Persistent Epstein-Barr virus infection: unrestricted latent and lytic viral gene expression in healthy immunosuppressed transplant recipients.
BACKGROUND
Posttransplant lymphoproliferative disease (PTLD) is a common Epstein-Barr virus (EBV)-associated complication of transplantation which, despite treatment, is often fatal. This study was undertaken to monitor persistent EBV infection in transplant recipients, to compare EBV load and gene expression in healthy individuals and EBV-associated diseases, and to highlight differences in PTLD that could be used to define those at risk of the disease.


METHODS
A cohort of 96 cardiothoracic transplant recipients was monitored posttransplant for up to 1110 days (median 268 days). Levels of EBV DNA and viral mRNA transcripts in peripheral blood mononuclear cells (PBMs) were measured at regular intervals and compared with those found in healthy individuals, infectious mononucleosis (IM) patients, and 12 PTLD patients bled at the time of diagnosis. Overall posttransplant levels were significantly higher than pretransplant and healthy subjects, and correlate with dose of immunosuppression. EBV DNA levels in both IM and PTLD were significantly higher than in healthy recipients, with the highest levels in PTLD patients. Individual measurements in 12 healthy transplant recipients reached levels seen in PTLD, and thus single estimations are not of predictive significance for PTLD development.


RESULTS
Analysis of viral gene expression in peripheral blood mononuclear cells showed a restricted (LMP 2 only) pattern in healthy subjects, and an unrestricted (latency 3) pattern with lytic replication in 14% of IM blood and 45% of cases of PTLD. A total of 55% of healthy transplant recipients had additional transcripts in one or more blood samples, and this finding correlated with high viral load. Analysis of the 12 samples from healthy recipients with viral loads equivalent to those seen in PTLD showed additional transcripts in all cases and latency 3 with lytic replication in 33%. Thus, an isolated finding of high viral load and/or unrestricted latent and lytic gene expression is not indicative of PTLD.
Hopwood
Paul A
PA
Medical Microbiology, University of Edinburgh Medical School, Edinburgh; Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.
Brooks
Louise
L
Parratt
Rachael
R
Hunt
Beverly J
BJ
Bokhari
Maria
M
Thomas
J Alero
JA
Yacoub
Magdi
M
Crawford
Dorothy H
DH
Maria
Bokhari
B
Alero
Thomas J
TJ
Magdi
Yacoub
Y
D000293:Adolescent; D000328:Adult; D000368:Aged; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D016027:Heart Transplantation / Q000009:adverse effects*; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D007165:Immunosuppression Therapy; D016040:Lung Transplantation / Q000009:adverse effects*; D008232:Lymphoproliferative Disorders / Q000821:virology; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000032:analysis; D019562:Viral Load
D004279:DNA, Viral; D012367:RNA, Viral