Ppt0000004 [Lecture seule]nephro- infection in renal allograft recipients: from latent infection to

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Text of Ppt0000004 [Lecture seule]nephro- infection in renal allograft recipients: from latent infection to

  • BK Virus

    Hans H Hirsch

    Transplantation & Clinical Virology Department Biomedicine (Haus Petersplatz)

    Division Infection Diagnostics Department Biomedicine (Haus Petersplatz) University of Basel

    Infectious Diseases & Hospital Epidemiology University Hospital Basel

    Switzerland

    Centre de ConfCentre de Conf öörencerence 28 rue du Docteur Roux 28 rue du Docteur Roux -- 7501575015 ParisParis 22.04.201322.04.2013

  • � Circular double-stranded DNA of 5100 bp � 2 regulatory proteins, 3 structural proteins

    – No classic antiviral target (viral polymerase, protease)

    Polyomavirus (PyV)Polyomavirus (PyV)

    early genes late genes

    non-coding control region

    Background

  • PolyomaviridaePolyomaviridae

    Background

    TSPyV

    O raPyV1BP

    yV

    S qP

    yV

    MPyV HaPyV

    LPyV

    OraPyV2

    MCPyV

    APyV FP

    yV

    Ca Py

    V

    C P

    yV

    G H

    P yV

    M P

    tV

    B at

    P yV

    SL Py

    V

    SV 40

    JCPy V

    SA12

    BKPyV

    HPyV7

    HPyV6

    K IP

    yV W

    U P

    yV

    Wukipolyomavirus Avipolyomavirus

    Orthopolyomavirus 0.2

  • Human Polyomavirus Infection and DiseaseHuman Polyomavirus Infection and Disease

    � BKV – Nephropathy (PyVAN) – Hemorrhagic cystitis (PyVHC)

    � JCV – Multifocal leukoencephalopathy (PyVML)

    � MCPyV – Merkel cell carcinoma

    � KIPyV – Bronchitis, pneumonia?

    � WUPyV – Bronchitis, pneumonia?

    � HPyV-6 – Unknown, skin?

    � HPyV-7 – Unknown, skin?

    � TS-PyV – Skin spiculae, alopecia

    � HPyV-9 – Unknown, lymphocytes?

    � …

    MCPyV Immunodeficient Merkel cell carcinoma

    PyVAN

    PyVHC Lacey et al 2007

    IgG Seroprevalence

    40-60%

    40-60%

    50-60%

    60-70%

    80-90%

    60-70%

    30-40%

    TS-PyV SOT Skin spiculae, alopecia

    10-80%

    40% ?

    Egli A, Infanti L, Dumoulin A, Buser A, Samaridis J, Stebler C, Gosert R, Hirsch HH (2009) Prevalence of Polyomavirus BK and JC Infection and Replication in 400 Healthy Blood Donors J Infect Dis 199 : 837-846 Dalianis T, Hirsch HH (2013) Human Polyomavirus and Cancer Virology 437: 63 - 72Background

  • � BK-VP1 and JC-VP1 expression in baculovirus SF9 – Virus-like particles (BK-VLP, JC-VLP)

    � N= 400 (100 per age decade from 20 – 59yrs) � IgG Seroprevalence

    – BKV 82% – JCV 58%

    � Viruria – BKV 7% (9%) – JCV 19% (33%)

    � No viremia

    BKV and JCV Infection and Replication BKV and JCV Infection and Replication in Healthy Blood Donorsin Healthy Blood Donors

    Egli A, Infanti L, Dumoulin A, Buser A, Samaridis J, Stebler C, Gosert R, Hirsch HH (2009) Prevalence of Polyomavirus BK and JC Infection and Replication in 400 Healthy Blood Donors J Infect Dis 199 : 837-846

    Kardas P, Weissbach F, Samarides J, Hirsch HH (unpublished)

    JC VP1 VLP

    BK VP1 VLP

    Background

  • Hirsch HH, Randhawa P and the American Society of Transplantation IDCOP (2013) AST Infectious Disease Community of Practice Guidelines: BK Polyomavirus Update 2012 Am J Transpl 13 (in press)

    � Incidence rate 5% (1% - 12%) after kidney transplantation – Functional deficits in ~90%, graft loss in ~50% (range 10% - 90%)

    � (Multi-)focal disease, proceeds through histology stages A, B, C � No effective antiviral drug � Treatment by improving immune control = reducing immunosuppression

    Large T-antigenAgnoproteinDecoy cell

    BK PolyomavirusBK Polyomavirus --associated Nephropathyassociated Nephropathy

    Background

  • The Issues of BKV in Kidney TransplantsThe Issues of BKV in Kidney Transplants

    The problem �Irreversible functional decline �Heterogeneous histological presentation

    – Refractory interstitial nephritis

    �Chronic allograft nephropathy (IF/TA) �Graft loss

    The challenge �Widespread viral infection �Complementing risk factors �Lack of early diagnosis �Uncertain response to modulating immunosuppression �No effective antivirals �Uncertainty about retransplantation

  • Refractory RejectionRefractory Rejection

    0

    100

    200

    300

    400

    500

    600

    0 20 40 60 80 100 120

    Weeks posttransplantation

    S er

    um C

    re at

    in in

    e -

    - -

    (u m

    ol /L

    )

    100

    1000

    10000

    100000

    1000000

    10000000

    P la

    sm a

    B K

    V Lo

    ad -

    -

    (G E

    q/ m

    L)

    AZA CsA

    AR AR PAN AR

    PAN Allograft removal

    PAN AR

    AZAMMF PRE

    TAC CsA

    Steroids i.v.

