HIV Eradication by Stem Cell Transplantation: Is It Feasible? G. - - PowerPoint PPT Presentation

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HIV Eradication by Stem Cell Transplantation: Is It Feasible? G. - - PowerPoint PPT Presentation

Dec 13, 2022 213 likes •431 views

HIV Eradication by Stem Cell Transplantation: Is It Feasible? G. Htter Institute for Transfusion Medicine and Immunology, Mannheim The weapons of allo SCT Depletion of host immune system Reduction of the HIV reservoir? Replacement of host

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SLIDE 1

HIV Eradication by Stem Cell Transplantation: Is It Feasible?

  • G. Hütter

Institute for Transfusion Medicine and Immunology, Mannheim

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SLIDE 2

The weapons of allo SCT

Depletion of host immune system Replacement of host immune system Graft vs leukemia/tumour activity Reduction of the HIV reservoir? Complete? Is there a graft vs HIV activity?

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SLIDE 3

Feasibility of allo SCT in patients with HIV

25 50 75 100 50 100

Without HAART (n=39) With HAART (n=16) Months elapsed Percent survival

But! No lasting effect on HIV infection!

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SLIDE 4

Case report: patient´s history

40-year-old patient

HIV infection since ´96 HAART since 2002

  • HIV-1 RNA < detection limit
  • CD4+ T-cells 300-400 /l
  • No AIDS defining illnesses

Spring 2006 weakness June ´06 anemia July ´06 pancytopenia

AML FAB M4 46XY

Donor request: 232 HLA identical!

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SLIDE 5

HIV-1 requires CD4 & CCR5 or CXCR4

HIV transmission

CCR5-32 deletion = >

  • Inactive receptor
  • Frequency 10-20% (1% homozygous)
  • CCR5-32/32 resistant against R5
  • in vivo highly resistant against X4 and dual
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SLIDE 6

Frequency of the CCR5-delta32 allele

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SLIDE 7

232 HLA identical donors 80 registered at the DKMS CCR5-32 screening

Donor search and genotyping

therefrom Request for blood samples

Donor 61 CCR5-32/32

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SLIDE 8

Development of the CCR5-32 genotype

Control 200bp 168bp CCR5-+/32 Patient after SCT CCR5-+/+ CCR5-32/32 (donor) Patient before SCT

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SLIDE 9

102 103 104 105 106 107

HIV-1 RNA (cop/mL)

AML diagnosis AML relapse 1st allogeneic transplantation HAART 2nd allogeneic transplantation HAART

100 200

CD4+ T-cells (/L)

HIV-1 RNA CD4+ T cell count

  • 227
  • 4

+ 61 + 108 + 332

  • 206
  • 85

+ 159 + 548 + 391

300

days

100% chimerism

+ 416

400

+ 1146

500 600

HIV DNA env HIV DNA LTR

800

HIV-1 & T-cell reconstitution after CCR5-delta 32 allo SCT

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SLIDE 10

env6537s and 7254as/env5as

97,1% R5 2,9 % X4 oder dual

Determination of patient´s virus

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SLIDE 11

Serodeconversion

p120 p41 p31 p24 p17 c

  • n

t r

  • l

B e f

  • r

e T x 2 m

  • .

a f t e r T x HIV-2

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SLIDE 12

Immunohistology of intestinal mucosa (day + 159)

CCR5+

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SLIDE 13

CCR5 tissue chimerism (gut)

6 mo. after Tx T-lymphocytes macrophages 2 years after Tx

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SLIDE 14

The “cure” question

…sterilizing cure in this patient can only be clarified post mortem…

Robert Gallo (Dec. 8, 2009 at the HIV Persistence Workshop, St. Martin)

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SLIDE 15

Arguments to solve the “cure” question

Good Fair Poor HIV RNA negative HIV DNA negative Single PCR negative Gut biopsies negative Brain biopsie negative No rebound Serodeconversion Normal CD4 cell count Tissue CCR5 chimerism

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SLIDE 16

Arguments to solve the “cure” question

Good Fair Poor HIV RNA negative X HIV DNA negative X Single PCR negative X Gut biopsies negative X Brain biopsie negative X No rebound X Serodeconversion X Normal CD4 cell count X Tissue CCR5 chimerism X

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SLIDE 17

The “cure” question

…sterilizing cure in this patient can only be clarified post mortem…

Robert Gallo (Dec. 8, 2009 at the HIV Persistence Workshop, St. Martin)

Does it make sense to search for sterilizing cure?

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SLIDE 18

The search for patient No. 2

No. gender age diagnosis location HLA matching Donors Donors CCR5 tested Status

(+ , + ) (+ , -) (-, -)

1 Male 40 AML Berlin, Germany 232 52 12 1 Tx Feb ` 08 2 Male adult lymphoma Freiburg, Germany yes ND died before Tx 3 Female 3 DBA Heidelberg, Germany 120 + 1* 103 17 1*

  • ngoing

4 Male adult MDS Lausanne, Switzerland 1 pending

  • ngoing

5 Male 29 lymphoma Mainz, Germany 1 1 Tx Nov 2009 6 Male 15 leukaemia Jerusalem, Israel 3 + 3* 3* Jan 2010, died after Tx 7 Male 50 CMML Berlin, Germany 60 5 5 Tx in April 2010 8 Male adult lymphoma Mannheim, Germany pending

  • ngoing

*only 3/6 HLA-match

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SLIDE 19

Summary

Allo SCT in patients with HIV is feasible Allo SCT alone does not improve course of HIV infection Case of allo SCT with a CCR5-delta32 homozygous donor highlights the decisive role of CCR5 in maintaining HIV infection More cases necessary for further conclusions Can we translate this approach into a more feasible way? Allo SCT is not a “standard”-option for HIV treatment

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SLIDE 20

Acknowledgements

  • Med. Dept. III Charité CBF
  • Dr. D. Nowak
  • S. Ganepola
  • M. Mossner
  • Dr. A. Müßig

PD Dr. I.W. Blau

  • Dr. O. Blau
  • Prof. L. Uharek
  • Prof. W.K. Hofmann
  • Prof. E. Thiel

DKMS

  • Prof. G. Ehninger
  • Dr. A. Schmidt
  • P. Leuker
  • Inst. of Virology Charité CM

PD Dr. J. Hofmann

  • Dr. M. Raftery
  • Inst. of Biochemistry

Charité CM

  • Dr. M. Meixner
  • Inst. of Immunology

Charité CM

  • S. Fuhrmann
  • M. Streitz

Robert-Koch-Institut, Berlin

  • Dr. C. Kücherer
  • Inst. of clin. & molec. Virology, Erlangen
  • Dr. K. Metzner

Stefan-Morsch-Foundation

  • E. Morsch
  • Med. Dept. I Charité CBF
  • Dr. K. Allers
  • Prof. T. Schneider

Max-Plank-Institut Informatik, Saarbrücken

  • A. Thielen

In cooperation with: Jeffrey Laurence, Cornell Frank Maldarelli, NCI Robert & Janet Siliciano, JHMI John Coffin, Tufts Nicole Bernard, McGill, Toronto John A. Zaia, City of Hope Supported by: amfAR