Role of the IL28B Rs12979860 C/T Polymorphism on the Incidence of Clinically-Active Cytomegalovirus Infection in Autologous Stem Cell Transplant Patients

Background

CMV infection represents one of the main cause of morbility and mortality after stem cell transplantation.  Type III interferons (IFNs), including IFNl1 (IL29), IFNl2 (IL28A) and IFNll3 (IL28B), are thought to display potent antiviral and  immunemodulatory properties in vivo, which may overlap partially with those exerted by type I IFNs. Type I and Type  III IFNsl both generate an antiviral state by triggering the JAK-STAT pathway, ultimately upregulating the expression of interferon-stimulated genes.

Rs12979860  single nucleotide polymorphism (SNP) in IL28B gene region is well known to influence the spontaneous and treatment-induced clearance in HCV infection. Data on the relevance of such a SNP in other viral infections is still debated even, Bravo et al. recently documented a protective effect of the T allele against CMV infection in the Allogenic stem cell transplantation (Allo-SCT) (Journal of Medical Virology 2014.86:838).

Aim of the study: the current study was aimed at investigating whether the IL28B polymorphism rs12979860 may effect on the incidence rate of clinically-relevant  active CMV infection in the Autologous  stem cell transplantation setting.

Patients and methods: From October 2014 45 patients were included in the study because underwent a autologous stem cell transplantation for hematological diseases. The  median age of the patients was 56 years ( 16-66 years).  Patients were distributed according to Hematologic disease as following: 73% of the patients  had Multiple Myeloma, 20% non Hodgkin Lymphoma, 5% Hodgkin Lymphoma e 2% Acute Myeloid Leukemia.

The rs12979860 IL28B SNP (C/T) genotype was determined by Melthing analysis on DNA derived from peripheral blood samples.

CMV DNAemia was determined by quantitative Real-Time PCR with a limit detection of 50 copies/mL (Artus, Qiagen). Patients were monitored for CMV DNAemia  weekly for the three months after stem cell transplantation.

RESULTS: CC genotype was detected in 51% of patients, CT genotype in 35.5% and TT genotype only in 13.5% of patients according to the lowest frequency of TT genotype harboring in general population. A clinically-active CMV infection was documented respectively in 66,6%, 17,4% and 12,5% of patients carrying TT, CT  and CC genotype.

A trend towards a higher incidence of clinically-active CMV infection was noted in the TT population with respect to CT and CC population (TT vs CC: P= 0.03 and TT vs  CT : P=0.02).

The duration and peak of CMV-DNAemia levels tended to be higher in patients carrying the TT genotype then in ones with CC or CT genotype, although statistical significance was not reached.

A positive correlation was observed between day 7 post ASCT CMV-DNAemia and the monocytes and neutrophils count.  By the contrast, a negative correlation was found between day 21 post ASCT CMV-DNAemia levels  and the monocytes count on 35th and 45th days after ASCT.

Conclusions

In conclusion, our data  suggest  that patients with TT genotype have higher incidence of  clinically-active CMV infection in Auto-SCT setting. Even though these results  should be confirmed by a larger sample size, the lowest prevalence of TT genotype in general population and higher (66.6%)  clinically-active CMV infection in TT genotype patients strongly support our data.