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HIV+ Long-Term Nonprogressors: Understanding Natural Immune Control of HIV. Stephen A. Migueles, M.D. HIV-Specific Immunity Section, Laboratory of Immunoregulation, NIAID, NIH, Department of Health & Human Services. Overview. LTNP Host Genetic Factors: HLA Associations

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hiv long term nonprogressors understanding natural immune control of hiv

HIV+ Long-Term Nonprogressors: Understanding Natural Immune Control of HIV

Stephen A. Migueles, M.D.

HIV-Specific Immunity Section,

Laboratory of Immunoregulation, NIAID, NIH,

Department of Health & Human Services

overview
Overview
  • LTNP
  • Host Genetic Factors:
    • HLA Associations
  • Host Immune Response Factors
    • HIV-Specific CD8+ T Cells
slide3

Patient 1

  • 46 year-old African American medical assistant from New Orleans diagnosed with HIV infection in 1989.
  • Her only risk factor was unprotected heterosexual intercourse.
  • Past medical history was significant for hypertension and depression.
  • At the time of her diagnosis, she was divorced and living with her three children, all HIV-negative and healthy.
  • She remained clinically well over time with stable, “low-normal” CD4 counts and “undetectable” viral loads despite no ART.
  • Her PCP referred her to NIH in 2004.
  • She was displaced by Hurricane Katrina and had a relapse of her depression.
  • Her CD4 counts have been stable and her HIV RNA levels have remained <50 copies/ml.
slide4

Patient 2

  • 44 year-old African American barber from Washington, D.C. diagnosed with HIV infection in 1986 and was lost to follow-up because “I wasn’t feeling bad.”
  • Risk factors were IDU and unprotected heterosexual intercourse.
  • He was incarcerated in 2004 and found to be infected with HCV 1a.
  • In 2006, his transaminases were 4x the upper limit of normal and his HCV load was 4.7 million IU/ml.
  • CD4 count was 1,314 cells/ml with HIV RNA levels <50 copies/ml.
  • Liver biopsy (6/07) revealed moderate portal inflammation, moderate piecemeal necrosis and focal mild peri-sinusoidal fibrosis.
  • SVR was achieved with 48 weeks of pegylated interferon--2b and ribavirin therapy.
  • He is antiretroviral naïve, yet has not experienced any opportunistic diseases.
  • He has maintained normal CD4 counts and his HIV RNA levels have been <50 copies/ml in 26 out of 27 determinations.
slide5

Patient 3

  • 73 year-old Caucasian divorced, retired businessman from Florida reported a rash and high fevers 2 weeks after after unprotected intercourse with a male acquaintance in 1987.
  • His sexual partner’s long-term companion had recently died from AIDS.
  • The sexual partner eventually died from fulminant AIDS-related Pneumocystis jiroveci pneumonia.
  • His past medical history was remarkable for ankylosing spondylitis, ulcerative colitis, type II DM and BPH.
  • A psychic friend told him that he would not die from HIV, had important “work” to do and should enroll in a study.
  • Since 1998, his course had remained stable with a CD4 nadir of 748 cells/ml and HIV RNA levels <50 copies/ml (31/32 measurements), except for one “blip” to 1,787 copies/ml in 1998.
  • He is antiretroviral naïve.
slide6

Why Study HIV+ LTNP?

  • As the AIDS pandemic continues to expand, the need for an effective HIV vaccine has never been greater.
  • Durable control of HIV replication does occur in rare individuals (<0.5% of the infected population) called long-term nonprogressors (LTNP), HIV controllers, elite controllers or elite suppressors.
  • Understanding the mechanisms of control in LTNP is likely to provide critical information for development of effective vaccines and immune-based therapies.
slide7

Protocol 02-I-0086: Leukapheresis Procedures to Study HIV-Specific Immunity Long-Term Nonprogressor (LTNP)

slide8

Benefits of Research Participation for LTNP

  • Remuneration
    • $100 for 2-pass leukapheresis; $200 for 4-pass
  • Insight into their disease course
  • Contribute to an important cause
  • Paying tribute to lost loved ones
  • Beacons of hope for their children and future generations
slide9

LTNP Case Definition

  • HIV+ by standard antibody tests
  • Healthy with stable clinical course
  • Negative history of opportunistic diseases
  • Stable, non-declining T cell counts
  • Set point HIV RNA levels <50 copies/ml
  • No antiretroviral or immunomodulatory treatment
slide13

