hiv and the immune system: complexities and...

HIV and the Immune System: Complexities and Consequences

Brinda Emu, MD 28 February 2013

HIV from 1981

HIV/AIDS Mortality Data, United States, 1987-2009

Presenter

Presentation Notes

The annual number of deaths of persons with AIDS (some of which were not caused by AIDS), as reported to the national HIV surveillance system through June 30, 2012, and adjusted for reporting delay, was 11% to 42% (depending on the year) greater than the number of deaths attributed to HIV infection in death certificate data (by ICD-10 rules for selecting the underlying cause of death). The greater number of deaths of persons with AIDS is partly because some persons with AIDS die of causes not attributable to HIV infection, such as motor vehicle accidents, and partly because some deaths due to HIV infection are not reported as such on death certificates. The blue line represents data from the national HIV surveillance system. The orange line represents death certificate data compiled by the National Center for Health Statistics (NCHS).

History of HIV from 1981

Priorities for HIV Care and Research

• Access to Care/HIV Medications • Prevention of New Infections • Treatment of Co-morbidities

• Vaccine Development • HIV Cure • Non-AIDS related mortality

} Immunologic Complexities

} Immunologic Consequences

Complexities of the Immune Response

Natural History of HIV Infection

Natural History of Untreated HIV Disease

Time

100

10000

100000

1000000

1000

1000000

Vira

l Loa

d

Non-controllers: 90-95%

Time

100

10000

100000

1000000

1000

1000000

Vira

l Loa

d Natural History of Untreated HIV Disease

Long-term Non-progressors (LTNP): 5-10%

Time

100

10000

100000

1000000

1000

1000000

Vira

l Loa

d Natural History of Untreated HIV Disease

Elite Controllers EC: <1%

LTNP: 5-10%

Viral control is a predictor of progression to AIDS

Ho, D. D. Science 1996

Vira

l Loa

d

Time after infection

Majority of Elite Controllers do not progress to AIDS.

Are they a model for functional HIV cure?

How do Elite Controllers maintain control?

• Are they really infected? – All seropositive (ELISA/ Western) – Proviral DNA and plasma viral

RNA present

• Is the virus defective? – Large deletions reported – Replication competent virus also

reported – Blips of replication – Transmission pairs identified

Host • Adaptive immune response • Innate immune response • Levels of T cell activation

Virus

Study Design

Flow Cytometry: “SCOPE” Cohort Study: San Francisco General Hospital

7000 patient cohort with specimens stored every 4 months Stimulation of PBMCs with HIV Gag peptide pools Staining for extracellular markers and intracellular cytokines

Comparator Groups Elite controllers: Documented VL<75 copies/mL off therapy Viremic Controllers: Documented VL<2000 copies/mL off therapy Non-controllers: Viral load >10000 copies/mL HAART Suppressed: Documented VL<75 copies/mL on therapy

Baseline Characteristics

Elite N=30

Controller N=34

Non- Controller N=68

Suppressed (HAART) N=131

Age Years infected CD4 CD8 HIV RNA (log)

48 16 (15-18) 711 (460-990) 822 (541-1116) 1.88

43 14 (8-16) 471 (347-702) 1115 (753-1454) 2.82 (2.27-3.18)

44 13 (9-16) 238 (158-398) 1554 (915-2414) 4.46 (4.15-4.87)

47 13 (9-17) 447 (306-653) 1.88

T cell activation in HIV

• T cell activation result in “bystander” effects on the immune system

• CD8 T cell activation is independent predictor of survival – Measured by expression of CD38 and HLA-DR

