Large-Scale Identification and Characterization of Hematopoietic Cell Transplant Recipients and their Donors with Inherited Chromosomally Integrated HHV-6

Background: Human herpesvirus 6 (HHV-6) species have a unique ability to integrate into chromosomal telomeres. Vertical transmission via germ cell integration results in offspring with latent HHV-6 in every nucleated cell. The epidemiology of inherited chromosomally integrated (iciHHV-6) in hematopoietic cell transplant (HCT) recipients is not well studied.

Methods: We identified 4,319 HCT donor-recipient pairs (8,638 subjects) who received an allogeneic HCT at Fred Hutch from 1992-2013 and had archived pre-HCT PBMC samples. Extracted DNA was screened by PCR for iciHHV-6 using a validated pooled testing method (Hill et al, J Clin Virol 2016). The prevalence of iciHHV-6 in donors and recipients was compared using McNemar's test. Characteristics of HCT recipients with and without iciHHV-6 were contrasted.

Results: We identified 60 HCT recipients (1.4%) and 40 donors (0.9%) with iciHHV-6. The proportion of individuals with iciHHV-6 was higher in HCT recipients than healthy donors (p=0.027), suggesting a potential association between iciHHV-6 and development of a disease requiring HCT. The distribution of underlying diagnoses and other characteristics did not differ between patients (Table 1) or donors (data not shown) with and without iciHHV-6.

Conclusion: The prevalence of iciHHV-6 was 1.4% in patients undergoing allogeneic HCT at our center, which was significantly higher than the prevalence in healthy donors. However, there were no differences in the distribution of demographic and clinical characteristics among HCT recipients with and without iciHHV-6.

Table 1. Demographic and Clinical Characteristics of HCT Recipients
	Total (n=4,319) Med (IQR) or N (%)	iciHHV-6 Positive (n=60)	iciHHV-6 Negative (n=4,259)
Age	44 (31 – 54)	42 (33 – 55)	44 (31 – 54)
Female	1,771 (41)	20 (33)	1,751 (41)
Race Caucasian Black Other	3,594 (85) 76 (2) 549 (13)	59 (98) 1 (2) 0	3,535 (85) 75 (2) 549 (13)
CMV Seropositive	2,334 (54)	28 (47)	2,306 (54)
Underlying Disease Acute leukemia Aplastic anemia Cancer, non-heme Chronic leukemia Lymphoma MDS Multiple myeloma Non-cancer Other heme	1,665 (39) 113 (3) 21 (0.5) 1,119 (26) 371 (9) 700 (16) 218 (5) 69 (2) 43 (1)	29 (48) 2 (3) 0 14 (23) 5 (8) 6 (10) 2 (3) 0 2 (3)	1,636 (38) 111 (3) 21 (0.5) 1,105 (26) 366 (9) 694 (16) 216 (5) 69 (2) 41 (1)