Transcript Slide 1

HIV Induced Aging of the
Immune System
Dr. Tammy Rickabaugh
February 4, 2013
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
Immunological Aging in
Seronegative Individuals
General Concepts of Aging
Kovaiou, Grubeck-Loebenstien, 2006
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
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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
The Human Thymus Involutes With Age
Fetal Thymus
Adult Thymus
Jamieson, BD, et al, Immunity, 1999
Age-Associated Changes in
CD4+ T Cells
• 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
• 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
Model for CD4+ T Cell Differentiation
During Healthy Aging
Kovaiou, Grubeck-Loebenstien, 2006
Summary of Age-Related Changes
Within the CD4+ T Cells
Kovaiou, Grubeck-Loebenstien, 2006
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
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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
What are the implications of
increased numbers of
senescent T-cells???
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
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
Mountz, JD, et al. Immunological Reviews, 2005
Increase in Senescent Cells Occupying
“Immunological Space” Results in a Decrease
in the Virus-Specific CTL Response
-This can also contribute to “inflammaging”
Mountz, JD, et al. Immunological Reviews, 2005
Consequences of “Inflammaging”
• In aging there is a profound modification in the
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cytokine network
General increase in the levels of proinflammatory cytokines
Chronic low grade pro-inflammatory condition is
called “inflammaging”
Inflammaging can trigger the
following conditions:
Franceschi, C., et al., Neuroimmunomodulation, 2008
Some of our data…….
The Proportion of Naïve T-cells Decreases
Only Moderately Throughout Adulthood
PERCENT OF CELLS EXPRESSING CD45RA
DECREASES SLIGHTLY WITH AGE
% OF
CD4+T-cells
T-CELLSExpressing
EXPRESSINGCD45RA
CD45RA
CD4+
% of
CD4+ CD45RA+
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100
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10
10
0
0
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PARTICIPANT AGE
Participant Age
50
50
55
55
60
60
Four CD4+ T-cell Subsets Defined by CD45RA
and CD31
Naive
RA+31+
8%
48%
Least Differentiated
CD31
TREC High
RA+3114%
Differentiated
TREC Low
CD45RA
Cross Sectional Study
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50
40
31+
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20
10
0
20
% CD45RA+CD31+ cells
Maintenance of Naïve CD4+ T-cells During Aging Is
Due To Stability of CD45RA+CD31- Subset
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40
50
60
Participant Age (Years)
p=0.38
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40
30
31-
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10
0
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60
Participant Age (Years)
% CD45RA+CD31- cells
60
Kilpatrick, R, Rickabaugh, T, et. al, J. Immunology, 2008
Telomeres
• Hallmark of cellular aging
• Region of repetitive DNA at the ends of
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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
Telomeres
Human chromosome is gray and telomeres are the white dots
Evidence of Telomere Shortening in
Naïve CD4+ T cells with Age
Kilpatrick, R, Rickabaugh, T, et. al, J. Immunology, 2008
CD45RA-
CD45RA+CD31+
CD45RA+CD31-
Premature Aging of the Immune
System in HIV-1+ Individuals:
Is This the Cause of AIDS?
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
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
HIV-1 Strategies to Evade Host
Immunity
Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002
HIV-1 Strategies to Evade Host
Immunity
Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002
The Adaptive Immune System in Aging
and HIV-1 Infection
Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002
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 cellsconsequence 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
Post-Thymic Development of CD8+
and CD4+ T cells
Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002
Accumulation of Terminally
Differentiated T cells in HIV infection
Appay, V, et al. Experimental Gerontology, 2007
Exhaustion of Immune Resources by
HIV-1 Leads to AIDS
• Chronic Immune Activation:
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-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
Exhaustion of HIV-specific CD8+ T cell
Clonal Populations
Appay, V, et al. Experimental Gerontology, 2007
Exhaustion of HIV-specific CD8+ T cell
Clonal Populations
Appay, V, et al. Experimental Gerontology, 2007
Exhaustion of HIV-specific CD8+ T cell
Clonal Populations
Appay, V, et al. Experimental Gerontology, 2007
Some of our own data regarding
naïve CD4+ T cells…….
Individuals Early in HIV Infection Have
Significantly Fewer Naïve CD4+ T-cells
Rickabaugh, TM, et al., PLoS ONE 2011
HIV Infection Results in a Greater Loss of
CD31- T-cells
Rickabaugh, TM, et al., PLoS ONE 2011
Naïve CD4+ T-cells of HIV Infected Men Have Shorter
Telomere Lengths
Rickabaugh, TM, et al., PLoS ONE 2011
CD31 Expression on CD4+ T-cells is
Associated with Progression to AIDS
* p=0.038
CD31 MFI
5000
4000
3000
2000
1000
0
Progressed to AIDS
within > 5 years
Progressed to
AIDS within 1 year
Cao, WW et al., J Acquir Immune Defic Syndr 2008
What is the Effect of HAART
on Naïve CD4+ T-cells?
Reconstitution by HAART Does Not
Completely Restore the CD31- Naïve TCell Compartment
Rickabaugh, TM, et al., PLoS ONE, 2011
CD31+/Hi T-cells Increase Significantly
Post-HAART
Rickabaugh, TM, et al., PLoS ONE, 2011
Reconstitution of CD31+ T-cells appears
to be better with more time on ART
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150
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Seronegative
12-16 years
4-8 years
0
Absolute Cell Counts
CD45RA+CD28+CD31+CD4+
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30
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50
Age at time of analysis
60
70
Time on ART does not appear to
increase CD31- naïve CD4+ T-cells
120
100
60
80
Seronegative
40
12-16 years
20
Absolute Cell Counts
CD45RA+CD28+CD31-CD4+
4-8 years
20
30
40
50
Age at time of analysis
60
70
CD45RA-
CD45RA+CD31+
CD45RA+CD31-
HIV-1 Infection Compared to Human
Aging
Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002
Implications of Premature
Immunological Aging of HIV-1+
Individuals
Evidence of Premature Aging Despite
Anti-Retroviral Treatment
Deeks, SG, and Phillips, AN, BMJ, 2009
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
Age-Related Diseases Diagnosed in
HIV+ Individuals
• 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
Older HIV+ individuals are at even greater risk due to normal
immunological aging coupled with aging caused by HIV-1 infection
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
Two reasons for this:
• Higher percentage of new infections in
people over 50
• Individuals with HIV infection are living
longer on drug treatment
CDC
~46%
We also see an increase in new
AIDS cases in >50 year olds
The Search for the Immunological
Fountain of Youth
Possible Therapies to Improve Naïve
T-cell Numbers and Function
• The first treatment in HIV patients was IL-2
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-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
Possible Therapies to Improve Naïve T-cell
Numbers and Function
• IL-7 is a very promising treatment
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-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+ Tcells
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
What About Telomere Length??
• A screen of Chinese medicine plant extracts for
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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
TAT2 Can Improve Cellular
Proliferation and Telomere Length
Fauce, SR, et al., J Immunol, 2008
Summary
• Immune resources decline with age leading to a
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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