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Temporal Virus Serological Profiling of Kidney Graft Recipients Using Virscan

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Temporal Virus Serological Profiling of Kidney Graft Recipients Using Virscan Temporal virus serological profiling of kidney graft recipients using VirScan Pierre Isnarda,b,1, Tomasz Kulac,d,1, Véronique Avettand Fenoele,f, Dany Anglicheaua,b,f, Fabiola Terzia, Christophe Legendrea,b,f, Stephen J. Elledgec,d, and Guillaume Canauda,b,f,2 aINSERM U1151, Institut Necker Enfants Malades, Hôpital Necker-Enfants Malades, 75015 Paris, France; bService de Néphrologie Transplantation Adultes, Hôpital Necker-Enfants Malades, 75015 Paris, France; cDivision of Genetics, Department of Medicine, Howard Hughes Medical Institute, Brigham and Women’s Hospital, Boston, MA 02115; dDepartment of Genetics, Harvard University Medical School, Boston, MA 02115; eLaboratoire de Virologie, Hôpital Necker-Enfants Malades, 75015 Paris, France; and fUniversité Paris Descartes, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, 75006 Paris, France Contributed by Stephen J. Elledge, April 7, 2019 (sent for review December 13, 2018; reviewed by Jae-Hyung Chang and Stephen R. Quake) At this time, pretransplant viral screening of donors and recipients is human virome, that is, all viruses known to infect humans, using a based on serological status and limited to certain viruses. After synthetic peptide array (7). VirScan is based on immunoprecipita- transplantation, patient follow-up is based on a monitoring strategy tion combined with next-generation sequencing of a bacteriophage using ELISA or PCR. Such approaches exclude other emerging viruses library containing peptides representing viruses known to infect that can affect the transplant outcome. Recently, a multiplex un- humans. The VirScan library displays viral peptides, each 56 amino biased array, VirScan, was developed. This tool allows the detection acids in length, from 206 species of viruses, corresponding to 1,000 of antibodies against viruses, using a synthetic human virome, with different strains known to infect humans. Serum antibodies are minimal serum and cost. We decided to test the value of VirScan in allowed to bind to phages displaying their cognate epitopes, and the follow-up of a cohort of transplant recipients. We enrolled 45 after immunoprecipitation of those phages with bound antibodies, kidney transplant recipients and performed virus serological profil- next-generation sequencing is used to identify the recognized epi- ing at day 0 and day +365, using VirScan. We compared the results topes. Because VirScan is based on the presence of IgG, the assay obtained with ELISA/PCR assays. We detected antibody responses provides information on both semirecent and past history of viral to 39 of the 206 species of virus present in the VirScan library, with infections over the individual’s lifetime. Importantly, only minimal an average of 12 species of virus per sample. VirScan gave similar volume of serum is needed for VirScan (1 μL), and the cost is $25 INFLAMMATION results to PCR/ELISA screening tests. Using VirScan, we found that per sample (excluding labor or capital depreciation) (7). Here, we IMMUNOLOGY AND anti-viral antibody responses were largely conserved in patients describe the potential value of VirScan in the context of post–kidney during the first year after transplantation, regardless of immuno- transplant follow-up. suppressive treatment. Our study suggests VirScan offers an unprec- edented opportunity to screen and monitor posttransplant virus Methods infection in a cost-effective, easy, and unbiased manner. Study Design and Patients. From 2014 to 2015, we prospectively enrolled 45 consecutive kidney transplant recipients in our transplant department (Hôpital virus | screening | transplant | immunosuppression Necker-Enfants Malades, Paris, France). At the time of transplantation (day 0), all donors and recipients were screened for HHV4, HHV5, HHV8, HIV 1 and 2, idney transplantation is recognized as the best therapeutic HCV, and HBV, using ELISA-based assays. After transplantation, based on clinical or biological assumption of viral infection, appropriate PCR tests were Koption for end-stage renal failure (1). However, the use of immunosuppressive drugs to prevent allograft rejection is asso- ciated with an increasing rate of opportunistic infections (2). Significance Among them, viral infections remain a significant cause of morbidity, reducing both allograft and patient survival through Viral infections after organ transplantation remain a significant the occurrence of virus-associated malignancies and kidney in- cause of morbidity, reducing both allograft and patient sur- flammation, and/or a playing a potent role in allograft rejection vival. At this time, pretransplant screening of potential donors (3). Transplant