• High levels of T cell activation predict CD4+ T cell decline

• Persistent T cell activation despite HAART predicts poor CD4+ T cell gains

Deeks Blood 2004, Giorgi JID 1999, Hazenberg AIDS 2003, Hunt JID 2003

ECs have lower levels of CD8+ T cell activation compared with controllers

0

10

20

30

40

ELITE CONTROLLER

%C

D8

T ce

lls C

D38

+HLA

DR

+

p=0.003

ECs have lower levels of CD8+ T cell activation compared with non-

controllers

0

10

20

30

40

NON- CONTROLLER

ELITE CONTROLLER

%C

D8

T ce

lls C

D38

+HLA

DR

+

P<0.0001

ECs have higher levels of of CD8+ T cell activation compared with Suppressed

0

10

20

30

40

SUPPRESSED NON- CONTROLLER

ELITE CONTROLLER

%C

D8

T ce

lls C

D38

+HLA

DR

+

p=0.04

ECs have higher levels of CD8+ T cell activation compared with HIV seronegatives

0

10

20

30

40

SUPPRESSED NON- CONTROLLER

ELITE CONTROLLER HIV NEGATIVE

%C

D8

T ce

lls C

D38

+HLA

DR

+

P<0.0001

Control of Viral Replication associated with T cells

• LNTP have higher CD8 and CD4 responses • Rise in CD8 correlates with fall in viral load • Depletion of CD8 T cells in macaques results in

higher SIV replication • Dual functional T cells (secreting Interferon-γ

and IL-2) associated with better viral control Do Elite Controllers control virus in the same way

as LTNP? Pantaleo G 1995 NEJM, Pitcher CJ 1999 Nat Med; Musey L 1997 NEJM; Schmitz JE 1999 Science; Pantaleo G 1995 NEJM, Kalams SA 1998 J Exp Med;

Boaz, M 2002 J Imm, Harari 2004 Blood, Younes 2003 J Exp Med; Emu B, 2005 J Vir

Presenter

Presentation Notes

l.) Long tern nonprogressors have demonstrated higher CTL responses compared with those with progressive disease [2-9]; 2) Temporal rise in CTL response in primary infection correlates with drop in viral load [10-12]; 3) Early treatment of recent HIV seroconverters with HAART preserves high level CTL responses and the ability to maintain a low viral set-point [13-14]; and 4) CD8+ depleted rhesus macaques have higher levels of SIV replication than controls [15-16]. We also know the importance of CD4+ positive T cell subset in-74- controlling viremia [4,13, 17-20]. CD4+ depleted mice infected with LCMV eventually had waning CD8+ activity over time [18,21-23]. 1) long term nonprogressors demonstrate higher CTL responses compared with those with progressive disease [4-7]; 2) a temporal rise in CTL response in primary infection is correlated with a drop in viral load [8-10]; and 3) CD8+ T cell-depleted rhesus macaques have higher levels of SIV replication than infected animals with normal CD8+ T cell counts [11]. It is also clear that HIV specific CD4+ T cells are important in controlling viremia [12-14] and that these cells are necessary for the maintenance of robust CD8+ T cell function over time [12,15-16].

ECs Have Comparable Levels of CD4+ Dual-functional T Cells Compared to Viremic

Controllers

P=0.22

Gag

-spe

cific

CD

4+IF

Nγ+

IL2+

0

0 . 1

0 . 2

0 . 3

0 . 4

Elite Controller

(VL<50) N=31

Viremic Controller

(VL 50-2000) N=30

ECs Have Higher Levels of CD4+ Dual-functional T Cells Compared to Non-

Controllers P=0.0002

Gag

-spe

cific

CD

4+IF

Nγ+

IL2+

0

0

0

0

0

0 . 1

0 . 2

0 . 3

0 . 4

Viremic Controller

(VL 50-2000) N=30

Non Controller

(VL>10,000) N=26

Elite Controller

(VL<50) N=31

P<0.0001

Gag

-spe

cific

CD

4+IF

Nγ+

IL2+

0

0 . 1

0 . 2

0 . 3

0 . 4

Viremic Controller

(VL 50-2000) N=30

Non Controller

(VL>10,000) N=26

HAART Suppressed

(VL<50) N=55

Elite Controller

(VL<50) N=31

ECs Have Higher Levels of CD4+ Dual-functional T Cells Compared to HAART

Suppressed

Elite and Viremic Controllers Have High Levels of Dual-functional CD8 T Cells

Gag

-spe

cific

CD

8 IF

Nγ+

IL-2

+

Elite Controller

(VL<50) N=31

Viremic Controller

(VL 50-2000) N=30

Non Controller

(VL>10,000) N=29

HIV Negative

N=37

HAART Suppressed

(VL<50) N=55

P=0.0009

0 . 0 0

0 . 0 5

0 . 1 0

0 . 1 5

0 . 2 0 P<0.0001

Marked Heterogeneity of HIV-specific CD8+ Responses Among ECs G

ag-s

peci

fic C

D8+

IFN

γ+ IL

2+

-0.1

0.0

0.1

0.2

0.3

"Elite"

