hiv induced aging of the immune system dr. tammy rickabaugh february 4, 2013
TRANSCRIPT
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
Kovaiou, Grubeck-Loebenstien, 2006
General Concepts of Aging
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
Jamieson, BD, et al, Immunity, 1999
Adult ThymusFetal Thymus
The Human Thymus Involutes With Age
• 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
Age-Associated Changes in CD4+ T Cells
Kovaiou, Grubeck-Loebenstien, 2006
Model for CD4+ T Cell Differentiation During Healthy Aging
Kovaiou, Grubeck-Loebenstien, 2006
Summary of Age-Related Changes Within the CD4+ T Cells
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
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
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
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”
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”
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
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+
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
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
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
Telomeres
Human chromosome is gray and telomeres are the white dots
Kilpatrick, R, Rickabaugh, T, et. al, J. Immunology, 2008
Evidence of Telomere Shortening in Naïve CD4+ T cells with Age
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
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
Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002
The Adaptive Immune System in Aging and HIV-1 Infection
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
Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002
Post-Thymic Development of CD8+ and CD4+ T cells
Appay, V, et al. Experimental Gerontology, 2007
Accumulation of Terminally Differentiated T cells in HIV infection
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
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
Exhaustion of HIV-specific CD8+ T cell Clonal Populations
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
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
What is the Effect of HAART on Naïve CD4+ T-cells?
Reconstitution by HAART Does Not Completely Restore the CD31- Naïve T-
Cell 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
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
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
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
Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002
HIV-1 Infection Compared to Human Aging
Implications of Premature Immunological Aging of HIV-1+
Individuals
Deeks, SG, and Phillips, AN, BMJ, 2009
Evidence of Premature Aging Despite
Anti-Retroviral Treatment
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
• 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
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
-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
• 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
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
TAT2 Can Improve Cellular Proliferation and Telomere Length
Fauce, SR, et al., J Immunol, 2008
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