Belief Systems and Behaviors of LTNP

  • “I exercise religiously and eat well.”
  • “I smoke 2 packs a day, drink 2 liters of diet Coke a day and never exercise. I have no clue!”
  • “I was feeling depressed and drank rat poison when I was in my 20’s. I’m convinced that’s what made my immune system different.”
  • “I drink only the most expensive red wines from France!”
  • “It’s because of my family’s support and my positive frame of mind.”
  • “God’s given me a gift for whatever reason; it’s got nothing to do with what I do. I’m just blessed.”
proposed mechanisms of non progressive hiv infection
Proposed Mechanisms of Non-progressive HIV Infection
  • Virus Factors
    • Inactivating mutations in nef, tat, rev or vpr
    • CTL-induced escape mutations
  • Host Genetics
    • Heterozygosity for CCR5 32 deletion
    • Protective HLA class I alleles
  • Host Immune Response Factors
    • Adaptive immune system
      • Effective humoral responses
      • HIV-specific CD4+ T cell responses
      • HIV-specific CD8+ T cells responses
proposed mechanisms of non progressive hiv infection1
Proposed Mechanisms of Non-progressive HIV Infection
  • Virus Factors
    • Inactivating mutations in nef, tat, rev or vpr
    • CTL-induced escape mutations
  • Host Genetics
    • Heterozygosity for CCR5 32 deletion
    • Protective HLA class I alleles
  • Host Immune Response Factors
    • Adaptive immune system
      • Effective humoral responses
      • HIV-specific CD4+ T cell responses
      • HIV-specific CD8+ T cells responses
hla and hiv infection
Protective

Heterozygote advantage

A*32

B*14

B*27

B*44

B*51

B*57

B*58

Cw*08

Homozygosity for Bw4

Bw4-80Ile alleles/KIR3DS1

B*57 supertype/KIR3DL1

Susceptible

A*24

B*3

B*8

B*35-Px

Cw*04

Cw*16

HLA and HIV Infection

Buchbinder et al., 1992; Klein et al., 1994; Goulder et al., 1996; Kaslow et al., 1996; Keet et al., 1999; Carrington et al., 1999; Hendel et al., 1999; Migueles et al., 2000; Flores-Villanueva et al., 2001; Martin et al., 2002; Leslie et al., 2004; Martin et al., 2005

slide17

HLA and Disease Association

  • B*27
    • Ankylosing spondylitis
    • Reactive arthritis
    • Arthritis associated with psoriasis, Crohn disease and ulcerative colitis
  • B*57
    • B*5701-Cw*0602 and psoriatic arthritis
    • B*5701 and Abacavir Hypersensitivity Syndrome (AHS)
      • Evidence for cellular immune basis, specifically CD8+ T cell responses (Chessman et al., 2008)
slide18

Soluble Antiviral Factors

(IFN-, TNF-, CAF)

HIV

T Cell Receptor

HIV Peptide-HLA Class I

CD8+ T Cell

Cytotoxic Granules

GrB

Perforin

Cytotoxicity Pathway

(Perforin, Granzymes)

The Immunologic Synapse

HIV-Infected Target Cell

slide19

Soluble Antiviral Factors

(IFN-, TNF-, CAF)

HIV

T Cell Receptor

HIV Peptide-HLA Class I

CD8+ T Cell

Cytotoxic Granules

GrB

Perforin

Cytotoxicity Pathway

(Perforin, Granzymes)

The Immunologic Synapse

HIV-Infected Target Cell

slide20

25

CD69+ IFN-+ CD8+ T cells (%)

Tat

Rev

20

Nef

Env

Pol

15

Gag

10

5

0

3

4

5

7

9

10

17

6

8

25

1

20

21

19

27

15

107

106

29

14

108

2

105

104

102

101

103

B

A

C

D

LTNP

<50

SP

3,996-7,774

Progressors

2,486-249,966

Treated

1,008-7,873

Migueles et al., Proc Natl Acad Sci, 2000

Gea-Banacloche et al., J Immunol, 2000

Migueles and Connors, Imm Letters, 2001

High Frequencies of HIV-Specific CD8+ T Cells Persist in Patients with Poor Restriction of Virus Replication
slide22

CFSE-Labeled Effectors

Fluorescent Dye to Track CD8+ T Cell Proliferation

Targets (CD4+ T Cells)

slide23

0.27

99.7

CD8+ T Cell Proliferation to Autologous HIV-Infected CD4+ T Cells is Greater in LTNP

Uninfected CD4 Targets

Infected CD4 Targets

4.67e-3

100

1.58

98.4

Progressor

CD8

75.6

24.4

LTNP

Migueles et al., Nature Immunol, 2002

CFSE

slide24

Infected

Uninfected

Day 1

0

26.5

1.19e-3

27

Day 2

1.49e-3

5.94e-3

73

73.5

0.02

22.6

3.2e-3

22.6

Day 3

0.019

77.4

0.027

77.3

7.36e-3

17

2.93

21.7

Day 4

0.046

23.1

14.1

22.3

0.037

83

0.3

75.1

0.81

62.9

0.019

76.8

Day 5

43.5

17.7

0.052

18

0.023

81.9

1.04

37.8

Day 6

0.03

18.9

63.7

18.7

Perforin

CFSE

0.044

81.1

0.32

17.2

CD8+ T Cell Proliferation Is Coupled with Perforin Expression

LTNP

Net Perforin Expression

Perforin+ CD8+ T Cells (%)

