HHV6 and PML

PML is an often fatal disorder of the CNS that primarily affects individuals with impaired immune systems including patients treated for cancers such as leukemia or lymphoma, allograft recipients, and up to 10% of patients with AIDS (Padgett et al., 1971; Berger and Major, 1999). The etiologic agent of PML is JC virus (JCV), a human neurotropic member of the polyomaviruses; a family of non-enveloped tumor viruses with small, circular, double-stranded DNA genomes. JCV is widespread throughout the human population with a worldwide distribution of more than 80% seropositivity (Major et al., 1992).

The pathology of PML is distinctive and characterized by multiple foci of demyelinating lesions of variable size caused by lytic infection of oligodendrocytes with JCV (Gordon and Khalili, 1998; Post et al., 1999; Safak and Khalili, 2003). This lytic infection represents reactivation of JCV in the immunocompromised host (Major et al., 1992). Oligodendrocytes in the peripheral zone surrounding an area of demyelination are grossly abnormal, exhibiting nuclei engorged with JC virions. The death of infected oligodendrocytes leads to the development of focal areas of progressive demyelination (White et al., 2005). In addition, recent evidence suggests that necrotic death of JCV-infected astrocytes may contribute to the pathogenesis of PML (Seth et al., 2004). The disease course of PML progresses rapidly with death typically occurring within 1 year (Hou and Major, 2000). However, prolonged survival of AIDS patients with PML has been achieved with the advent of highly active antiretroviral therapy (HAART) (Albrecht et al., 1998).

After several reports had suggested an association of HHV-6 with MS, Mock et al. (1999) examined the possible association of HHV-6 with the demyelinative lesions of PML. In this study, a highly sensitive, two-step in situ PCR (ISPCR) procedure was used to amplify HHV-6 DNA from formalin-fixed paraffin-embedded archival brain tissues from normal, AIDS, and other neurological disease controls. A significantly higher frequency of infected cells was found in PML white matter compared to control tissues. Of interest, the HHV-6 genome was detected primarily within oligodendrocytes (Mock et al., 1999). Immunocytochemistry for HHV-6 antigens revealed active HHV-6 infection of the abnormal oligodendro-cytes within demyelinative PML lesions, but not in adjacent, unaffected tissue or control tissues, including brains from individuals with HIV-1 encephalopathy. The detection of active HHV-6 infection coupled with the collocation of JCV large T antigen and HHV-6 in swollen intralesional oligodendrocytes suggested an association of HHV-6 activation in the context of JCV infection with PML lesions.

ISPCR was again employed to amplify HHV-6 genome from normal, PML, AIDS (no PML), MS, and other neurologic disease control brains (Blumberg et al., 2000). In support of the previous report, a high frequency of HHV-6 DNA was detected in demyelinative white matter lesions from both PML and MS compared with controls. Remarkably, a greater frequency of HHV-6 than JCV genomes was detected in oligodendrocytes from PML lesion areas. HHV-6 p41 and gp101 antigens were detectable by immunocytochemistry in PML lesions. Subsequently,

HHV-6 was detected in demyelinating PML lesions of a Japanese patient with follicular lymphoma (Daibata et al., 2001) and an HIV-infected patient with both PML and meningoencephalitis (Ito et al., 2000) further supporting the possible association of HHV-6 with PML. 0f interest, in cultured human fetal astrocytes, both HHV-6 and the related p-herpesvirus CMV transactivate the HIV-1 long terminal repeat (LTR) (McCarthy et al., 1998). Co-infection of oligodendrocytes with HHV-6 and JCV presents an opportunity for these ordinarily commensal viruses to stimulate or activate one another in a synergistic fashion, thereby participating as co-factors in the pathogenesis of PML (Blumberg et al., 2000).

In recent years, RRMS patients have participated in a clinical trial investigating the efficacy of natalizumab (Tysabri; Biogen Idec and Elan) in combination with interferon beta-1a (Avonex; Biogen Idec). Tragically, two MS patients on combination therapy have developed the seemingly unrelated, demyelinating disorder, PML (Langer-Gould et al., 2005; Kleinschmidt-DeMasters and Tyler, 2005). Natal-izumab is a humanized monoclonal antibody against a4 integrins that is thought to prevent migration of autoreactive T-cells into the CNS. The development of PML in these patients raises several questions. Does the inhibition of normal immune cell trafficking into the brain allow for opportunistic reactivation of JCV? Is HHV-6, a virus speculated to be involved in the pathogenesis of MS, implicated in the reactivation of JCV or development of PML in these RRMS patients? It remains to be determined whether there will be an increased frequency in the detection of HHV-6 in the CSF of MS patients who received natalizumab compared with control patients.

HHV-6 is a highly neurotropic virus that has been both tentatively and firmly associated with a wide array of CNS disorders. Further understanding of the biology of this virus is paramount in deciphering the neuropathology of several diseases of the CNS including encephalitis, seizure disorders, MS, and PML. Further, the development of antiviral agents for HHV-6A and B may result in new treatment modalities for many neurological diseases.

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