Immune signatures of CMV disease risk after orthotopic liver transplant

Background: Cytomegalovirus (CMV) is a highly seroprevalent human herpesvirus (HHV) of particular clinical significance in the immunocompromised patient population. Solid organ transplant (SOT) from a CMV-infected donor (D+) to a naïve recipient (D+/R-) leads to a unique mechanism of primary CMV infection in ~80% of recipients. CMV disease, such as pneumonitis, retinitis, or primary CMV syndrome, occurs in ~30% of patients, most commonly after cessation of antiviral prophylaxis after day 100. The immune mechanisms of protection from disease risk in this scenario are not known, but this risk was reduced to 10% in a randomized, controlled trial of pre-emptive therapy vs prophylaxis in orthotopic liver transplant (OLT) (CAPSIL study). Pre-emptive therapy, where viremia is monitored and treated only when it reaches above pre-specified levels, is thought to enable the development of immunity in the early post-transplant period. Evaluation of participant samples from the CAPSIL study showed increased CMV-specific CD4 and CD8+ T cells, expression of markers of terminal differentiation in the T cell and NK cell populations, and neutralizing antibody (nAb) levels in patients managed with pre-emptive CMV therapy. A clinically useful measure of risk of CMV disease is urgently needed to guide efforts at prevention. Summary of Proposal: We propose here to identify the factors of the humoral CMV response most correlated with CMV disease risk and combine this with quantification of the CMV-specific T cell repertoire by T cell receptor (TCR) sequencing and sequence-similarity methods. The Central Hypothesis is that a measure of immunity inclusive of both humoral and cellular factors will be most informative to predict disease risk. Rationale: While nAb levels, thought to substantially reflect antibodies specific to CMV surface pentameric complex, are seen to be increased in patients treated pre-emptively for CMV, gB-binding antibody levels are a known correlate of protection in primary, natural infection. Antibodies preventing cell-to-cell viral spread may also be influential. Elucidation of the mechanism by which CMV nAb levels correlate with disease risk in D+/R- OLT is needed. Prior to CAPSIL, T cell immunity was thought to be the primary mediator of CMV protection in SOT but has not been shown to correlate with disease risk in D+/R- OLT. Intrinsic limitations of T cell assay-based correlates of disease risk, such as lab-to-lab variability, would be improved by use of a sequence-based measure. In Aim 1 we will characterize the neutralizing and non-neutralizing antibody response and map the CMV-specific B cell repertoire in samples from the CAPSIL trial. In Aim 2, we will quantify and characterize the CMV-specific T cell repertoire using TCR sequence-based analysis. We will correlate findings from both Aims with the results from the CAPSIL trial to characterize the immune signatures of CMV disease risk in D+/R- OLT. Together, these aims will inform further CMV disease prevention strategies, the primary goal being identification of persons at high risk of CMV disease who would benefit from prolonged monitoring, or persons at low risk of CMV disease who could safely shorten prophylaxis or monitoring. Project Number: 1R01AI189491-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Emily Ford | Institution: UNIVERSITY OF WASHINGTON, SEATTLE, WA | Award Amount: $832,910 | Activity Code: R01 | Study Section: Immunobiology of Transplantation and Alloimmunity Study Section[ITA] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18949101