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HIV Induced Aging of the Immune System
Dr. Tammy Rickabaugh
February 4, 2013
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Overview
I. Immunological Aging in Seronegative Individuals
II. Premature Aging of the Immune System in HIV-1+ Individuals: Is this the cause of AIDS?
III. Implications of Premature Immunological Aging of HIV-1+ Individuals
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Immunological Aging in Seronegative Individuals
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Kovaiou, Grubeck-Loebenstien, 2006
General Concepts of Aging
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Age-Associated Changes in the Immune System
• Elderly people are more susceptible to infections• Less protected by vaccines• Infections in the elderly are characterized by
more severe symptoms, longer duration, and poorer prognosis
• Reactivation of Varicella-Zoster, risks for pneumonia, urinary tract infections, meningitis, TB and viral gastroenteritis
• Related to age-related changes in the immune system
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Jamieson, BD, et al, Immunity, 1999
Adult ThymusFetal Thymus
The Human Thymus Involutes With Age
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• Significant decrease in naïve T cell number and increase in memory T cells
-hinders ability to respond to new infections
• Diversity of the naïve CD4+ T cell compartment is maintained until about 70 years of age
-a dramatic and sudden collapse of diversity occurs
-less diversity in T cell receptor, hinders ability to respond to new antigens
Age-Associated Changes in CD4+ T Cells
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• Using cell surface markers normally used to identify naïve T cells is difficult
- “naïve” cells in the elderly express receptors and functional abilities more like memory cells
• Signaling and cytokine secretion in naïve CD4+ T cells is altered and the activation potential of memory cells is also decreased
-hinders ability to mount effective immune responses to antigens
Age-Associated Changes in CD4+ T Cells
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Kovaiou, Grubeck-Loebenstien, 2006
Model for CD4+ T Cell Differentiation During Healthy Aging
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Kovaiou, Grubeck-Loebenstien, 2006
Summary of Age-Related Changes Within the CD4+ T Cells
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Summary of Age-related Changes Within the CD8+ T Cells
• Increase in terminally differentiated cells• Decrease in naïve CD8+ T cells• See an increase in Type 1 (IL-2, IFN-g,TNF-a) and
Type 2 (IL-4, IL-6, IL-10) cells- associated with chronic pro-inflammatory status
• Increase in clonal expansions• Decrease in T cell receptor diversity• Shortening of telomere length
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What are the implications of increased numbers of senescent T-cells???
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Why Do Senescent Cells Accumulate With Age?
• One main reason is an age-related decrease in apoptosis
• Apoptosis is necessary to create “immunological space” for naïve cells to inhabit
• This is more prominent in CD8+ T-cells• Senescent cells are not susceptible to
normal death signals
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Mountz, JD, et al. Immunological Reviews, 2005
T-cells Become Resistant to Activation-Induced Cell Death (AICD)
-Happens at a stage prior to complete senescence-AICD is a mechanism to prevent the expansion of unwanted T-cells
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Increase in Senescent Cells Occupying “Immunological Space” Results in a Decrease
in the Virus-Specific CTL Response
Mountz, JD, et al. Immunological Reviews, 2005
-This can also contribute to “inflammaging”
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Consequences of “Inflammaging”
• In aging there is a profound modification in the cytokine network
• General increase in the levels of pro-inflammatory cytokines
• Chronic low grade pro-inflammatory condition is called “inflammaging”
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Inflammaging can trigger the following conditions:
Franceschi, C., et al., Neuroimmunomodulation, 2008
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Some of our data…….
