New Features of PML in the HAART and natalizumab era

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1 New Features of PML in the HAART and natalizumab era Igor J. Koralnik, M.D. HIV/Neurology Center Beth Israel Deaconess Medical Center Harvard Medical School

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3 Classical AIDS-associated PML in the pre-haart era CD4+ T cell counts < 200 l non-enhancing white matter lesions on MRI, without edema and mass effect detectable JCV DNA by PCR in CSF Absence of inflammatory infiltrates in brain biopsy Progressive evolution and fatal outcome in few months

4 Good prognostic markers in PML Inflammatory infiltrates in PML lesions (Richardson 75) PML heralding AIDS, CD4 > 300/ l (Berger 98) Faint peripheral contrast enhancement of lesions on MRI (Berger 98) Low JCV viral load in CSF (Taoufik 98, Yiannoutsos 99) Presence of JCV-specific CD8+ Cytotoxic T Lymphocytes in blood (Koralnik 01,02, Du Pasquier 03,04) Elevated mi/cr ratio in PML lesions on MRS (Koralnik 03)

5 Unifying Hypothesis PML can be contained if Sufficient number of CD4+ T cells presence of JCV-specific CD8+ cytotoxic T lymphocytes in the blood these CD8+ T cells infiltrate the brain lesions and destroy JCV-infected cells This inflammatory reaction causes a break-down of the blood-brain-barrier and contrast enhancement on MRI decreases viral replication in the brain and JCV VL in CSF

6 Atypical presentation of PML in the HAART era HIV-infected patients with CD4+ T cell counts < 200 l, high plasma HIV VL Initiation of HAART good immunologic and virologic response: increased CD4, decreased HIV VL paradoxical development of an inflammatory form of PML manifestation of IRIS?

7 Immune reconstitution inflammatory syndrome (IRIS) Also known as immune restoration disease (IRD),or immune reconstitution syndrome (IRS) - preexisting infection, clinically silent - recovery of the immune system - local inflammatory reaction - paradoxical deterioration in clinical status

8 Classical manifestations of IRIS CMV retininis mycobacterium avium complex lymphadenitis cryptococcal meningitis may occur also in HIV-negative individuals after discontinuation of immunosuppressive therapy may require treatment with steroids

9 How frequent is PML/IRIS? Retrospective study of 39 PML patients (31 HIV+ and 8 HIV-) since JCV PCR in CSF or brain biopsy PML presentation in context of increased CD4+ counts, decreased HIV VL on HAART, or with signs of inflammation on neuroimaging studies or biopsy 5/39 patients (13 %) (4 HIV+/1HIV-)

10 Contrast enhancement on MRI

11 Contrast enhancement and CD8+ T cell infiltrates (pt #5) % specific lysis :1 10:1 5:1 2.5:1 E:T ratio

12 PML/IRIS: case reports 3 HIV+ pts with PML 5-8 w after HAART (Mayo et al. AIDS 98) 1 HIV+ pt with enhancing PML lesions (Kotecha et al. Am J Med 98) 4 HIV+ pts with enhancing PML lesions (Collazos et al. AIDS 99) 3 HIV+ with PML soon after HAART. Two treated with steroids. Inflammation in brain bx of 4/9 PML pts on HAART vs 1/19 HAART naïve pts (Miralles et al. AIDS 01)

13 PML/IRIS: case reports (cont.) 2 HIV+ pts with PML 4w - 4mo after HAART. (Safdar et al CID 02). Transient response to steroids but fatal outcome in both JCV CSF PCR neg in CSF Biopsy: lymphocytic infiltrates, gliosis and giant multinucleated histiocytes, c/w viral encephalitis No histological features of PML No report of IHC or ISH for JCV or HIV JCV PCR + on DNA from biopsy tissue Are these cases PML?

