Immunosuppression is required for BK viremia and polyomavirus BK–associated nephropathy (PVAN) in kidney transplants (KTs), but the role of viral determinants is unclear. We examined BKV noncoding control regions (NCCR), which coordinate viral gene expression and replication. In 286 day–matched plasma and urine samples from 129 KT patients with BKV viremia, including 70 with PVAN, the majority of viruses contained archetypal (ww-) NCCRs. However, rearranged (rr-) NCCRs were more frequent in plasma than in urine samples (22 vs. 4%; P < 0.001), and were associated with 20-fold higher plasma BKV loads (2.0 × 104/ml vs. 4.4 × 105/ml; P < 0.001). Emergence of rr-NCCR in plasma correlated with duration and peak BKV load (R2 = 0.64; P < 0.001). This was confirmed in a prospective cohort of 733 plasma samples from 227 patients. For 39 PVAN patients with available biopsies, rr-NCCRs were associated with more extensive viral replication and inflammation. Cloning of 10 rr-NCCRs revealed diverse duplications or deletions in different NCCR subregions, but all were sufficient to increase early gene expression, replication capacity, and cytopathology of recombinant BKV in vitro. Thus, rr-NCCR BKV emergence in plasma is linked to increased replication capacity and disease in KTs.

Fast BK virus (BKV) replication in renal tubular epithelial cells drives polyomavirus-BK-associated nephropathy (PVAN) to premature kidney transplant (KT)failure. BKV also replicates in urothelial cells, but remains asymptomatic in two-thirds of affected KT patients. Comparing 518 day-matched plasma-urine samples from 223 KT patients, BKV loads were ∼3000-fold higher in urine than in plasma (p < 0.000001). Molecular and quantitative parameters indicated that >95% of urine BKV loads resulted from urothelial replication and <5% from tubular epithelial replication. Fast BKV replication dynamics in plasma and urine with half-lives of <12 h accounted for daily urothelial and tubular epithelial cell loss of 4×10 7 and 6×10 7 , respectively. BKV dynamics in both sites were only partly linked, with full and partial discordance in 36% and 32%, respectively. Viral expansion was best explained by models where BKV replication started in the kidney followed by urothelial amplification and tubular epithelial cell cross-feeding reaching a dynamic equilibrium after ∼10 weeks. Curtailing intrarenal replication by 50% was ineffective and >80% was required for clearing viremia within 7 weeks, but viruria persisted for >14 weeks. Reductions >90% cleared viremia and viruria by 3 and 10 weeks, respectively. The model was clinically validated in prospectively monitored KT patients supporting >80% curtailing for optimal interventions.

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The results emphasize that high-level BKV replication is a major pathogenetic factor that may have implications for genome rearrangements, immune evasion, and antiviral resistance.

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Virus replication and progression to disease in transplant patients is determined by patient-, graftand virus-specific factors. This complex interaction is modulated by the net state of immunosuppression and its impact on virus-specific cellular immunity. Due to the increasing potency of immunosuppressive regimens, graft rejections have decreased, but susceptibility to infections has increased. Therefore, cytomegalovirus (CMV) remains the most important viral pathogen posttransplant despite availability of effective antiviral drugs and validated strategies for prophylactic, preemptive and therapeutic intervention. CMV replication can affect almost every organ system, with frequent recurrences and increasing rates of antiviral resistance. Together with indirect long-term effects, CMV significantly reduces graft and patient survival after solid organ and hematopoietic stem cell transplantation. The human polyomavirus called BK virus (BKV), on the other hand, only recently surfaced as pathogen with organ tropism largely limited to the reno-urinary tract, manifesting as polyomavirus-associated nephropathy in kidney transplant and hemorrhagic cystitis in hematopoetic stem cell transplant patients. No licensed anti-polyoma viral drugs are available, and treatment relies mainly on improving immune functions to regain control over BKV replication. In this review, we discuss diagnostic and therapeutic aspects of CMV and BKV replication and disease posttransplantation.

Based on a mathematical model, we analyze the dynamics of CD4+ cells, actively, latently, persistently, and defectively infected cells and plasma virus after initiation of antiretroviral therapy in 14 HIV-1-infected asymptomatic patients. By simultaneous fitting of our model to clinical data of plasma HIV-1 RNA, peripheral blood mononuclear cell (PBMC)-gag RNA, proviral DNA, and CD4+ cell counts, we estimate kinetic parameters to determine the basic reproductive rate (R0) of the virus in different infected cell compartments as a measure of the replicative capacity of the virus in vivo. We find that the basic reproductive rate is larger than 1 before treatment only in actively infected cells (mean R0(act) approximately 2.46) indicating that only in this compartment the virus can maintain an ongoing infection. In latently and persistently infected cells the basic reproductive rate is considerably smaller (R0(lat) approximately 0.03 and R0(pers) approximately 0.008, respectively) indicating that these compartments contribute little to the total basic reproductive rate and cannot maintain an ongoing infection in absence of actively infected cells.