Characterization of JC virus in cerebrospinal fluid from HIV-1 infected patients with progressive multifocal leukoencephalopathy: insights into viral pathogenesis and disease prognosis.
OBJECTIVE
To analyze virological and immunological features of AIDS-related progressive multifocal leukoencepalophathy (PML) and their association to disease prognosis.


METHODS
In HIV-infected patients with virologically confirmed PML, JC virus (JCV) DNA load and levels of Macrophage Chemoattractant Protein (MCP)-1 were determined in cerebrospinal fluid. JCV genotypes, rearrangements and JCV DNA binding sites for cellular transcription factors were analyzed by sequencing the viral VP1 region and regulatory region (RR).


RESULTS
45 patients were analyzed: 60% were exposed to highly active antiretroviral therapy (HAART) after PML and 24% before the disease onset. JCV DNA load in cerebrospinal fluid was a strong predictor of patients survival. Lower levels of JCV DNA in cerebrospinal fluid were associated with the following virologic factors: viral genotype 4 (p = 0.043), more rearrangements in the RR (p = 0.046), duplication of RR block B (p = 0.028), and duplication of binding sites for cellular transcription factor NF-1 (p = 0.060). In patients with prior antiretroviral exposure there was a trend towards a higher number of binding sites for cellular transcription factors (p = 0.068). Lower JCV load was also predicted by exposure to HAART (p = 0.010), higher baseline CD4 counts (p = 0.009) and higher cerebrospinal fluid MCP-1 levels (p = 0.036). In a multiple regression model, MCP-1 levels were independently associated with JCV load.


CONCLUSIONS
HAART leads to a partial immune-mediated control of JCV replication; the virus may tend to escape through the selection of rearrangements in the RR, some associated with enhanced viral replication efficiency, other resulting in multiplication of binding sites for cellular transcription factors.
Marzocchetti
Angela
A
Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Rome, Italy. amarzocc@bidmc.harvard.edu
Sanguinetti
Maurizio
M
Giambenedetto
Simona Di
SD
Cingolani
Antonella
A
Fadda
Giovanni
G
Cauda
Roberto
R
De Luca
Andrea
A
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D001665:Binding Sites; D015415:Biomarkers / Q000134:cerebrospinal fluid; D004279:DNA, Viral / Q000134:cerebrospinal fluid; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000401:mortality*; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D007577:JC Virus / Q000235:genetics / Q000302:isolation & purification* / Q000472:pathogenicity; D007968:Leukoencephalopathy, Progressive Multifocal / Q000134:cerebrospinal fluid* / Q000401:mortality* / Q000821:virology; D008297:Male; D011379:Prognosis; D012367:RNA, Viral / Q000134:cerebrospinal fluid; D015996:Survival Rate; D014157:Transcription Factors / Q000378:metabolism; D014774:Virulence; D014779:Virus Replication
D015415:Biomarkers; D004279:DNA, Viral; D012367:RNA, Viral; D014157:Transcription Factors