VL < 50 n=56

Controller

50-2000 n=77

Non- controller > 10,000

n=37

HAART Suppressed

< 75 n=40

HIV Negative

n=38

0.3

0.6

0.9

1.2 0.23

< 0.0001

< 0.0001

< 0.0001

Human Leukocyte Antigen (HLA)

• HLA molecules on the surface of cells bind peptides (bacteria, viruses, self) and present these to T cells

APC



• T cells recognize HLA-peptide complex and become activated

APC CD8



• T cells recognize HLA-peptide complex and become activated

• HLA type is determined genetically with hundreds of variants

APC CD8

Protective HLA types are Enriched among Controllers

Non Controller

N=73

0

10

20

30

40

50

60

70

Viremic Controller

N=21

Elite Controller

N=22

P=0.001

P=0.01

Freq

uenc

y of

Pro

tect

ive

HLA

Cla

ss I

60% 52%

16%

***HLA types B57, B27, B13, B58, B81 are considered protective

Controllers With Protective HLA Alleles Have Higher CD8 Gag-specific

Responses

Controllers

.05

.1

.15

.2

.25

.3 P=0.01

Protective Non- Protective

CD

8 D

ual F

unct

iona

l res

pons

es

Controllers With Protective HLA Alleles Have Higher CD8 Gag-specific

Responses

Controllers

.05

.1

.15

.2

.25

.3 P=0.01


NS

Non-Controllers


CD

8 D

ual F

unct

iona

l res

pons

es

Summary of Elite Controllers • Maintain tight viral control despite HIV infection

• High levels of dual-functional T cells

– Marked heterogeneity!!!!

• Heterogeneity suggests different mechanisms of control – Protective HLA alleles enriched – Protective HLA alleles associated with CD8 T cell responses – Protective HLA alleles are not necessary for viral control – Protective HLA alleles are not sufficient for viral control

HIV Pathogenesis in HIV Elite Controllers

Replication Incompetent Virus

Seropositive, but no latent Infection and no ongoing viral

Replication


Replication Incompetent Virus


Replication

Replication-competent virus

Strong T cell response (previous exposure and/or protective HLA)

Kills virus prior to CD4 infection, no infection

Low level infection because of strong T

cell response


Kills virus prior to CD4 infection,

no infection

Defective virus particle Incapable of replication


replication

Replication-competent virus

Other arms of host immune response (innate immunity,

coreceptors, etc)

Lowers peak viral load, allowing cells to control viremia

early

T cell response (previous exposure and/or protective HLA)

Kills virus prior to CD4 infection, no infection

Low level infection because of strong T

cell response

Elite Controllers as a Model for HIV Cure?

• Elite controllers are a small, unique group of individuals who spontaneously suppress HIV replication

• They represent the “ideal” response to HIV infection

• Goal is to understand and “mimic” the host response in EC to develop effective vaccine strategies

• Important to remember that not all ECs control in the same way and careful attention is needed to determine what can be replicated

HIV and the Immune System: the Consequences

Presenter

Presentation Notes

This slide shows increases in the number of adults and adolescents living with an AIDS diagnosis in the United States and dependent areas from 1993 through the end of 2009. The increase is due primarily to the widespread use of highly active antiretroviral therapy, introduced in 1996, which has delayed the progression of AIDS to death.��At the end of 2009, an estimated 487,414 adults and adolescents were living with an AIDS diagnosis; of these, 76% were male and 24% were female. ��All displayed data are estimates. Estimated numbers resulted from statistical adjustment that accounted for reporting delays, but not for incomplete reporting. Persons living with an AIDS diagnosis are classified as adult or adolescent based on age at end of 2009.

Dramatic Decrease in Mortality with HAART

Krentz, 2005, n=560

Increased Rates of Morbidity/Mortality

• Cardiovascular, Liver, Kidney Disease • Metabolic Disorders • Osteoporosis • Malignancies

Many of these conditions are associated with aberrations of Immune Response

Overview of Talk

• CD4/CD8 T cell ratio • Loss of Naïve T cell numbers • CD28 T cell expansion • CMV infection • Similarity of HIV disease and aging

Groups Studied

• HAART-suppressed: On successful antiretroviral therapy with plasma viral load <75 copies/mL