    Biopsy

    Intensified Immunosuppression

    Nickeleit V, Hirsch HH, Binet I, Gudat F, Prince O, Dalquen P, Thiel G, Mihatsch MJ (1999) Polyomavirus infection in renal allograft recipients: from latent infection to manifest disease J Am Soc Nephrol 10: 1080 Hirsch & Steiger (2003) Polyomavirus BK Lancet Infect Dis 3: 611

  • Progressive Allograft FailureProgressive Allograft Failure

    0

    100

    200

    300

    400

    500

    600

    0 20 40 60 80 100 120

    Weeks posttransplantation

    S er

    um C

    re at

    in in

    e -

    - -

    (u m

    ol /L

    )

    100

    1000

    10000

    100000

    1000000

    10000000

    P la

    sm a

    B K

    V Lo

    ad -

    -

    (G E

    q/ m

    L)

    AZA CsA

    AR AR PAN AR

    PAN Allograft removal

    PAN AR

    AZAMMF PRE

    TAC CsA

    Steroids i.v.

    Biopsy

    Nickeleit V, Hirsch HH, Binet I, Gudat F, Prince O, Dalquen P, Thiel G, Mihatsch MJ (1999) Polyomavirus infection in renal allograft recipients: from latent infection to manifest disease J Am Soc Nephrol 10: 1080 Hirsch & Steiger (2003) Polyomavirus BK Lancet Infect Dis 3: 611

  • Chronic Allograft NephropathyChronic Allograft Nephropathy

    0

    100

    200

    300

    400

    500

    600

    0 20 40 60 80 100 120

    Weeks posttransplantation

    S er

    um C

    re at

    in in

    e -

    - -

    (u m

    ol /L

    )

    100

    1000

    10000

    100000

    1000000

    10000000

    P la

    sm a

    B K

    V Lo

    ad -

    -

    (G E

    q/ m

    L)

    AZA CsA

    AR AR PAN AR

    PAN Allograft removal

    PAN AR

    AZAMMF PRE

    TAC CsA

    Steroids i.v.

    Biopsy decoy cells in urine

    plasma BKV DNA positive

    plasma BKV DNA negative

    Nickeleit V, Hirsch HH, Binet I, Gudat F, Prince O, Dalquen P, Thiel G, Mihatsch MJ (1999) Polyomavirus infection in renal allograft recipients: from latent infection to manifest disease J Am Soc Nephrol 10: 1080 Hirsch & Steiger (2003) Polyomavirus BK Lancet Infect Dis 3: 611

  • Heterogenous HistologyHeterogenous Histology

    Courtesy of M.J. Mihatsch & H.Hopfer, Basel

  • Immunohistochemistry for SV40 large TImmunohistochemistry for SV40 large T --antigenantigen

    Courtesy of M.J. Mihatsch & H.Hopfer, Basel

    Purighalla et al. 1995 Am J Kid Dis 26: 671

  • PyVAN without PyVAN without →→→→→→→→ with significant inflammationwith significant inflammation

    Gosert R, Rinaldo CH, Funk GA, Egli A, Ramos E, Drachenberg CB Hirsch HH (2008) Polyomavirus BK with rearranged Non-Coding Control Region emerge in vivo in Renal Transplant Patients and increase Viral Replication and Cytopathology J Exp Med 205: 841

  • BK PyVAN and Plasma BKV loadBK PyVAN and Plasma BKV load

    100

    1000

    10000

    100000

    1000000

    10000000

    0

    100

    200

    300

    400

    500

    600

    0 20 40 60 80 100 120

    P la

    sm a

    B K

    V Lo

    ad -

    -

    (G E

    q/ m

    L)

    S er

    um C

    re at

    in in

    e -

    - -

    (u m

    ol /L

    )

    Weeks posttransplantation

    AZA CsA

    AR AR PyVAN

    AR PyVAN

    Allograft removal

    PyVAN AR

    AZA MMF PRE

    TAC CsA

    Steroids i.v.

    Biopsy A B C

    Nickeleit V, Hirsch HH, Binet I, Gudat F, Prince O, Dalquen P, Thiel G, Mihatsch MJ (1999) Polyomavirus infection in renal allograft recipients: from latent infection to manifest disease J Am Soc Nephrol 10: 1080 Hirsch & Steiger (2003) Polyomavirus BK Lancet Infect Dis 3: 611

  • � BKV plasma viral half-life t 1/2 ~1-2h � Steady-state: High viral turnover ~99% per day � Renal tubular epithelial cell loss ~106 to ~107 /day � In silico model to predict viral cytopathology and clearance

    BKV Dynamics after Transplant NephrectomyBKV Dynamics after Transplant Nephrectomy

    B K

    V lo

    ad lo

    g 10

    Funk GA, Gosert R, Comoli P, Ginevri F, Hirsch HH (2008) Polyomavirus BK Replication Dynamics in vivo and in silico to predict Cytop