recipients are exposed to virus transmission from and recipients is based on serological status and is limited to the allograft but also, because of the immunosuppression ther- certain viruses. Recently, a multiplex unbiased array, called apy, to virus reactivation. VirScan, was developed. This tool allows the detection of an- At this time, pretransplant serological screening of a potential tibodies against viruses, using a synthetic human virome. Here, we tested the value of VirScan in the follow-up of a cohort of donor and recipients is limited to antibodies targeting only certain kidney transplant recipients. We found that VirScan is easy to virus species, including HIV, hepatitis B virus (HBV), hepatitis C use, cost-effective, safe, and reproducible, and gives an un- virus (HCV), human herpes virus 5 (HHV5 or CMV), HHV4 (or biased approach to monitor patients after transplantation, EBV), and human T-lymphotropic virus I/II (4). Therefore, cur- but in addition, the anti-viral antibody responses were largely rent screening approaches risk missing important emerging viruses, conserved in patients, regardless of immunosuppressive such as West Nile virus (5) or lymphocytic choriomeningitis virus treatment. (6), that can adversely affect transplant outcomes. A limitation of the current screening methods is that clinical immunoassays Author contributions: S.J.E. and G.C. designed research; P.I., T.K., V.A.F., and G.C. per- aimed at detecting recent or past virus exposures remain largely formed research; S.J.E. contributed new reagents/analytic tools; P.I., T.K., V.A.F., D.A., F.T., singleplex assays, targeting one virus exposure at a time. There- C.L., and G.C. analyzed data; and G.C. wrote the paper. fore, cost and sample requirements generally prohibit screening Reviewers: J.-H.C., Columbia University Medical Center; and S.R.Q., Stanford University. against a wide range of virus exposures, especially those that are The authors declare no conflict of interest. of low prevalence. What is needed is an unbiased method Published under the PNAS license. of screening against a much larger number of potential virus 1P.I. and T.K. contributed equally to this work. exposures. 2To whom correspondence should be addressed. Email: [email protected]. Recently, a technology named VirScan was developed that has This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. been demonstrated to be a robust platform capable of very high 1073/pnas.1821166116/-/DCSupplemental. complexity serological screening for virus exposure across the entire Published online May 13, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1821166116 PNAS | May 28, 2019 | vol. 116 | no. 22 | 10899–10904 Downloaded by guest on September 26, 2021 performed. All patients received CMV prophylaxis based on day 0 serological Table 1. Demographic characteristics status of the donor/recipient pairs (i.e., donor−/recipient− received acyclovir = for 4 mo, donor+/recipient− received ganciclovir for 6 mo, and donor+/ Demographic and clinic characteristics Patients (n 45) + recipient received ganciclovir for 4 mo). Recipients demographic data For each of the 45 patients, serum was collected on the day of trans- Sex ratio, male/female 3.5 plantation (D0) and at 1 y posttransplant (D+365). All serum samples (n = 90) were analyzed with VirScan (SI Appendix, Fig. S1A). Age, y (range) 49 (22-77) Our institutional review board Commité de Protection des Personnes Ile Origin, n (%) de France 2 (CPP IdF2) approved the study, and written informed consent European 26 (58) was obtained from each patient. North African 10 (22) Black African 5 (11) VirScan Construction and Procedure. VirScan is a high-throughput method of Asian 4 (9) serological profiling requiring only 2 μgIg(1μL serum) to detect antiviral Causes of end-stage renal disease, n (%) antibodies from all known human viruses (7). Briefly, the virome peptide Diabetic nephropathy 3 (7) – library consists of 93,904 distinct 56 aminoacidpeptidestilingacrossthe Vascular nephropathy 2 (4) proteomes of 206 species of virus. DNA sequences encoding the peptides Glomerular diseases 14 (31) were cloned into a T7 bacteriophage display vector for screening. Ampli- CAKUT 11 (24) fication and sequencing of the insert DNA from bound phage reveals peptides targeted by potential antiviral antibodies from the sample (SI ADPKD 5 (11) Appendix,Fig.S1B). For determining whether a patient has been infected Other 10 (22) with a certain virus, a minimum threshold of 3 virus-specific enriched CAKUT: Congenital anomalies of the kidney and urinary tract; ADPKD: peptides per virus was required for all viruses except for HHV5, where a Autosomal polycystic kidney disease. minimum threshold of 5 virus-specific enriched peptides was used to account for the larger size of the viral proteome (7). To validate this threshold, a threshold performance
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