• Non-controllers: Plasma viral load >10,000 copies/mL

• HIV negative: High-risk individuals presenting for post-exposure prophylaxis

Patient characteristics N=50

Non-controller N=29

HAART Suppressed N=21

Age

44 (33-66)

47 (32-61)

Years infected

15 (3-25)

10 (5-20)

CD4

274 (10-687)

497 (300-1079)

CD8

911 (230-2644)

1037 (484-1693)

HIV RNA (log) 4.46 (4.15-4.87)

1.88

HIV and CD4/CD8 ratio

• Decreased CD4/CD8 ratio reported as hallmark of infection

• CD4/CD8 ratio associated with increased T cell activation

• Inverted CD4/CD8 ratio predictor of mortality in general population

Gerstoft J, Scand J Infect Dis; Frazer I.H. Q J Med 1986; Serrano-Villar, S AIDS 2012

Decreased CD4/CD8 Ratio Persists Despite HIV therapy

0

.25

.5

.75

1

1.25

1.5

1.75

2

2.25

HAART Suppressed

N=62

Non Controller

N=38

HIV Negative

N=44

<0.0001

<0.0001

<0.0001

CD

4:C

D8

Rat

io

Presenter

Presentation Notes

Could look at cd4 count and CD8 count as well to see what factor contributes to ratio

Decreased CD4 and Increased CD8 contribute to Inverted Ratio

HAART Suppressed

N=62

Non Controller

N=38

HIV Negative

N=44

CD4 CD8

200

400

600

800

1000

1200

1400

HAART Suppressed

N=62

Non Controller

N=38

HIV Negative

N=44

0.005

NS

Cel

ls/m

cl

Presenter

Presentation Notes

Could look at cd4 count and CD8 count as well to see what factor contributes to ratio

NAIVE

NON-EFFECTOR

EFFECTOR EFFECTOR MEMORY

CENTRAL MEMORY

Generation of CD8+ T cell memory

Function of T cell Subsets

Naïve Memory Effector

Memory

IL-2 Proliferation

IL-2 IL-4 IFNg TNFa B cell diff

IFNγ TNFα Perforin Granzyme Cytotoxic

CD45RA CCR7 CD28 CD27

+ + + +

- + + +

+ - + +

- - + +

+ - + -

- - + -

+ - - +

- - - +

+ - - -

- - - -

0 5

10 15 20 25 30 35 40 45 50

Seronegative Subjects Mainten Naïve CD8+ T cells

% o

f CD

3+C

D8+

Pop

ulat

ion

SERONEGATIVE


+ + + +

- + + +

+ - + +

- - + +

+ - + -

- - + -

+ - - +

- - - +

+ - - -

- - - -

0 5

10 15 20 25 30 35 40 45 50

Progressive HIV Disease Causes Loss of Naïve T cells

% o

f CD

3+C

D8+

Pop

ulat

ion

PROGRESSOR SERONEGATIVE


+ + + +

- + + +

+ - + +

- - + +

+ - + -

- - + -

+ - - +

- - - +

+ - - -

- - - -

0 5

10 15 20 25 30 35 40 45 50

HAART SUPPRESSED PROGRESSOR SERONEGATIVE

HAART Treatment Does Not Restore Naïve CD8+ T Cells

% o

f CD

3+C

D8+

Pop

ulat

ion

T cells can respond to cancer cells

T cells can respond to invading pathogens

Uncontrolled HIV Increases Frequency of CD8+CD28- Population

0 10 20 30 40 50 60 70 80


+ +

+ -

- +

- -

CD28 CD27

% o

f Tot

al C

D8+

T c

ells

Antiretroviral Therapy Does Not Restore CD28+:CD28- Balance

0 10 20 30 40 50 60 70 80

+ +

+ -

- +

- -


CD28 CD27

% o

f Tot

al C

D8+

T c

ells

HIV and Expansion of CD28

• Expansion of CD28- T cells have been reported in HIV disease

• Telomere length of CD28- cells equal to those of HIV-uninfected centenarians

Effros, RB AIDS 1996

Consequences of HIV on the Immune System (Despite Effective Therapy)

• Continued decrease of CD4/CD8 • Continued decrease of Naïve CD8+ T

Cells • Persistent CD28- Expansion • Increased secretion of IFN-γ • Heightened CMV-specific responses

Changes in Immune System Seen During Human Aging

• Inverted CD4:CD8 ratio ** • Decline in CD4+ T cells • Lower Naïve/Memory T cell ratio • Accumulation of CD28- T cells ** • Increased production of IFN among CD8+ T cells • Decreased ability to proliferate or produce IL-2 • Increased CMV seropositivity and CMV-specific T cell

response ** • Increased levels of proinflammatory cytokines

Potential Implications for ARV-Treated Individuals

• Does HIV cause premature aging of the immune

system?

