An in vitro method of identifying a subject as being at an increased risk for Progressive Multifocal Leukoencephalopathy (PML), wherein the subject is identified as being at an increased risk for PML if a biological sample obtained from the subject is positive for JCV antibody, wherein the level of JCV antibody is determined by: (a) contacting a biological sample obtained from a subject with highly purified virus-like particles (HPVLPs), consisting predominantly of the VP1 protein of the JC Virus (JCV), in solution under conditions suitable for binding of a JCV antibody in the sample to an HPVLP, thereby providing a pre-incubated sample; (b) contacting the pre-incubated sample with HPVLPs, consisting predominantly of the VP1 protein of the JCV, immobilized on a solid substrate under conditions suitable for binding of a JCV antibody in the sample to an HPVLP; (c) detecting the level of JCV antibody in the pre-incubated sample binding to the immobilized HPVLPs; (d) contacting a portion of the biological sample that was incubated in solution without HPVLPs under the same conditions used for step (b), and detecting the level of JCV antibody binding to the immobilized HPVLP, and (e) comparing the detected level of JCV antibody in the pre-incubated sample of steps (a) to (c) to the level of JCV antibody detected in the sample of step (d); wherein a decrease in the detected level of JCV antibody in the pre-incubated sample compared to the sample obtained from the subject that was incubated in solution without HPVLPs indicates that the sample is positive for JCV antibody, and a change in the detected level of JCV antibody below a specified percentage indicates that there is no JCV-specific antibody present in the sample, wherein the HPVLPs are composed of more than 5, at least 50, 150 or 360 VP1 polypeptides; wherein the method further includes determining the level of anti-JCV antibodies in the subject in a sample from a date subsequent to the initial sample, comparing the level of anti-JCV antibodies in the sample from the subsequent date to the level in the sample from the initial sample; and determining whether the subject is at increased risk of PML at the subsequent date compared to the time of the initial sample. (a) contacting a biological sample obtained from a subject with highly purified virus-like particles (HPVLPs), consisting predominantly of the VP1 protein of the JC Virus (JCV), in solution under conditions suitable for binding of a JCV antibody in the sample to an HPVLP, thereby providing a pre-incubated sample; (b) contacting the pre-incubated sample with HPVLPs, consisting predominantly of the VP1 protein of the JCV, immobilized on a solid substrate under conditions suitable for binding of a JCV antibody in the sample to an HPVLP; (c) detecting the level of JCV antibody in the pre-incubated sample binding to the immobilized HPVLPs; (d) contacting a portion of the biological sample that was incubated in solution without HPVLPs under the same conditions used for step (b), and detecting the level of JCV antibody binding to the immobilized HPVLP, and (e) comparing the detected level of JCV antibody in the pre-incubated sample of steps (a) to (c) to the level of JCV antibody detected in the sample of step (d); wherein a decrease in the detected level of JCV antibody in the pre-incubated sample compared to the sample obtained from the subject that was incubated in solution without HPVLPs indicates that the sample is positive for JCV antibody, and a change in the detected level of JCV antibody below a specified percentage indicates that there is no JCV-specific antibody present in the sample, <EOS>