Day #

slide25

87.9

85.6

58.4

61.5

45.7

46.4

Day 6 HIV-Specific CD8+ T Cells of LTNP Exhibit Greater Up-Regulation of Cytotoxic Proteins than Cells of Progressors

P<0.01

P=0.004

P>0.5

GrB

Perforin

CD107

LTNP

Progressors

slide26

Fluorogenic GrB Substrate

Cytotoxic Granules

“Day 6 or “Day 0” CD8+ T Cell

GrB

Perforin

6 hours

1 hour

GrB Activity

ICE

Infection by p24 (E:T)

IFN-(E:T)

In Vitro Cytotoxicity Assay for Measuring Granzyme B Activity in Live Cells and Infected Cell Elimination (ICE)

Effector

Target

HIV

HIV-Infected CD4+ T Cell

slide27

Quantitative and Qualitative Models of a Recall Response of HIV-Specific CD8+ T Cells

Memory Cell

Effector Cell

Antigen

Recognition

Primarily Quantitative Expansion

Cytolytic

Antigen

Recognition

Quantitative and Qualitative Expansion

Poorly

Cytolytic

slide28

Granzyme B Target Cell Activity

Infected CD4 Elimination

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

P=0.01

GrB Substrate+ Targets (%)

Infected CD4 Elimination (%)

100

50

40

75

30

50

20

25

10

0

0

LTNP

Prog

Rx<50

LTNP

Prog

Rx<50

LTNP

Prog

Rx<50

LTNP

Prog

Rx<50

D#0

D#0

D#0

D#0

D#0

D#0

D#6

D#6

D#6

D#6

D#6

D#6

Perforin+ CD8+ T cells D#6 (%)

100

Infected CD4 Elimination D#6 (%)

70

60

75

50

40

50

30

R=0.79, P<0.001

R=0.92, P<0.001

20

25

10

0

0

0

10

20

30

40

50

0

10

20

30

40

50

60

70

GrB Substrate+ Targets D#6 (%)

GrB Substrate+ Targets D#6 (%)

Day 6 HIV-Specific CD8+ T Cells of LTNP Mediate Greater Cytotoxicity of HIV-Infected CD4+ T Cell Targets than Cells of Progressors

Migueles et al., Immunity, 2008

slide29

Two Models Demonstrating Similar or Disparate Per-Cell Cytotoxic Capacity of HIV-Infected CD8+ T Cells

LTNP

P>0.5

P<0.001

100

100

Progressors

Infected CD4 Elimination D#6 (%)

Infected CD4 Elimination D#6 (%)

80

80

60

60

True Effector:Target Ratio

40

40

20

20

0

0

0

5

10

0

5

10

15

20

15

20

25

25

slide30

100

80

60

40

20

0

0

5

10

15

20

25

Day 6 HIV-Specific CD8+ T Cells of LTNP Mediate Greater Cytotoxicity of HIV-Infected CD4+ T Cell Targets on a Per-Cell Basis than Cells of Progressors

LTNP

LTNP

Progressors

Rx<50

Infected CD4 Elimination D#6 (%)

P<0.001

P<0.001

(IFN-+ CD8+ T Cells) Effector:Target (p24+) Ratio

Migueles et al., Immunity, 2008

Migueles et al., J Virol, 2009

summary conclusions
Summary/Conclusions
  • Immune-mediated control is associated with HLA B*57, but not with increased frequencies of HIV-specific CD8+ T cells.
  • HIV-specific CD8+ T cell proliferation in LTNP is significantly greater than the responses observed in progressors.
  • Expanded HIV-specific CD8+ T cells of LTNP have increased expression of the proteins contained within cytotoxic granules.
  • Following this lytic granule loading, HIV-specific CD8+ T cells of LTNP exhibit extraordinary cytotoxic capacity on a per-cell basis and eliminate HIV-infected CD4+ T cell targets by the efficient delivery of functional GrB.
  • These HIV-specific functions distinguish patients who maintain control of HIV and should be considered in the next generation of HIV vaccines.
slide33

Acknowledgements

CMRS/LIR

Julia Rood

Amy Berkley

Daniel Mendoza

Tiffany Guo

Christine Osborne

Alex Compton

Rohan Joshi

Kristin Weeks

Prasanna Jagannathan

Andy Patamawenu

Alisha C. Laborico

Claire W. Hallahan

JoAnn Mican

Richard T. Davey

Mark Connors

H. Clifford Lane

Anthony S. Fauci

SAIC/NCI/Frederick

Hiromi Imamichi

Frank Maldarelli

Sarah Palmer

Ann Weigand

Clinics

Nancy Cogliano-Shutta

Margaret Lloyd

Mary McLaughlin

Richard Kwan

Gregg Roby

Julia A. Metcalf

Sara Stallings

Catherine Rehm

NIH HLA Laboratory

Sharon Adams

SAIC/NCI/Frederick

Beverly Z. Packard

Akira Komoriya

*The Patients