• Do these abnormal phenotypes relate to clinical outcomes?

• Do these aberrancies improve with time on therapy? • Does earlier treatment prevent some of these

abnormal immunologic phenotypes?

• What is contribution of antitretroviral therapy itself to immunologic changes?

Ongoing studies

• Does HIV cause premature aging of the immune system? – Carefully controlled studies of HIV-infected and uninfected

individual

• Do these abnormal phenotypes relate to clinical outcomes? – Association of phenotypes and clinical outcomes

• Do these aberrancies improve with time on therapy?

– Longitudinal evaluation of patients on HAART

• Does earlier treatment prevent some of these abnormal immunologic phenotypes?

• What is contribution of antitretroviral therapy itself to immunologic changes?

Acknowledgements

Mike McCune Steve Deeks

Douglas Nixon Jeff Martin

Walter Moretto Elizabeth Sinclair

Rebecca Hoh Priscilla Hsue Hiroyu Hatano

All participants in SCOPE cohort

There Is Marked Heterogeneity of HIV-specific CD4+ Responses Among Elite

Controllers

Gag

-spe

cific

CD

4+IF

Nγ+

IL2+

0

1

2

3

Elite Controller

VL<50

N=31

Viremic Controller

(VL 50-2000)

N=30

Non Controller

(VL>10,000)

N=26

HIV Negative

N=36

HAART Suppressed

(VL<50)

N=55

Elite Controllers Have Higher Levels CD8+IFN-γ+t Cells Compared With

Suppressed P<0.0001

4

0

1

2

3

Gag

-spe

cific

CD

8 IF

N γ "b

right

"

Elite Controller

(VL<50) N=31

Viremic Controller

(VL 50-2000) N=30

Non Controller

(VL>10,000) N=34

HAART Suppressed

(VL<50) N=55

Cytokines being used: IL-2, IFN-γ, MIP1β, TNFα

0 5000 10 4 50000 10 5

MIP1β

0

10 3

10 4

10 5

0.11

0 10 3 10 4 10 5

IFNγ

0

10 3

10 4

10 5

2.81

0 10 2

10 3

10 4

10 5

IL-2

0

10 3

10 4

10 5

CD

4 6.86

0 10 3

10 4

10 5

TNFα

0

10 3

10 4

10 5

CD

4 13.6

Elite and Viremic Controllers Have High Gag Specific CD4 Responses

Any

com

bina

tion

of c

ytok

ines

0

1

2

3

4

5

CD4

Elite

Con

trol

ler

Non

-con

trol

ler

Supp

ress

ed

Controllers and Non-controllers Have High Levels of Gag-specific

CD8 T Cells

Non-controller

Any

com

bina

tion

of c

ytok

ines

Elite Controller Suppressed 0

2

4

6

8

10

12 CD8

Elite

Con

trol

ler

Non

-con

trol

ler

Supp

ress

ed

Among All Groups, the Majority of CD8 Cells Produce 1 Cytokine

Only

0

1

2

3

4

5

6

7

8

Elite

Con

trol

ler

Non

-con

trol

ler

Supp

ress

ed

Elite

Con

trol

ler

Non

-con

trol

ler

Supp

ress

ed

Elite

Con

trol

ler

Non

-con

trol

ler

Supp

ress

ed

Elite

Con

trol

ler

Non

-con

trol

ler

Supp

ress

ed

2 cytokines 3 cytokines 4 cytokines 1 cytokine

Controllers Have High Levels of T Cells That Secrete Four Cytokines

Elite

Con

trol

ler

Non

-con

trol

ler

Supp

ress

ed

Elite

Con

trol

ler

Non

-con

trol

ler

Supp

ress

ed

0

.002

.004

.006

.008

.01

.012

.014

.016

.018

0

.005

.01

.015

.02

.025

.03

CD4 CD8

HLA type and Gag-specific T-cell responses.

