Glucocorticoid treatment as a means to the decrease the CD16+ ...

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Glucocorticoid treatment as a means to the decrease the CD16+ ...

“Towards an HIV Cure”

Pre-Conference Symposium

20 & 21 July 2012

Glucocorticoid treatment as a means to

the decrease the CD16 + monocyte virus

reservoir in SIV/HIV infection

Marcin Moniuszko, MD, PhD

Department of Allergology and Internal Medicine

Medical University of Bialystok, Poland


Monocyte subsets

CD14+CD16+

CD14

CD16


Increased numbers

of CD16+ monocytes

• Bacterial infections (including sepsis, tuberculosis)

• Inflammatory disorders:

rheumatoid arthritis

diabetes

atherosclerosis

sarcoidosis

Kawasaki disease

pancreatitis

• Hemodialysis


Monocyte subsets

CD14++CD16-

classical

CD14++CD16+

intermediate

CD14

CD14+CD16++

non-classical

(most mature

stage)

CD16


CD16+ monocytes

and HIV infection


CD16+ monocytes in HIV infection

Han et al., J AIDS 2009


CD16+ monocytes in HIV infection

CD14++CD16+

intermediate

CD14+CD16++

non-classical

Han et al., J AIDS 2009


CD16+ monocytes

and HIV reservoir


CD16+ monocytes preferentially harbor

HIV in HAART-treated patients

Ellery PJ et al., J Immunol. 2007


CD16+ monocyte subset is more

permissive to HIV infection

Ellery PJ et al., J Immunol. 2007


How to decrease

CD16+ monocyte

reservoir?


Lessons from GC

use in asthma


Effects of GC on monocyte subsets

in asthma

Before oral GCS

After 7 days

of oral GCS

Moniuszko et al., Clin Immunol 2009


CD16+ monocytes in

pathogenic and nonpathogenic

SIV and HIV

infection


Naïve

rhesus macaque

C

4.96%

I

SIV-infected

rhesus macaque

15.2%

CD14

CD16

NC

4.49%

CD14

CD16

8.33%

Naïve

sooty mangbey

6.61%

SIV-infected

sooty mangbey

13.6%

CD14

CD14

CD16

2.1%

CD16

1.1%


%CD14++CD16+

%CD14+CD16++

20

p


humans

humans

un-infected human

HIV infected

6.47%

46.8%

CD14

6.37%

14.5%

CD16

CD14++CD16+

CD14+CD16++

P=0.004

P=0.03

50

16

% of monocytes

40

30

20

10

12

8

4

0

0

un-infected

HIV

un-infected

HIV


Effects of in vitro GC

treatment on CD16+

monocytes in SIV- and HIVinfected

subjects


No drug

GC

11.5%

9.87%

un-infected

RM

SIV mac251

infected RM

SIV mac251

infected RM

+HAART

CD14 CD14

CD14

1.98%

CD16

41.8%

2.64%

CD16

34.4%

2.93%

CD14 CD14

CD14

0.83%

CD16

7.92%

0.12%

CD16

12.2%

0.42%

CD16

CD16


CD14++CD16+

CD14+CD16++

un-infected

RM

n=6

% of monocytes

50

40

30

20

10

0

p


No drug

GC

HIV

infected humans

85.1%

3.1%

26.7%

1.27%

CD14

69.2%

40.9%

HIV

infected

+HAART

8.37%

3.09%

CD16


CD14++CD16+

CD14+CD16++

P=0.035

P=0.063

HIV

infected

humans

(N=5)

% of monocytes

80

60

40

20

0

% of monocytes

20

15

10

5

0

0 24h 0 24h

HIV

infected

humans

+HAART

(N=5)

% of monocytes

80

60

40

20

0

P


MP

sixfold

higher doses

3 SIV-positive

macaques

421

444

507

2 SIV-negative

macaques

439

442

D0 D4 D7

BLOOD

Rectal biopsies

BAL

MP

clinically applied doses

BLOOD

EUTHANASIA

Blood and tissue

collection


Day 0 Day 4

12.8%

8.25%

SIV (+)

421

CD14

5.98%

CD14

0.28%

CD16

CD16

14.3%

10.1%

SIV (+)

444

CD14

5.10%

CD14

1.09%

CD16

CD16

10.3%

6.46%

SIV (+)

507

CD14

7.29%

CD14

0.68%

CD16

CD16


Day 0 Day 4

2.38%

3.29%

SIV (-)

439

CD14

1.16%

CD14

0.43%

CD16

CD16

6.39%

16.8%

SIV (-)

442

CD14

CD14

3.00%

0.27%

CD16

CD16


CD16+

CD14++CD16+

CD14+CD16++

P=0.005

P=0.002

P=0.019

% of monocytes

20

15

10

5

0

% of monocytes

15

10

5

0

D0 D4 D0 D4 D0 D4

% of monocytes

8

6

4

2

0


Rectal HAM56-positive

macrophages

Rectal HAM56-positive

macrophages

total area occupied by

macrophages /

/10 high power fields

150

125

100

75

50

25

0

D 0 D 7


Conclusion

There is a chance that treatment with GC in

combination with HAART, by decreasing the

CD16 + monocyte populations, a long lived cellular

reservoir for HIV, could contribute to HIV

eradication.


Acknowledgments

NIH, Bethesda, MD

Genoveffa Franchini

Katherine McKinnon

Charles Brown

Vanessa Hirsch

Monica Vaccari

Shari Gordon

Poonam Pegu

Namal Liyanage

Claudio Fenizia

Robyn Washington-Parks

Marjorie Robert-Guroff

Doster Melvin

Emory University, Atlanta,

GA

Guido Silvestri

Medical University of

Bialystok, Poland

Robert Flisiak

Anna Grzeszczuk

Milena Dabrowska

ABL, Rockville,

MD

Hue Chung

Ranajit Pal


Viral loads

100000

10000

1000

MP

Clinically

applied

doses

MP

fourfold

higher

doses

100

10

1

D 0 D4 D 7

detection

threshold


Fig. 6 A

3000

2000

1500

cells/µL

2000

1000

CD3+CD4+

cells/µL

1000

500

CD3+CD8+

0

D 0 D 4

0

D 0 D 4

B

CD3+CD4+Ki-67+

CD3+CD4-Ki-67+

150

150

cells/µL

100

50

cells/µL

100

50

C

0

250

D 0 D 4 D 0 D 4

0

CD3+CD4+CD25+ CD3+CD4-CD25+ CD4+FoxP3+

10

D

200

cells/µL

200

150

100

50

cells/µL

8

6

4

2

cells/µL

150

100

50

0

D 0 D 4 D 0 D 4

0

0

D 0 D 4


Fig. 2A

CCR5

expression

CD14++CD16-

SIV-infected

rhesus

8.38

SIV-infected

sooty mangabey

5.58

CD14++CD16+

12.2

5.91

CD14+CD16+

6.59

5.43


Fig. 2B

Naïve RM

CCR5 MFI

SIV-infected RM

25

P

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