12/16/2023 0 Comments Macsentry trialPrevious studies have provided direct evidence for JCV infection in the kidney ( Bolderini et al., 2005 Chesters et al., 1983) and have shown that reactivation of JCV occurs in the kidney resulting in an accumulation of virus in the urogenital tract and the excretion of virus and epithelial cells containing virus in the urine ( Dorries, 2006). At present, it is not known whether PML is caused by reactivation of JCV in the brain or, alternatively, JCV that is reactivated in the peripheral tissues, such as the kidney or blood, and then traffics to the CNS. It has not yet been established if and what latent sites play important roles in the pathogenesis of JCV. A study of humoral immune responses in patients with PML showed high levels of anti-JCV IgG rather than IgM, suggesting that PML is most likely a result of a reactivation of latent virus rather than a pathological consequence associated with primary infection ( Weber et al., 1997). The mechanisms that result in JCV infection of oligodendrocytes in the central nervous system (CNS) and subsequent PML disease are also not well known. The role that anti-inflammatory therapies play in the development of PML is not yet clear. Some anti-inflammatory therapies have also been linked to PML, most notably natalizumab (Tysabri), an alpha-4 integrin inhibitor that showed promise as a treatment for relapsing multiple sclerosis (MS) in clinical trials ( Garcia-Suarez et al., 2005 Kiewe et al., 2003 Vidarsson et al., 2002 Yousrey et al., 2006). Low CD4 T-cell counts and increasing age are associated with greater risk for PML, but only a small fraction of persons with immunosuppressive conditions will develop the disease ( Richardson, 1988 Weber et al., 2001 Ahsan and Shah, 2006). Little is known about the risk factors for PML. Today, PML is recognized as an AIDS-defining illness occurring in three to five percent of all AIDS patients ( Selik et al., 1997 Ahsan and Shah, 2006). PML was a rare disease prior to the advent of the AIDS pandemic in the 1980's ( Brooks and Walker, 1984), but its incidence since has increased dramatically ( Berger, 2003 Holman et al., 1998). ![]() PML, which has a case fatality rate of almost 100% and no specific treatment, occurs on a background of conditions associated with T-cell deficiencies, such as HIV-infection ( Richardson, 1988 Berger and Major, 1999 Weber et al., 2001). Between 40 and 75% of people worldwide have antibody to JCV ( Carter et al., 2003 Rollison et al., 2003), and in approximately 20 to 30% of infected persons, JCV actively replicates in the kidneys and is shed in the urine ( Markowitz et al., 1993 Shah, 1996). JCV may also persist as a latent infection of the brain ( Eisner and Dorries, 1992 Ferrante et al., 1997). ![]() JCV infects during late childhood and then persists indefinitely as a latent infection of the kidneys and B-lymphocytes ( Chesters et al., 1983 Dorries and Meulen, 1983 Gallia et al. Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disorder of the central nervous system caused by a lytic infection of oligodendrocytes with JC virus (JCV), a human polyomavirus ( Astrom et al., 1958) ( ZuRhein, 1969). The results suggest that persistent JCV viruria and increasing urinary concentration of JCV DNA may be predictive of PML for some patients. Smoking was the only demographic variable analyzed associated with an increased risk for PML (MOR: 9.0, 95% CI: 1.2–394.5). JCV DNA was detected in the serum of one HIV-positive control. Four cases tested JCV seronegative, including one case only 5 months prior to diagnosis with PML. JCV seropositivity did not differ between cases or controls (p = 0.42). Presence of JCV viruria was not related to the time to PML diagnosis (OR: 1.03, 95% CI: 0.8 – 1.4) however, the urinary concentration of JCV DNA increased with proximity to the date of PML diagnosis in cases. Among persons with JCV viruria, persistent viruria was more common in cases (89%) than in HIV- positive controls (33%) (p = 0.02). Prevalence of JCV viruria was 37% in cases, 42% in HIV-positive controls, and 28% in HIV-negative controls (p = 0.43). The study population included 28 incident cases of PML, 26 matched HIV-positive controls, and 50 HIV-negative controls. Other demographic and immunologic factors were examined also. We conducted a case-control study nested within the Multicenter AIDS Cohort Study to examine the association between JCV viruria and viremia and serum antibody to JCV capsids, in relation to subsequent PML diagnoses, 5 months to 12 years later. Pre-diagnostic biological markers and risk factors for PML are not well understood. ![]() Progressive multifocal leukoencephalopathy (PML) is a severe neurological disorder due to JC virus (JCV) infection.
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