Emu B et al. J. Virol. 2008;82:5398-5407

Presenter

Presentation Notes

HLA type and Gag-specific T-cell responses. The frequency of Gag-specific CD8+ and CD4+ IFN-γ+ IL-2+ T-cell responses among controllers and noncontrollers with protective and without protective HLA alleles is shown. Protective alleles are defined as HLA-B*13, HLA-B*27, HLA-B*57, HLA-B*58, and HLA-B*81.

Gating strategy Si

de S

catte

r

0 10 2

10 3

EMA-PE-Cy5.5

CD3 ECD

0 10 3 10 4 10 5

10 1

10 2

10 3

10 4

10 5

81.6

0 10 3 10 4 10 5 0

1000

2000

3000

4000

0 10 3 10 4 10 5

10 1

10 2

10 3

10 4

10 5

64.3

0 10 3 10 4 10 5 0

1000

2000

3000

4000

Num

ber o

f cel

ls

CD3 ECD

0 10 3 10 4 10 5

0

10 3

10 4

10 5

CD

28 A

PC 24.7

0.77

21.9

52

0 10 3 10 4 10 5

0

10 3

10 4

10 5 29.1

16

CCR7 PE-CY7 CD27 APC-CY7

CD

45R

A PE

18

36.8

CD3 ECD 0 10 2 10 3 10 4 10 5

0

10 2

10 3

10 4

10 5

1.04

IFN-GAMMA FITC

CD

8 C

asca

de B

lue

0 10 2 10 3 10 4 10 5

0

10 2

10 3

10 4

10 5

CD

8 C

asca

de B

lue

15.3

84.2

Gating strategy

Increased IFNγ but not IL-2 Production in Response to SEB

0

2.5

5

7.5

10

12.5

15

17.5

20


IL-2 IFN-γ

NS P<0.005

Across Subsets, Maintained or Increased IFNγ Production with HIV

0

5

10

15

20

25

30

35

40



+ + + +

- + + +

+ - + +

- - + +

+ - + -

- - + -

+ - - +

- - - +

+ - - -

- - - -

IFN

γ Pr

oduc

tion

amon

g C

D8+

T c

ells

Decreased IL-2 Production in CD28- Subsets in Treated Individuals

2

4

6

8

10

12

14

16



+ + + +

- + + +

+ - + +

- - + +

+ - + -

- - + -

+ - - +

- - - +

+ - - -

- - - -

IL-2

Pro

duct

ion

amon

g C

D8+

T c

ells

CD38 Expression Better Predictor of Survival than Viral Load

Giorgi, J, JID, 1998

Increased Production of CMV-specific IFN-γ Responses in T cells

of Elderly

Vescovini, J. Imm 2007

Presenter

Presentation Notes

Also true for TNFa

CMV-specific T cells in elderly are more differentiated

CD3 Counts remain stable even with Viral Replication

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

CD3

Cel

ls/m

L

HAART Suppressed

N=53

Non Controller

N=42

HIV Negative

N=22

CMV-Specific IFNγ Response is Associated with Increased Frequency

of Differentiated T cells

CD

4 H

ighl

y D

iffer

entia

ted

P=0.06

CD4 CMV IFNγ Response CD8 CMV IFNγ Response

CD

8 H

ighl

y D

iffer

entia

ted

0

10

20

30

40

50

60

-2 0 2 4 6 8 10 12 14

P<0.0001

0

5

10

15

20

25

30

35

40

45

50

-1 0 1 2 3 4 5 6 7 8 9 10

During HAART, CD4 CMV-specific Response Associated with Decreased

Frequency of Naïve CD4

CD

4 N

aive

P=0.06


CD

4 H

ighl

y D

iffer

entia

ted

10 15 20 25 30 35 40 45 50

-5 0 5

-1 0 1 2 3 4 5 6 7 8 9 10

P=0.01

-10

0

10

20

30

40

50

60

70

-1 0 1 2 3 4 5 6 7 8 9 10

CMV-Specific IFN Response is Associated with Decreased Frequency

of Naïve T cells

-10

0

10

20

30

40

50

60

70

-1 0 1 2 3 4 5 6 7 8 9 10

P=0.002

CD

4 N

aive

-10

0

10

20

30

40

50

60

70

-2 0 2 4 6 8 10 12 14

P=0.0003


CD

8 N

aive

Cell Receptors for HIV Entry

CD4

Chemokine Receptor 5 (CCR5)

Target cell

Y. Feng et al. Science, 1996.

CCR5-∆32: Mutant Protein

Y. Feng et al. Science, 1996.

2006 Diagnosed with acute leukemia (AML).

Received standard chemotherapy* (106 copies of HIV-1 RNA)

Relapsed 7 months later Allogenic stem cell transplant from a

CCR5∆32 homozygous donor in Feb. 2007

AML Relapsed 1 year after transplantation Re-induction chemotherapy

Day 391: received a second transplant from same donor

2013: Antiviral therapy has never been re-started because patient has

remained HIV undetectable Cured ?

