Abnormal Seroresponse to Common Viruses in CLL RAI0
Authors: de Sanjosé Silvia , Robles Claudia , Waterboer Tim , Casabonne Delphine , Michel Angelika , Benavente Yolanda , Costas Laura , Gonzalez-Barca Eva , Aymerich Marta , Campo Elias , Tardon Adonina , Garcia Sanmartin Paloma , Castaño-Vinyals Gemma , Dierssen-Sotos Trinidad , Aragones Nuria , Pollan Marina , Kogevinas Manolis , Pawlita Michael 
Published: October 2019

Abstract
Background: Chronic Lymphocytic Leukemia (CLL) has been related to an increased susceptibility to infections particularly in advanced stages. Evidence is accumulating of an immune impaired response at early stages that could affect prognosis. We evaluated the pattern of seroresponse to common infections in CLL Rai0 cases and in general population controls.
Methods: A case-control study within the multicase-control study (MCC Spain) and the International Cancer Genome Consortium (ICGC) was designed. 204 CLL cases, 69.6% newly diagnosed and 30.4% prevalent, and 370 population controls matched by sex, age and recruitment area were analyzed. All subjects provided a blood sample and answered a personal interview. In addition to socio-demographic, behavioral and medical characteristics for cases and controls, data on CD38, ZAP70 and common CLL deletions were available for analysis. Seroreactivities against the antigens from JC polyomavirus (JCPyV; VP1), Merkel cell poliomavirus (MCPyV; VP1), herpes simplex 1 (HSV1; gB), Epstein-Barr virus (EBV;zebra, EBNA, EA-D and VCAp18) and cytomegalovirus (CMV;­ pp150, CM2, pp52, pp28 and pp65) were measured using bead-based multiplex serology technology. Multivariate logistic regression models were used to examine seroprevalence to different viral infections and seroreactivity intensity (in tertiles) in cases and controls. Generalised additive models were used to explore seroreactivity patterns.
Results: Seropositivity was very high in both cases and controls and was significantly higher for all infections tested among controls: HSV1 92.0% cases vs. 94.4% controls; CMV 84,4% vs. 88,3%; EBV 97,5% vs. 98,9%; JCPyV 56.6% vs. 68.9% and MCV 81.4% vs. 83.4%. Among seropositive subjects, a statistically significant decrease in antibody response was observed among CLL cases compared to controls (HSV-1 p<0.009; EBV_EBNA, p<0.000; CMV overall, p<0.0279; CMV_pp28, p<=0.001). No changes in the estimates were observed when adjusting for family history, smoking, or alcohol intake. Increased antibodies to EBV and CMV lytic antigens were detected among cases compared to controls for both EA_EBV (OR=1.36, 95%CI=0.8-2.2) and pp65_CMV (OR=1.42, 95%CI=0.9-2.3).Survival analysis is ongoing and results will be presented.
Conclusions: CLL Rai0 cases showed a reduced ability to mount or maintain seroresponses against common viral infections. Despite this immune suppression, increased antibody titers to EBV and CMV lytic antigens were present indicating a response to reactivated infections; this could potentially be an early sign of CLL.
This work was partially supported by the Spanish Ministry Council: PI11/01810, PI11/02213, the ICGC CLL-Genome Project is supported by Spanish Ministerio de Economía y Competitividad (MINECO) and the Red Temática de Investigación del Cáncer [RTIC RD12/0036/0036].

Disclosures
No relevant conflicts of interest to declare.