BackgroundThe present study was undertaken to determine the rate of occurrence of Human cytomegalovirus (HCMV) among kidney transplant recipients and donors by application of direct detection methods and to understand HCMV infection/disease development among transplanted patients as a prospective study.ResultsPeripheral blood samples collected from 76 kidney donors and 76 recipients from September 2007 to August 2009 were subjected to pp65 antigenemia and Quantitative real-time PCR (qRT-PCR) assays. Data were analyzed under Group A, B and C. Group A was further divided into sub-groups I, II, III, IV, and V for better understanding. Three, one and two donors in sub-group I, III, IV of Group A tested positive for real time PCR respectively. One recipient from group III tested positive for HCMV by qRT- PCR prior transplantation and remained positive one month post-transplantation. Three other recipients, tested negative prior to transplantation became positive a month after transplantation. Group B consisted of 18 donor-recipient pairs and one of the donor tested positive for HCMV by qRT-PCR. Eight recipients tested positive for HCMV one month after transplantation. The pp65 positivity and HCMV DNA load was high among group C recipients who mostly had symptoms of active disease. Significantly high values of pp65 antigenemia were observed among recipients of sub-group II (non-parametric chi-square test p = 0.007). Positive correlation between pp65 antigenemia and qRT-PCR value was observed. Thirty three of the recipients with disease treated with Valgancyclovir showed improved clinical outcome.ConclusionOur study showed that a significant proportion of kidney recipients develop HCMV infection following renal transplantation in spite of the absence of HCMV among donors. pp65 antigenemia assay and qRT- PCR methods can be applied to detect HCMV among kidney donors and recipients to monitor development of disease and these assays were predicative of HCMV infection among them. Clinical resistant to valganciclovir was not observed.
This study reports the probable impact of the coupled mutations observed in our clinical isolate of HCMV UL54 polymerase, through structural bioinformatics approaches. The reported variant was found to be resistant to Ganciclovir (GCV) as per the clinical records. The presence of Glutamine deletion at 639 (Glu639) and a mis sense mutation of Serine 655 Leucine (Ser655Leu) in UL54 were identified by DNA sequencing and were predicted to lie in the DNA polymerase type-II domain. Docking simulation studies of the phosphorylated forms of Ganciclovir (GCV), Cidofovir (CDV) and Foscarnet (PFA) with the reported mutants showed significant variation in terms of binding affinity and inhibitory constant (Ki) in comparison to wild type UL54. The findings of this study revealed that the observed coupled mutation could potentially induce allosteric effects in the binding pockets of UL54 and thereby alter the drug binding affinity. In specific, it was observed that this coupled mutation could confer changes in the binding affinity of GCV and PFA by altering the binding energies and inhibitory constants to -0.88Kcal/mol and 226.71mM, -5.81Kcal/mol and 54.83µM, respectively, in comparison to Wild Type. On the other hand, CDV showed increased susceptibility for the reported mutant with a binding energy of -6.16Kcal/mol and inhibitory constant of 30.47µM.
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