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The Proportion of Naïve T-cells Decreases Only Moderately Throughout Adulthood
PERCENT OF CELLS EXPRESSING CD45RA DECREASES SLIGHTLY WITH AGE
PARTICIPANT AGE
25 35 45 5520 30 40 50 60
% O
F C
D4
+ T
-CE
LL
S E
XP
RE
SS
ING
CD
45
RA
10
30
50
70
90
0
20
40
60
80
100
% o
f C
D4+
T-c
ells
Exp
ress
ing
CD
45R
A
Participant Age
100
90
80
70
60
50
40
30
20
10
020 25 30 35 40 45 50 55 60
CD4+ CD45RA+
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8% 48%
14%CD
31
CD45RA
Four CD4+ T-cell Subsets Defined by CD45RA and CD31
Naive
RA+31+
RA+31-
TREC High
TREC Low
Least Differentiated
Differentiated
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Maintenance of Naïve CD4+ T-cells During Aging Is Due To Stability of CD45RA+CD31- Subset
p=0.38
Participant Age (Years)
20 30 40 50 60
60
40
50
30
20
10
0
60
50
40
30
20
10
0
20 30 40 50 60
Cross Sectional Study
31+
31-
Kilpatrick, R, Rickabaugh, T, et. al, J. Immunology, 2008
Participant Age (Years)
% C
D45
RA
+C
D31
- ce
lls
% C
D45
RA
+C
D31
+ c
ells
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Telomeres• Hallmark of cellular aging• Region of repetitive DNA at the ends of
chromosomes• Protects the end of chromosome from damage
-similar to tips on shoelaces that keep it from unraveling-shortens with each replication of the cell
• Telomere shortening in humans can result in senescence (cells lose the ability to divide) and block cell division
• Cells have a limited capacity to replicate and this appears to be partly determined by telomere length
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Telomeres
Human chromosome is gray and telomeres are the white dots
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Kilpatrick, R, Rickabaugh, T, et. al, J. Immunology, 2008
Evidence of Telomere Shortening in Naïve CD4+ T cells with Age
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HomeostaticProliferation
CD45RA+CD31+ CD45RA+CD31-
Antigen
CD45RA-
Memory
Model of CD4+ T-cell Differentiation
DifferentiatedNaive
Least DifferentiatedNaïve
• We observe telomere shortening in both subsets with age
WITH AGE
Thymus
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Premature Aging of the Immune System in HIV-1+ Individuals:Is This the Cause of AIDS?
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Some Causes of Clinical Immunodeficiency
• Not completely clear why the immune system initially controls HIV-1 infection and then ultimately fails to control viral replication
– Viral escape with mutations in epitopes recognized by cytotoxic T lymphocytes (CTLs)
– Functional impairment of HIV-specific CTLs
– High levels of immune activation
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HIV-specific CD8+ T cell response: Impaired or Fully Functional?
• In primary HIV-1 infection there is a rapid expansion of HIV-specific effector CD8+ T cells-phenotypically the cells appear to be at an intermediate stage of differentiation-but they are fully functional
• Why is the virus not cleared??-the combination of CD4+ T cell depletion and immune escape may lead to an inability of the CD8+ T cells to respond to low levels of viral replication (around the set point)
- fully functional but unable to mount an effective response
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HIV-1 Strategies to Evade Host Immunity
Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002
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HIV-1 Strategies to Evade Host Immunity
Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002
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Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002
The Adaptive Immune System in Aging and HIV-1 Infection
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Parallels Between HIV-1 Pathogenesis and Human Aging
• Lifespan of both CD4+ and CD8+ T cells is shortened to about a third of normal
-increase of CD8+ T cells but CD4+ cannot keep up with the pace of destruction
• Increase in the amount of terminally differentiated T cells- consequence of immune activation
-leads to immunosenescence, also occurs with CMV
-get an accumulation of immune cells that cannot function or replicate normally, but are more resistant to apoptosis
• AIDS is much more severe immune senescence than what is seen in normal aging
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Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002
Post-Thymic Development of CD8+ and CD4+ T cells
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Appay, V, et al. Experimental Gerontology, 2007
Accumulation of Terminally Differentiated T cells in HIV infection
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Exhaustion of Immune Resources by HIV-1 Leads to AIDS
• Chronic Immune Activation:-In primary infection there is massive immune activation-In chronic infection still have chronic immune activation due to viral rebounds-Indirect immune activation as depletion of CD4+ T cells results in more common infections and opportunistic infections
• This can result in premature aging of the immune system and exhaustion of immune resources
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Appay, V, et al. Experimental Gerontology, 2007
Exhaustion of HIV-specific CD8+ T cell Clonal Populations
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Appay, V, et al. Experimental Gerontology, 2007
Exhaustion of HIV-specific CD8+ T cell Clonal Populations
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Appay, V, et al. Experimental Gerontology, 2007
Exhaustion of HIV-specific CD8+ T cell Clonal Populations
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Some of our own data regarding naïve CD4+ T cells…….
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Individuals Early in HIV Infection Have Significantly Fewer Naïve CD4+ T-cells
Rickabaugh, TM, et al., PLoS ONE 2011
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HIV Infection Results in a Greater Loss of
CD31- T-cells
Rickabaugh, TM, et al., PLoS ONE 2011
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Naïve CD4+ T-cells of HIV Infected Men Have Shorter Telomere Lengths
Rickabaugh, TM, et al., PLoS ONE 2011
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CD
31 M
FI
0
1000
2000
3000
4000
5000
Progressed to AIDS within 1 year
Progressed to AIDS within > 5 years
* p=0.038
CD31 Expression on CD4+ T-cells is Associated with Progression to AIDS
Cao, WW et al., J Acquir Immune Defic Syndr 2008
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What is the Effect of HAART on Naïve CD4+ T-cells?
