Nave CD4 Tcell Homeostasis During HIV1 Disease

1
Naïve CD4 T-cell Homeostasis During HIV-1 Disease
Dr. Tammy Rickabaugh IAS 2007
July 23, 2007
2
The Human Thymus Involutes With Age
Adult Thymus
Fetal Thymus
3
The Proportion of Naïve T-cells Decreases Only
Moderately Throughout Adulthood
CD4 CD45RA
100
90
80
70
60
of CD4 T-cells Expressing CD45RA
50
40
30
20
10
0
20
25
30
35
40
45
50
55
60

Participant Age
4
Four CD4 T-cell Subsets Defined by CD45RA and
CD31
RA31
Least Differentiated
TREC High
Differentiated
RA31-
TREC Low
5
TREC Content Correlates With CD31 Expression
28000
28000
24000
24000
TREC/105 cells
20000
20000
16000
16000
12000
12000
8000
8000
4000
4000
0
0
AGE
52
25
6
Maintenance of Naïve CD4 T-cells During Aging Is
Due To Stability of CD45RACD31- Subset
Cross Sectional Study
60
50
40
31
CD45RACD31 cells
30
20
10
0
20
30
40
50
60
Participant Age (Years)
p0.38
60
50
40
31-
30
CD45RACD31- cells
20
10
0
20
30
40
50
60
Participant Age (Years)
7
Model of CD4 T-cell Differentiation
Thymus
Homeostatic Proliferation
CD45RA- Memory
Antigen
CD45RACD31
CD45RACD31-
Differentiated Naive
Least Differentiated Naïve
WITH AGE

• We observe telomere shortening in both subsets
  with age

8
What Is The Impact of HIV-1 on T-cell Homeostasis?
9
Individuals Early in HIV Infection Have
Significantly Fewer Naïve CD4 T-cells


600

500
SP seropositive SN seronegative
400
Absolute lymph/mm3
300
plt0.05 plt0.005
200
100
0
31
31-
SP
SN
SN
SP
SP
SN
SN
SP
lt30
gt37
lt30
gt37
AGE
10
Naïve CD4 T-cells of HIV Infected Men Have
Shorter Telomere Lengths
35




30
25
SP seropositive SN seronegative
20
of 1301 cell telomere length
15
plt0.05 plt0.005
10
5
31
31-
0
SP
SP
SN
SN
SN
SN
lt30
gt47
lt30
gt47
AGE
11
Median Fluorescence Intensity of CD31 on CD4
T-cells is Associated with Progression to AIDS
p0.038
5000
4000
CD31 MFI
3000
2000
1000
0
Progressed to AIDS within 1 year
Progressed to AIDS within gt 5 years
Wei Wei Cao, et al
12
What is the Effect of HAART on Naïve CD4 T-cells?
13
Reconstitution by HAART Does Not Completely
Restore the CD31- Naïve T-cell Compartment
p0.20
1400

plt0.05


1200
plt0.005
1000
Absolute lymph/mm3
800
600
400
200
0
-1
1
2
SN
-1
1
2
SN
31
31-
14
MFI of CD31 on CD31/Hi T-cells Increases
Significantly Post-HAART


plt0.05 plt0.005
7000
6000
5000
CD31 MFI
4000
3000
2000
1000
0
-1
1
2
SN
15
Model of CD4 T-cell Differentiation
Thymus
Homeostatic Proliferation
CD45RA- Memory
Antigen
CD45RACD31
CD45RACD31-
Differentiated Naive
Least Differentiated Naïve
HIV
AGE
HIV
AGE

• We observe telomere shortening in both subsets
  with age and HIV

16

• HIV infection appears to accelerate aging of the
  naïve CD4 T-cell compartment
• - significant loss of cell number
• - significant shortening of telomere length
• 2 years post-HAART treatment there is evidence of
  longer telomere length and higher expression of
  CD31 on naïve CD4 T-cells
• Incomplete reconstitution of CD45RACD31- T-cells
  2 years post-HAART

Conclusions
17
Possible Mechanisms for Aging of the Naïve
T-cell Compartment

• Immune activation due to chronic infection
• Rapid recruitment of naïve T-cells into the
  effector/memory pool
• Loss due to direct infection by HIV-1

18
Acknowledgements
Jamieson Lab Ryan Kilpatrick
Nancy Halnon Lance Hultin
Patti Hultin
Rita Effros Mary Ann Hausner
Steve Fauce Roger Shih Marianne
Chow Wei Wei Cao MACS Charlie
Price Dr. Roger Detels Effie
Eraklis Dr. John Phair Alfonso Coro
Participants Javier Ibarrondo Yvette
Trejo