*Purpose: Human cytomegalovirus (CMV) infects over half the global population, leading to a mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. To identify host responses indicative of acute CMV DNAemia and signatures of CMV primary infection and/or reactivation prior to detection by PCR, we analyzed immune responses in 31 kidney transplant recipients with CMV DNAemia (CMV PCR+) and 31 matched, CMV PCR-negative controls (CMV PCR-).

*Methods: Peripheral blood was sampled three months post-transplant for all patients. Those who became DNAemic were also sampled one-week post-DNAemia. We profiled patients’ immune status using high-throughput technologies, including 17-color immunophenotyping of peripheral blood mononuclear cells (PBMC), whole blood RNA-Seq, PBMC reduced representation bisulfite sequencing (RRBS), and plasma cytokine and chemokine detection by multiplex Luminex and/or Simoa. Integrated datasets were analysed by partial least squares regression.

*Results: After detection of CMV DNAemia, we observed increased plasma inflammatory cytokines, interferon signaling (ME18), and expansion of terminally differentiated CD8 T cells, with contraction of naïve CD8 T cells and downregulation of transcripts associated with MHC Class-II (ME16) (Fig. 1A). Pre-DNAemia, CMV PCR+ patients had increased plasma IL-15 and IL-2, with downregulation of T cell signaling (ME8) and translational machinery (Fig. 1B), and evidence of advanced epigenetic age by RRBS.

*Conclusions: Immunophenotyping post-initial detectable CMV DNAemia highlighted the importance of interferon signaling and expansion of effector CD8 T cells in control of DNAemia. Pre-CMV DNAemia immune profiling identified dynamic changes in IL-15 and IL-2, which may identify kidney transplant recipients at risk of CMV DNAemia prior to detection of virus in the periphery.

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