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Reconstitution by HAART Does Not Completely Restore the CD31- Naïve T-
Cell Compartment
Rickabaugh, TM, et al., PLoS ONE, 2011
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CD31+/Hi T-cells Increase Significantly Post-HAART
Rickabaugh, TM, et al., PLoS ONE, 2011
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Reconstitution of CD31+ T-cells appears to be better with more time on ART
050
10
015
020
0
20 30 40 50 60 70
Age at time of analysis
Seronegative
4-8 years
12-16 years
CD45RA+CD28+CD31+CD4+
Ab
solu
te C
ell C
ou
nts
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Time on ART does not appear to increase CD31- naïve CD4+ T-cells
20
40
60
80
10
012
0
20 30 40 50 60 70
Seronegative
4-8 years
12-16 years
CD45RA+CD28+CD31-CD4+
Age at time of analysis
Ab
solu
te C
ell C
ou
nts
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HomeostaticProliferation
CD45RA+CD31+ CD45RA+CD31-
Antigen
CD45RA-
Memory
Model of CD4+ T-cell Differentiation
DifferentiatedNaive
Least DifferentiatedNaïve
• We observe telomere shortening in both subsets with age and HIV
AGE HIVHIV AGE
Thymus
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Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002
HIV-1 Infection Compared to Human Aging
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Implications of Premature Immunological Aging of HIV-1+
Individuals
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Deeks, SG, and Phillips, AN, BMJ, 2009
Evidence of Premature Aging Despite
Anti-Retroviral Treatment
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Age-Related Diseases Diagnosed in HIV+ Individuals
• Cardiovascular Disease
-higher in untreated versus treated
-link between lower CD4+ T cells and CD
-some anti-retroviral drugs are associated with CD
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• Cancer- Untreated HIV is associated with Kaposi’s Sarcoma and non-Hodgkin’s lymphoma- Even treated HIV individuals at increased risk
for lung cancer, skin cancer, colorectal cancer, prostate cancer, anal cancer- Higher risk is associated with less CD4+ T cells, similar to immune compromised transplant patients
Age-Related Diseases Diagnosed in HIV+ Individuals
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Age-Related Diseases Diagnosed in HIV+ Individuals
Older HIV+ individuals are at even greater risk due to normal immunological aging coupled with aging caused by HIV-1 infection
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Another problem….HIV infected people are getting older
CDC estimates that by 2015 over 50% of all HIV infected people will be over the age of 50 in the US
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Two reasons for this:
• Higher percentage of new infections in people over 50
• Individuals with HIV infection are living longer on drug treatment
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CDC
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~46%
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We also see an increase in new AIDS cases in >50 year olds
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The Search for the Immunological Fountain of Youth
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Possible Therapies to Improve Naïve T-cell Numbers and Function
• The first treatment in HIV patients was IL-2
-some evidence of efficacy
-results of the trials were not consistent and there are concerns with toxicity
• Human growth hormone (HGH) and Insulin Growth Factor-1 (IGF1)
- increased thymic volume in children with AIDS but did not affect T-cell function significantly
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• IL-7 is a very promising treatment-cytokine that plays a key role in the thymus in lymphocyte development and survival-in the periphery it is important for T-cell homeostasis and is required for homeostatic proliferation of CD4+ and CD8+ T-cells
• When used in cancer patients it preferentially expanded naïve T-cells
• In a phase I/IIa clinical trial in HIV+ patients it was shown to increase naïve and central memory CD4+ and CD8+ T-cells
• The T-cells are functional and the patients had improved cell mediated immunity
• There also seem to be very little side effects
Possible Therapies to Improve Naïve T-cell Numbers and Function
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What About Telomere Length??
• A screen of Chinese medicine plant extracts for telomerase inducing agents resulted in the discovery of TAT2
• TAT2 has been shown to transiently increase telomerase levels in vitro in cells from HIV-, HIV+, and individuals with AIDS (highest amounts)
• This increase was associated with longer telomere lengths, improved immune effector function, and increased ability for cellular proliferation
• In vitro it has also been shown to reduce viral load and this is correlated to telomerase induction
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TAT2 Can Improve Cellular Proliferation and Telomere Length
Fauce, SR, et al., J Immunol, 2008
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Summary• Immune resources decline with age leading to a
reduced ability to respond to new and old antigens• HIV-1 infection appears to prematurely age both
CD8+ and CD4+ T cells - this leads to immune exhaustion and senescence- may be a significant factor in the development of AIDS
• HIV-1+individuals, treated or untreated, are at a higher risk for non-AIDS related diseases seen in much older individuals
• There are some promising therapeutics but more work must be done to develop safe, effective, therapies to improve immune function