Cellular Immunity Against BK Polyomavirus in Kidney Transplant Recipients: A Comprehensive Review

Abstract

BK polyomavirus (BKPyV) is an important opportunistic viral infection that complicates kidney transplantation. Uncontrolled viral replication may result in BKPyV-associated nephropathy (BKPyVAN), a major cause of premature allograft damage and failure. In the continued absence of proven treatments, management relies on the empirical reduction of immunosuppression to facilitate an effective host immune response to clear the virus. This may be complicated by the risk of allograft rejection. There is compelling evidence that cellular immune responses are key to establishing control after viral reactivation. Measurable peripheral BKPyV-specific T cell responses temporally correlate with declining viral loads and subsequent clearance. Conversely, these responses are delayed or absent in BKPyVAN. How these peripheral findings correspond to the intragraft response, and whether BKPyV-specific T cells contribute to the immunopathology of BKPyVAN, remains poorly understood. Molecular techniques have provided some insights; however, these have been unable to fully discriminate BKPyVAN from cellular rejection to date. Furthermore, the contributions of components of innate cellular immunity, such as natural killer cells, are not known. Herein, we review the role of cellular immunity in BKPyV infection in kidney transplant recipients. We discuss advances in the understanding of how the development, phenotype, and functionality of these responses may determine the balance between viral control and immunopathology, and how this knowledge is being translated into tools to prognosticate and guide individualized immunosuppression reduction. Lastly, we consider how further elucidation of these responses may inform the design of therapies that would revolutionize how BKPyV is managed after transplantation.

Keywords: BK Polyomavirus | BKPyVAN | cellular immunity | NK cells | T cells.

FIGURE 1

Mechanisms through which kidney transplant recipients are at risk of uncontrolled BK polyomavirus (BKPyV) replication and subsequent graft damage. (A) Intermittent episodes of viral replication trigger innate, humoral, and cellular immune responses that establish viral control. (B) Viral replication in the immunosuppressed kidney transplant recipient abrogates immune responses, resulting in uncontrolled viral replication and graft damage (BK polyomavirus‐associated nephropathy) through multiple mechanisms.

FIGURE 2

Schematic representation of the BK polyomavirus virion. (A) The BK polyomavirus (BKPyV) capsid consists of 360 VP1 monomers arranged as 72 pentamers in a T = 7d icosahedral structure 40–45 nm in diameter. (B) Each VP1 pentamer is associated with a single copy of either minor capsid protein VP2 or VP3 at the internal surface.

FIGURE 3

Overview of natural killer (NK) cell recognition of healthy and virus‐infected cells. (A) Balance of inhibitory and constituent activating signals from health cells prevents NK cell activation. (B) NK cell targeting of an infected cell through multiple mechanisms including upregulation of activating ligands on the infected cell; CD16‐mediated antibody‐dependent cellular cytotoxicity and loss of inhibitory killer‐cell immunoglobulin‐like receptor (KIR) signaling due to down‐regulation of major histocompatibility complex (MHC) class I expression on the virus‐infected cell (so‐called “missing‐self”).