40 yo man HIV+ Stable on HAART

Virus not found Antibody response negative

Fraction of Naïve CD4 or CD8 T cells do not increase with time

0

10

20

30

40

50

60

70

80

CD8 CD4

Prop

ortio

n

First Second First Second

Absolute number of Naïve T cells also did not Increase

0

200

400

600

800

1000

1200

CD8 CD4

Cel

ls/µ

L

First Second First Second

Increased Differentiation of CD4 T Cells With HIV Infection

0

5

10

15

20

25

30

35

40

45


+ + + +

- + + +

+ + + -

- + + -

+ - + +

- - + +

+ - + -

- - + -

+ - - +

- - - +

+ - - -

- - - -


HAART Treatment Does Fully Decrease Frequency of Mature CD4

0

5

10

15

20

25

30

35

40

45


+ + + +

- + + +

+ + + -

- + + -

+ - + +

- - + +

+ - + -

- - + -

+ - - +

- - - +

+ - - -

- - - -


Naïve CD8 T cell percentage is not associated with Total CD4 count or Nadir

0

5

10

15

20

25

30

35

40

45

50

200 400 600 800 1000

CD4

R2=0.139 P=0.3384

0

5

10

15

20

25

30

35

40

45

50

-50 0 50 100 150 200 250 300

Nadir

R2=0.029 P=0.4527

Prop

ortio

n of

Naï

ve C

D8

T ce

lls

Naïve CD8 T cell percentage Not Associated With Length of Infection or Length of Viral Suppression

Naïve CD8 T cell percentage not associated with Age

Total T cell Proliferation Decreased with HAART

.2

.4

.6

.8

1

1.2

1.4

1.6

.1

.2

.3

.4

.5

.6

.7

.8

.9

Expr

essi

on o

f Ki6

7

CD4 CD8

HIV Negative Non-Controller HAART Suppressed

P=0.05 P=0.13

P=0.12 P=0.81

Ki67 Decreased in HAART Suppressed Individuals

1

2

3

4

5

6

7



+ + + +

- + + +

+ - + +

- - + +

+ - + -

- - + -

+ - - +

- - - +

+ - - -

- - - -

Ki6

7 Ex

pess

ion

Amon

g C

D8+

T c

ells

Decrease in Naïve T cells with Aging

Gupta, S, Imm Rev 2005

Presenter

Presentation Notes

Young here are 30 folks 20-35 years Aged ar 45 folks aged 65-90 Cd28 and cd45raand ccr7 are used

Expansion of CD28- Cells with Age

Fagnoni, FF, Immunology 1996

CMV Seropositive individuals have Expansion of CD28- cells

Pawelec G, 2007

Naïve T cell populations Lost During Untreated HIV infection

Roederer M, JCI, 1995

CMV-specific Responses Persist with Viral Suppression

0

.2

.4

.6

.8

1

1.2

1.4

1.6

CD

8 IF

Nγ

RES

PON

SE

LTNP Non- Controller

Virally Suppressed

• >90% HIV+ individuals are also CMV seropositive

• Most HIV-infected individuals have robust CMV-specific T cell response, even in absence of HIV-specific T cell response

• CMV responses are associated with atherosclerosis among HIV-infected individuals

Decreased CD4/CD8 Ratio in Elderly Predicts 4-year Mortality

Survivors Non-survivors % dead P-value

CD4/CD8

<1.0 5 17 77% .005

>1.0 65 50 43%

Wikby A, 2005

Elderly have increased CMV-specific CD8 T cells

• CMV Seropositivity associated with increased mortality

• Elderly have ncreased T cells specific for CMV-derived epitopes

• CMV-specific cells have restricted clonality, terminally differentiated, with some dysfunctional aspects

hiv and the immune system: complexities and...

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