14 PML/IRIS: series Review of 118 cases in Spain (Berenguer et al CID 03) : 36% PCR or bx proven and 64% possible PML 10/118 (8%) PML 3-13 w after HAART. 2/10 enhancing lesions 8/118 (7%) treated with steroids Only CD4 > 100 associated with good outcome Review of 43 cases of PML in Italy (Cinque et al JNV 03) 8/43 (19%) PML 3-9w after HAART. 4/8 fatal outcome

15 PML in 2 MS and 1 Crohn s pt rx with natalizumab (Tysabri) Humanized monoclonal ab against 4 1 integrins Given once/month iv. Biological activity up to 3 months Prevents lymphocyte and monocyte trafficking in brain, gut and other organs Promising rx of MS and Crohn s Disease (Affirm and Sentinel trial) Voluntary withdrawal on 2/28/05

16 Natalizumab Crohn s/pml

17 Natalizumab Crohn s/pml (2)

18 Natalizumab MS/PML case #1 PML 20 months after natalizumab/inf -1a Cavitary lesions, death in 3 months Extensive PML lesions in cerebral hemispheres and brainstem at autopsy Absence of inflammatory infiltrates NO MS lesions found

19 Natalizumab MS/PML case #1 (2)

20 Natalizumab MS/PML case #1 (3)

21 Natalizumab MS/PML case #2 PML 2 years after natalizumab/inf -1a Incidental PML lesion seen in MRI IRIS 3 months after d/c natalizumab, associated with clearance of JCV from blood and decrease in JCV CSF viral load Transient worsening of T2 hyperintense lesions on MRI and of neurological function Improvement concomitant with ARA-C rx Surviving 8 months after PML onset with severe neurologic deficits

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23 Natalizumab MS/PML case #2 (3)

24 Immunopathogenicity of PML/IRIS ( hyp. #1) Latent subclinical infection of glial cells by JCV in some patients. Expression of early T ag but not capsid proteins HAART induces increase in CD4+ T cells, which help CD8+ T cells attack latently JCVinfected glial cells in the brain Symptomatic inflammatory PML, which is detrimental to the patient and should be treated with steroids

25 hyp. #1 (cont.) JCV PCR + in brain of 4/13 HIV+ pts without PML (Quinlivan et al. JID 92) JCV ISH + in brain of 4/10 elderly HIV-negative individuals without PML (Mori et al.ann Neurol 91) JCV PCR + in brain of 68% HIV-negative patients (Whyte et al) But: At least 4 published negative studies presence of DNA alone not sufficient to trigger immune response block in lytic cycle of JCV never been demonstrated in vivo

26 Immunopathogenicity of PML/IRIS ( hyp. #2) Cytokine-mediated mechanisms variation of INF- and IL-12 after onset of HAART implicated in increased Hep C VL and crypto meningitis (DeSimone et al. Ann Int Med 00) HAART induces a decrease of HIV VL, which in turn lower cytokines levels and may promote JCV reactivation (within CNS, or from kidneys and lymphoid organs)

27 Immunopathogenicity of PML/IRIS ( hyp. #3) PML develops during decreased immunosurveillance on natalizumab Rush of T lymphocytes in PML lesions after d/c natalizumab creates intense inflammatory reaction Incidental development of productive, yet subclinical infection of oligos by JCV around time of HAART onset Immune reconstitution concomitant to PML development leads to an inflammatory reaction in PML lesions which is beneficial and should not be treated with steroids

28 PML/IRIS: questions If inflammatory reaction is beneficial, why do some patients still have a fatal outcome? Multiple factors associated with survival: timing of response to HAART, size and location of the lesions, JC CSF VL, structure of JCV regulatory region, size of pool of memory CTL Inflammation may be too little too late Inflammation may be detrimental in some cases

29 Practical issue in PML/IRIS: steroid treatment Challenge in diagnosis of inflammatory PML Edema and mass effect are rare Many cases of PML/IRIS appear to have a favorable outcome Steroids are immunosuppressants Steroids may promote JCV replication (CRE element) Steroids should be reserved in cases with major neurological worsening or with clinical or radiological signs of impending brain herniation

30 Collaborators HIV/Neurology Center Renaud Du Pasquier Xin Dang Christian Wuethrich Yiping Chen Marco De Lima Jims Jean-Jacques Luz-Andrea Pfister Yue Zheng Division of Viral Pathogenesis (BIDMC) Marcelo Kuroda Jörn Schmitz Michelle Lifton Patrick Autissier Kristi Martin Norman Letvin Funding: NINDS RO and , R and Harvard CFAR, Harvard Center for Neurodegeneration and Repair, Milton Fund