KIR and HLA interactions are associated with control of primary CMV infection in solid organ transplant recipients

Cytomegalovirus (CMV) infection remains a major source of morbidity and mortality in solid organ transplant recipients. Killer immunoglobulin-like receptors (KIR) are genetically polymorphic natural killer (NK) cell receptors important in antiviral responses. A retrospective, single-center cohort study was performed to study the interaction of KIR genotype and primary control of CMV infection after transplantation. Time to first CMV viremia was determined for a cohort of 531 CMV serology donor positive/recipient negative solid organ transplant recipients. Of the KIR genes, KIR2DL3 and KIR2DS2 were most strongly associated with time to CMV viremia in random survival forest analysis. As KIR2DL3 and KIR2DS2 both interact with HLA-C1, these interactions were evaluated. Seventy-six recipients were found to be positive for both KIR2DL3 and KIR2DS2 and expressed only HLA-C1 antigens in both recipient and donor. These patients had a substantially reduced hazard of CMV viremia in the first year after solid organ transplantation (hazard ratio 0.44, 95% CI 0.27-0.72, p = 0.0012). In KIR2DL3+/KIR2DS2+/HLA-C1/1 recipients who received an organ from a non-C1/1 donor, this protective effect was not observed. These results improve our understanding of human NK cell function in primary CMV infection after transplant. In cytomegalovirus recipient seronegative/donor seropositive organ transplant recipients, a specific combination of genotypes of killer immunoglobulin-like receptors and human leukocyte antigens is associated with control of cytomegalovirus primary infection.