Researchers have detected John Cunningham virus DNA in the mononuclear cells of patients with multiple sclerosis who have been treated with natalizumab, suggesting a possible mechanism to explain the association of natalizumab with the development of progressive multifocal leukoencephalopathy.
The results from the study, published online March 24 in JAMA Neurology, also suggest that some patients who test seronegative for antibodies against John Cunningham virus (JCV) and undergo treatment with natalizumab have cell-associated viremia that goes undetected by current assays.
More than 440 cases of progressive multifocal leukoencephalopathy (PML) have been reported since the monoclonal antibody natalizumab was reintroduced in 2006 for the treatment of relapsing-remitting forms of multiple sclerosis (MS), and approximately 11 new cases are reported each month.
"Natalizumab is known to promote mobilization of hematopoietic stem cells from the bone marrow, a putative site for JCV latency, into the peripheral circulation, resulting in higher-than-normal physiological levels of CD34-positive cells for months to years after treatment," wrote Dr. Elliot M. Frohman from the University of Texas Southwestern Medical Center, Dallas, and his colleagues.
"The observation of JCV latency within these characterized mononuclear cells makes a direct mechanistic link between natalizumab and the occurrence of PML."
Researchers collected peripheral blood samples from 26 MS patients at baseline before initiation of natalizumab, and at approximately 3-month intervals over the next 10 monthly infusions. They also collected blood samples at a single time point from 23 MS patients who had received 24 or more natalizumab infusions and 19 healthy age- and sex-matched controls (JAMA Neurol. 2014 March 24 [doi: 10.1001/jamaneurol.2014.63]).
They found JCV DNA in half of the 26 MS patients with baseline and follow-up blood samples at one or more points, and significantly more MS patients had detectable JCV DNA in either the CD19-positive or CD34-positive cell compartments, compared with the healthy volunteers.
However, the investigators observed a low viral copy number, as compared with what would usually be seen in virus excreted in urine, regardless of which cell compartment the viral DNA was detected in. The viral copy numbers were generally higher in patients treated for longer periods.
"The low viral copy number in our study is consistent with a latent or a persistent infection," the investigators wrote. "In previous work, a cell culture model had shown that even a low level of persistence of JCV has significance because JCV can be transferred to other cells."
Of 23 MS patients overall who had cell-associated viremia, 14 were seronegative for antibodies against JC virus. One healthy control patient who had cell-associated viremia also tested seronegative. The investigators cautioned that serology alone may not be enough to identify all patients with prior exposure to JCV.
"Other measures of JCV infection may be of equal importance and should be considered, including T-cell responses, a rise in antibody titer indicating active infection, and the presence of JCV DNA variants in peripheral circulation, particularly in cell compartments."
The study was supported by intramural research funds within the National Institute of Neurological Disorders and Stroke and the National Institute of Allergy and Infectious Disease and a grant from the National Multiple Sclerosis Society. Four researchers declared that they received speaking and consultancy fees, honoraria, and grant support from a range of pharmaceutical companies that market drugs for MS, including Biogen Idec, manufacturer of natalizumab.