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. 2019 Jul 31;220(5):752-760.
doi: 10.1093/infdis/jiz181.

Prospective Assessment of Cytomegalovirus Immunity in High-Risk Donor-Seropositive/Recipient-Seronegative Liver Transplant Recipients Receiving Either Preemptive Therapy or Antiviral Prophylaxis

Ajit P Limaye  1 , Margaret L Green  1   2 , Bradley C Edmison  2 , Terry Stevens-Ayers  2   3 , Sam Chatterton-Kirchmeier  2   3 , Adam P Geballe  1   2   3 , Nina Singh  3 , Michael Boeckh  1   2   3
Affiliations

Prospective Assessment of Cytomegalovirus Immunity in High-Risk Donor-Seropositive/Recipient-Seronegative Liver Transplant Recipients Receiving Either Preemptive Therapy or Antiviral Prophylaxis

Ajit P Limaye et al. J Infect Dis. .

Abstract

The differential impact of preemptive therapy (PET) and antiviral prophylaxis (AP) on development of cytomegalovirus (CMV)-specific neutralizing antibody (nAb) and T-cell responses have not previously been directly compared in high-risk donor-seropositive/recipient-seronegative (D+R-) organ transplant recipients. We prospectively assessed T-cell and nAb responses 3 months after transplantation in cohorts of high-risk D+R- liver transplant recipients who received either PET (n = 15) or AP (n = 25) and a control group of CMV-seropositive transplant recipients (R+) (AP; n = 24). CMV phosphoprotein 65 (pp65)- and immediate early protein 1-specific multifunctional T-cell responses were determined by means of intracellular cytokine staining and nAbs against BADrUL131-Y4 CMV in adult retinal pigment epithelial cell line-19 human epithelial cells; nAbs were detected in 8 of 12 (67%) in the PET group, none of 17 in the AP group, and 20 of 22 (91%) in the R+ group. Multifunctional CD8 and CD4 T-cell responses to pp65 were generally similar between PET and R+ groups, and lower for the AP group; multifunctional CD4 responses were similar across all groups. Among D+R- liver transplant recipients, PET was associated with the development of greater nAb and multifunctional CD8 T-cell responses compared with AP, providing a potential mechanism to explain the relative protection against late-onset disease with PET. Future studies are needed to define specific immune parameters predictive of late-onset CMV disease with AP.

Keywords: Cytomegalovirus; immunity; transplant.

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Figures

Figure 1.
Figure 1.
Cumulative incidence of cytomegalovirus (CMV) disease in first year after transplantation, stratified by serogroup. Abbreviation: R+, CMV-seropositive transplant recipients (control group).
Figure 2.
Figure 2.
Neutralizing antibody titer to a virus containing a reconstructed pentameric complex, stratified by cohort. Each black dot indicates the result for an individual patient. Boxes represent first to third quartiles; lines within boxes, medians; whiskers, minimum and maximum values; and dotted line, cutoff for quantitation. Projected median inhibitory concentration (IC50) values <5 that showed evidence of some neutralizing capacity at only the highest plasma dilutions were considered to have a detectable but not quantifiable response and were scored as 2.5. If there was no evidence of any neutralization even at the highest concentrations of plasma, the result was shown as 0. Abbreviations: AP, antiviral prophylaxis; Ctrl+, cytomegalovirus (CMV)–seropositive healthy controls; Ctrl−, CMV-seronegative healthy controls; PET, preemptive therapy; R+, CMV-seropositive transplant recipients who received AP as controls.
Figure 3.
Figure 3.
CD8 and CD4 T-cell responses to Staphylococcal enterotoxin B months after transplantation, expressed in cells per microliter, collectively for any cytokine or degranulation marker for CD8 (A), CD4 (D), and multifunctional CD8 (B), and CD4 (C) T cells, defined as those expressing ≥2 markers. Each black dot indicates results from an individual patient, and whiskers represent minimum and maximum values. Abbreviations: AP, antiviral prophylaxis; PET, preemptive therapy; R+, cytomegalovirus-seropositive transplant recipients who received AP.
Figure 4.
Figure 4.
Multifunctional CD8 (A, B) and CD4 (C, D) cytomegalovirus (CMV)–specific T-cell responses to phosphoprotein 65 (pp65) (A, C) and immediate early protein 1 (IE-1) (B, D) 3 months after transplantation. Each black dot represents results from an individual patient, and whiskers represent minimum and maximum values. A multifunctional T-cell response was defined as expressing ≥2 cytokines or degranulation markers. Abbreviations: AP, antiviral prophylaxis; PET, preemptive therapy; R+, CMV-seropositive transplant recipients who received prophylaxis.
Figure 5.
Figure 5.
Summary of quantitative neutralizing antibody (nAb) and multifunctional cytomegalovirus (CMV)–specific T-cell responses according to CMV prevention strategy and the seropositive-recipient (R+) control group. Data were normalized for display, with orange representing the maximum response and blue, no response. CD4 and CD8 multifunctional CMV-specific T-cell responses were log-transformed before normalization. Abbreviations: AP, antiviral prophylaxis; PET, preemptive therapy; R+, CMV seropositive control transplant patients.
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