Mutations Allow JC Polyomaviruses to Elude Antibody Recognition
The progression of progressive multifocal leukoencephalopathy (PML) lesions in a single patient were monitored over time using magnetic resonance imaging. The yellow areas seen in the merged images (bottom row) indicate active development of new PML lesions. After vaccination (columns on the right), PML lesion development subsided.
JC polyomavirus (JCV) infects the urinary tract of most adults. In healthy individuals, JCV infection does not cause noticeable symptoms. However, in those with compromised immune systems, JCV can cause a lethal brain disease called progressive multifocal leukoencephalopathy (PML). Data from a recently approved assay to detect serum antibodies specific for the JCV protein VP1 revealed that patients with antibodies are at increased risk of developing PML. At the same time, sequencing studies of JCV in cerebrospinal fluid (CSF) identified a number of mutations in VP1. Christopher Buck, Ph.D., and Diana Pastrana, Ph.D., of CCR’s Laboratory of Cellular Oncology, and their colleagues hypothesized that the VP1 mutations could allow the virus to evade antibody-mediated elimination.
To test this idea, the researchers analyzed sera from 96 healthy individuals. They found that 60 had a sufficiently high level of neutralizing antibodies against pseudoviruses based on the wild type 2A JCV genotype. While most samples neutralized all other JCV genotypes tested, 11 failed to neutralize a mutant that is commonly found in PML patients, S269F. These data support the idea that mutations could allow virus to escape detection by neutralizing antibodies.
The investigators next evaluated JCV neutralization by plasma samples from patients with PML. Because samples needed to be collected prior to PML diagnosis and from patients whose JCV sequences in the CSF were known, only samples from six patients, all with immunodeficiency due to human immunodeficiency virus (HIV) infection, met the criteria. The scientists constructed pseudoviruses that matched the sequence of each patient’s CSF-derived JCV as well as related wild type sequences. All patients showed low or no neutralization of their own JCV mutant even when there was strong neutralization of the wild type pseudovirus. The three patients who survived PML developed broader antibody responses that recognized their JCV mutation, suggesting patients were capable of mounting a cross-neutralizing antibody response. The remaining patients had fatal disease and failed to develop a neutralizing response to their JCV mutants. Interestingly, two patients had antibodies against the S269F 2A JCV genotype but failed to recognize S269F mutants in another genotype, supporting the idea that it is important to analyze the neutralization of the exact sequences observed in each individual subject.
Polyomaviruses share several key features with papillomaviruses, and vaccination with virus-like particles (VLPs) targeting the latter produce potent, long-lasting neutralizing antibody responses. The researchers wondered whether a JCV VLP vaccine could promote a similar response against JCV so they treated mice with one intramuscular dose of wild type 2A JCV VLPs. The single dose elicited strong serum antibody responses that could neutralize the cognate JCV-2A pseudovirus but failed to cross-neutralize at least one other JCV genotype. The investigators then administered a booster of the same VLP. All mice that received the booster developed antibodies that could cross-neutralize all the JCV variants tested, suggesting that so-called “neutralizing blind spots” can be closed through prime-boost vaccination. The study also showed that double inoculation with wild type 2A JCV VLPs caused uniformly strong cross-neutralization, demonstrating that it is unnecessary to inoculate with mutant VLPs.
The scientists also described the case of a 75-year-old female patient with T cell immunodeficiency who was diagnosed with PML in May 2012. When the patient’s condition deteriorated, she was treated with an experimental regimen of separate doses of interleukin-7 and wild type 1A JCV VLP plus imiquimod, an immune response modifier. She had a roughly 100-fold increase in antibody levels against her cognate mutant JCV pseudovirus, which was followed by a gradual decrease in virus levels in her blood and an arrest of PML lesion progression. However, it is not clear whether the improved neutralizing antibody response caused the disease to stop progressing.
These results indicate that a deficient antibody response to mutant JCV is a common feature of PML development and that vaccination with VP1 VLPs is capable of restoring antibody-mediated immunity. Despite the promising data from the single treated patient, whether VLPs are therapeutically useful is unclear and will require further studies. If the VLP vaccines do prove effective, they could prevent or treat PML in individuals living with long-term HIV infection or receiving monoclonal antibodies for diseases such as rheumatoid arthritis, multiple sclerosis, and some lymphoid cancers.Summary Posted: Tue, 09/01/2015
Ray U, Cinque P, Gerevini S, Longo V, Lazzarin A, Schippling S, Martin R, Buck CB, and Pastrana DV. JC Polyomavirus Mutants Escape Antibody-Mediated Neutralization. Sci Transl Med. September 23, 2015. PubMed Link