Transplantation and Clinical Virology

Transplantation and Clinical Virology: Virus, Immune Response and Clinical Implication

Virus infection and host response enter a critical virus-host balance, which is influenced by pathogenic factors of the virus and innate and adaptive host responses. Our approach is translational: Clinical observations suggesting a viral complication are corroborated through specific and quantitative virus diagnostics in the Division of Infection Diagnostics, a fully accredited medical microbiology laboratory according to the EN17025 (Swiss Testing Site 217). In the research group Transplantation & Clinical Virology, we aim at characterizing 1) key determinants of virus biology, 2) potential targets of antiviral intervention, 3) relevant immune responses. This combined approach should allow to improve the risk stratification and monitoring of patients, the identification of antiviral targets, and the design of protective vaccines and/ or adoptive transfer of T-cells for clinical use.

Community-acquired respiratory virus (CARV) are detected by a multiplex PCR covering >16 different respiratory pathogens including Influenza (FLU) A and B, A/H1N1v (“swine” FLU), bird flu, respiratory syncytial virus (RSV), Metapneumo-, Parainfluenza-, Corona-, Adeno, and Rhinoviruses. Together with colleagues in the clinics for hematology, infectious diseases, and pneumology, we are characterizing virus epidemiology, and trying to link the qualitative and quantitative detection of viruses with clinical presentation and outcomes (Hirsch et al. 2013 Clin Inf Dis 56: 258).

Human Herpes viruses (HHV) now encompass 9 members including cyto- megalovirus (CMV) and Epstein-Barr virus (EBV). CMV and EBV are frequent challenges in immunocompromized patients causing viral syndromes, organ-invasive disease and lymphoproliferative disorders such as PTLD. By integrating the replication biology of EBV the contribution of free EBV virion and viral episomal DNA from lysed cells to EBV load, we could develop a first innovative mathematical model allowing to predict the impact of impaired T- cell function, T-cell depletion, and EBV infection recruiting new B-cells (Funk et al. 2007 Lancet Inf Dis 6: 460).

The role of CMV, and specifically the impact of antiviral prophylaxis versus preemptive therapy were studied in the frame of the Swiss Transplant Cohort Study suggesting that graft survival was better in patients receiving antiviral prophylaxis. CMV specific T-cell function appears inactive, but can be restored in vitro using PD-1 receptor blockade. Our recent data support the use of viral loads assays using International Units according to the 1st CMV WHO standard. As a result, International Units for CMV are now recommended in international guidelines (see refs.).

Human Polyomaviruses (HPyV) now consist of 12 different species, 9 of which have only been discovered since 2007. Significant human diseases are recognized for BK virus (BKV), JC virus (JCV), Merkel cell carcinoma and Trichodysplasia spinulosa PyV, all of which arise almost exclusively in immunocompromized patients. BKV causes PyV-associated nephropathy (PyVAN) in kidney transplant patients and late-onset hemorrhagic cystitis in allogeneic bone marrow transplantation. We established that PyVAN is preceded by high-level BKV viruria with decoy cell shedding and BKV viremia. In an international 1:1 randomized-controlled trial comparing tacrolimus with cyclosporine in 682 de novo kidney transplant recipients, we found that BKV viremia was more frequent and higher in the tacrolimus arm posttransplant (see refs.). Based on BKV viremia, reducing immunosuppression becomes an efficient intervention strategy. Accordingly, screening kidney transplant patients for plasma BKV loads is now recommended by international guidelines to identify kidney patients at risk for BKV disease. We speculate that BKV proteins subvert innate and adaptive immune responses (see refs.). Until now, there are no antivirals of proven clinical efficacy, but our recent in vitro study suggests that the lipid derivative CMX001 may be 400-fold more active compared to the parent cidofovir.
JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML). Together with the US MACS and Swiss HIV Cohort Study, we found that survival of PML patients is associated with early increasing JCV antibody responses. We also showed that CMX001 shows a good JCV inhibitory activity in vitro.

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