The BK polyomavirus infects almost every human being in the world. After primary childhood infection, it persists in the kidney and the urothelium, without causing overt pathology - at least in immunocompetent hosts. In kidney transplant (KTx) recipients, however, the immunosuppressive treatment that prevents graft rejection also blocks the cellular immune response which would normally keep the virus in check. Hence 20-50% of KTx recipients experience reactivation of BK virus replication, resulting in excretion of the virus in the urine. In most cases, virus is only found in the urine and the graft is not harmed. In a minority of KTx recipients, BK virus can also be found in the blood, and persisent, high-level viremia leads to polyomavirus nephritis in 2-5% of KTx recipients. The inflammation that accompanies polyomavirus nephritis can lead to graft loss, and according to some studies, favors the emergence of donor-specific antibodies. There is currently no effective antiviral treatment for polyomavirus nephritis, or for the hemorrhagic cystitis caused by BK virus in hematopoietic stem cell recipients.
I am interested in the role of the antibody response in controlling BK virus replication in KTx recipients. In the Nantes cohort set up by CRTI researchers Celine Bressollette and Maryvonne Hourmant (ajouter des liens ici….) we found that in some patients (For example - Fig1 - Left Panel), a robust neutralizing antibody response against BK virus is associated with control of viral replication, whereas in others (Fig 1 Right panel) virus replication persists even in the presence of a strong neutralizing antibody response.
Figure 1 - Viral load in urine (Pink lines) and blood (Blue lines) after KTx in two patients. Neutralizing antibody titres are shown by the dark grey bars
In this type of patient, with high-level replication lasting more than six months, we found that the virus accumulates mutations in the major capsid protein, VP1. The mutations cluster around the receptor binding pocket, suggesting that they could allow the virus to escape from the neutralizing antibody response, or possibly modify its tropism. My current work aims to explore these two possibilities, using pseudotype virus particles composed of VP1 proteins that carry the different mutations we observed in patients.
Figure 2 - Accumulation of VP1 mutations in a patient with persistent BK virus replication The alpha2-8 disialic acid motif that is part of the cellular receptor for BKPyV is shown in yellow, bound to a VP1 pentamer. Residues of VP1 that are critical for interaction with this structure are shown in blue, and other residues contributing to receptor binding are shown in green. Residues that mutate over time are shown in red.
Applications - In future work we hope to obtain broadly neutralizing monoclonal antibodies that are able to neutralize all observed virus variants. These antibodies could be used as therapeutics to treat polyomavirus nephritis, and thereby prevent graft loss caused by BK virus.
External collaborations - I am working with Christine Hanssen Rinaldo to understand the roles of the minor capsid proteins VP2 and VP3 in virus entry.