kinos
”
“cyto”
“cyto”
HIV
infection
From Mandell & Mildvan (Eds.). 1997. Atlas of Infectious Diseases, Volume I-AIDS.
STEP 1:
STEP 2:
CYTOKINES
RECEPTORS
STEP 3:
STEP 4:
SIGNALING
GENE
EXPRESSION
% of B cells
CD126’IL6R’ +
% of monocytes
CD126’IL6R’ +
Heterosexual
1.8 ± 0.3
26.8 ± 3.7
HIV –
2.9 ± 0.2
27.5 ± 3.8
HIV+, CD4 <500
8.2 ± 0.9
60.6 ± 4.9
HIV+, CD4 200-500
8.2 ± 0.7
66.6 ± 4.3
HIV+, CD4 <200
6.8 ± 0.6
64.7 ± 4.6
0.0001
<0.0001
P value
From van der Meijden et al. 1998. IL-6 receptor (CD126’IL-6R’) expression is increased on
monocytes and B lymphocytes in HIV Infection. Cell. Immunol. 190:156-166.
From: ELHED and UNUTMAZ, Curr Opin HIV AIDS 5:146-150, 2010
Possible contributions of cytokines to HIV/AIDS
pathogenesis
• Immune system dysfunction/activation
• Regulation of HIV replication
“kinos
”
“cyto”
“cyto”
HIV
infection
From Mandell & Mildvan (Eds.). 1997. Atlas of Infectious Diseases, Volume I-AIDS.
= increase HIV replication/viral load
*
*
* Can also enhance immune function
From G. Poli. 1999. Cytokines and the human immunodeficiency virus:
from bench to bedside. Eur. J. Clin. Invest. 29:723-732.
From Mandell & Mildvan (Eds.). 1997. Atlas of Infectious Diseases, Volume I-AIDS.
= decrease HIV replication/viral load
= increase and decrease HIV replication/viral load
From G. Poli. 1999. Cytokines and the human immunodeficiency virus:
from bench to bedside. Eur. J. Clin. Invest. 29:723-732.
= decrease HIV replication/viral load
= increase and decrease HIV replication/viral load
Generation of CD4 T Regulatory Cells
Adapted from Weaver et al, Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties, 2006,
Immunity 24, 677–688
Single Nucleotide Polymorphisms in the
promoter region of the human IL10 gene
-1082
-851
-592
G/A
C/T
C/A
= high IL10 secretor genotype
= low IL10 secretor genotype
0
IL10-5’ -592 genotype
• C or A at nucleotide -592
• A allele is dominant for low IL10 secretion
C/C = high secretor
C/A = intermediate/low secretor
A/A = low secretor
• Frequency of C/C varies by ethnicity, from
~60% for Caucasians to ~40% for Asians
• C/A and A/A alleles reported to be
associated with more rapid progression to
AIDS (Shin et al, PNAS 97:14467, 2000)
HIV
IL1
TNF
IL6
High IL10
secretion
HIV
macrophage
IL1
TNF
IL6
Low IL10
secretion
From Breen, E.C. 2002. Pro- and anti-inflammatory
cytokines in HIV Infection and AIDS. Pharmacology
and Therapeutics 95:295-304.
Slower progression
to AIDS
HIV
IL1
TNF
IL6
Faster progression
to AIDS
Possible contributions of cytokines to HIV/AIDS
pathogenesis
• Immune system dysfunction/activation
• Regulation of HIV replication
• B cell activationAIDS-associated B cell lymphoma
“kinos
”
“cyto”
“cyto”
HIV infection
Increased B cell stimulatory cytokines
B cell
Increased
activation,
isotype
switching
Increased risk of
AIDS lymphoma
Elevated serum levels of some B cell activation markers
are seen >3 years preceding AIDS-NHL
>3 years prior
1 – 3 years prior
0 – 1 year prior
ORs ( 95% CI) of elevated serum cytokine levels, adjusted for CD4 T cell number
= non-CNS cases,
= CNS cases, compared to HIV+ controls
From Breen et al, 2011. Cancer Epidemiology Biomarkers & Prevention 20:1303-1314.
100
0.1
1
10
Increased frequency
of detectable
serum
IL10100
is seen
ORs (+/95% CIs) AIDS-NHL
only in the year immediately
preceding
f
detectable IL10
>3yrs
yrs
>3
unable to calculate
1-3 yrs
yrs
0-1 yr
0-1
yr
unable to calculate
100
0.01
0.1
1
10
ORs (+/- 95% CIs)
100
HIV
HIV
IL1
TNF
IL6
macrophage
IL1
TNF
IL6
macrophage
Slower progression
High IL10
to AIDS
secretion
B cell
activation,
isotype
switching
From Breen, E.C. 2002. Pro- and anti-inflammatory
cytokines in HIV Infection and AIDS. Pharmacology
and Therapeutics 95:295-304.
B cell lymphoma
Increased risk of
AIDS lymphoma
Distribution of sCD27 over time
The effect of HAART on markers
of B cell activation in HIV infection
800
sCD27
sCD27 U/mL
600
400
200
-2yr
-1 yr
Time point
+1 yr
+2yr
HIV-
Distribution
of IL6 over time
HAART
5
IL6
IL6 pg/mL
4
3
2
1
0
Time point
From Regidor et al, 2011. AIDS 25:303–314
HIV
infection
From Mandell & Mildvan (Eds.). 1997. Atlas of Infectious Diseases, Volume I-AIDS.