A prospective assessment of cytomegalovirus immune evasion gene transcription profiles in transplant patients with cytomegalovirus infection.
BACKGROUND
The cytomegalovirus (CMV) immune evasion genes US3, US6, and US11 may disrupt the host immune response via downregulation of major histocompatibility complex molecules. Transplant recipients with CMV infection were prospectively assessed for immune evasion gene expression.


METHODS
Seventy solid organ transplant patients with CMV infection who were given antiviral therapy were enrolled. Quantitative mRNA levels of US3, US6, and US11 were assessed using real-time polymerase chain reaction assays from peripheral blood mononuclear cells at regular time-points after starting therapy.


RESULTS
High immune evasion mRNA levels were detectable at start-of-therapy (median US3-4.5 log10 copies; US6- 3.7 log10 copies, and US11-3.3 log10 copies/10 cells). With therapy, immune evasion mRNA levels declined exponentially. For example, median calculated US3 half-life was 1.59 days (range 0.74-12.5 days). By day7, US3 mRNA was detectable in 55.7%, US6 in 38.6%, and US11 in 41.4% of patients. Early phase kinetics correlated with outcomes. When adjusted for baseline DNA level, there was a trend to higher mRNA levels in patients who relapsed. Also, detectable mRNA at day 14 after start of therapy was associated with virologic relapse after initial treatment (P<or=0.001 for US3, US6, and US11). For example, if US3 mRNA was still detectable at day 14, then risk of relapse was 84.2% vs. 29.4% if US3 mRNA not detectable at day 14 (P<0.001). This correlation was independent of the DNA viral load.


CONCLUSIONS
CMV immune evasion gene expression is detectable at high levels in patients with CMV infection and declines exponentially with therapy. Expression levels can be independently correlated with outcomes.
Humar
Atul
A
Infectious Diseases, Microbiology, and Transplantation, University of Toronto, Toronto, Ontario, Canada. atul.humar@uhn.on.ca
Kumar
Deepali
D
Gray
Michael
M
Moussa
George
G
Venkataraman
Srividhya
S
Kumar
Raahul
R
Tipples
Graham A
GA
D000998:Antiviral Agents / Q000627:therapeutic use; D003586:Cytomegalovirus Infections / Q000097:blood*; D004279:DNA, Viral / Q000097:blood; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007700:Kinetics; D008565:Membrane Proteins / Q000235:genetics*; D016377:Organ Transplantation; D011446:Prospective Studies; D012333:RNA, Messenger / Q000097:blood*; D016601:RNA-Binding Proteins / Q000235:genetics*; D012008:Recurrence; D013997:Time Factors; D014764:Viral Proteins / Q000235:genetics*
D000998:Antiviral Agents; D004279:DNA, Viral; D006023:Glycoproteins; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C074546:US11 protein, herpesvirus; C095111:US3 protein, cytomegalovirus; C432877:US6 protein, Human cytomegalovirus; D014764:Viral Proteins