Impact of NK Cells on Control of BK Polyomavirus

About This Grant

Most healthy individuals are persistently infected with the human polyomavirus BK (BKPyV) without significant consequences, yet in immunocompromised hosts such as kidney transplant or bone marrow transplant recipients, BKPyV is associated with significant morbidity. In particular, kidney transplant patients with active BKPyV are at highest risk to develop BKPyV-associated nephropathy (BKVN), one of the leading causes of graft loss. There is currently no effective treatment to prevent or treat BKPyV-associated diseases and recent clinical trials have focused on immune-based therapies, including infusion of immunoglobulins and allogeneic BKPyV- specific T cells. These strategies have been successful in subsets of patients but have shown limited efficacy in others, suggesting other immune factors contribute to control of BKPyV. In particular, Natural killer (NK) cell- based immunotherapy has the potential to help treat BKPyV-associated diseases in immunosuppressed individuals. However, NK cell responses to BKPyV are poorly understood. Our published and ongoing work is providing new insights into NK cell responses to polyomaviruses. Specifically, our preliminary data now show robust NK cell responses to BKPyV, modulation of NK cell responses against polyomaviruses via receptors that are checkpoint targets for cancer immunotherapies, and clonal expansion of single NK cells with potent cytotoxic responses against BKPyV. Importantly, we also identified significant differences in NK cell phenotypic profiles between kidney transplant recipients who control BKPyV following reactivation and those who don’t, with control being associated with lower expression of terminal differentiation markers and higher expression of key activating receptors. In this proposal, we will test the overarching hypothesis that specific subsets of NK cells mediate potent antiviral responses against BKPyV and protect immunocompromised patients against BKPyV- associated diseases. We will test our hypotheses using longitudinal samples from kidney transplant recipients and heathy donors, BKPyV-infected human renal proximal tubule epithelial cells and kidney organoids, through three focused independent Aims: (i) Characterize NK cell antiviral responses to BKPyV, (ii) Determine how mutations in BKPyV antigens modulate NK cell antiviral function, and (iii) Define NK cell signatures that are associated with control of BKPyV in kidney transplant recipients. If successful, the results of these innovative studies will contribute new knowledge of human NK cell immune responses against BKPyV and guide the development of novel immunotherapeutic approaches aimed at harnessing NK cells to target BKPyV.