HHV-6A IE1 antibodies associated with increased risk of non-Hodgkin lymphoma

An international group of collaborators examined antibodies for 13 viruses in the blood of non-Hodgkin lymphoma (NHL) patients. Patients with HHV-6A immediate-early 1 (IE1A) antigen antibodies were found to be at a greater risk of developing NHL (OR=1.85, 95% CI=1.04-3.29), and a higher risk was also seen among seropositive patients with high anti-IE1A antibody levels corresponding to the 2nd and 3rd tertile versus seronegative individuals.

Serum or plasma was collected before diagnosis of NHL and was later tested using a multiplex antibody detection assay, which measured antibody levels against 21 antigens specific to 13 viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), polyomaviruses, and the human herpesviruses. The patient cohorts from Shanghai and Singapore included 214 patients who developed non-Hodgkin lymphoma (NHL) and 214 cancer-free matched controls.

In total, 39 NHL patients and 24 controls were seropositive for HHV-6A IE1. EBV ZEBRA and EA-D antibody levels were slightly correlated with IE1A, which may point to a “co-carcinogen” role for HHV-6A in NHL, in which the virus augments the oncogenic activities of EBV. HHV-6A, but not HHV-6B, is able to infect EBV-infected B lymphocytes and trigger reactivation of EBV (Cuomo 1995, Flamand 1993, Flamand 1996), and it has been suggested that HHV-6 may upregulate the expression of LMP1, an EBV oncoprotein (Chen 1999). Moreover, in previous studies, HHV-6/EBV coinfections have been detected in NHL biopsies (Zhou 2007). Intriguingly, the association between IE1A seropositivity, as well as ZEBRA and EA-D seropositivity, and a heightened risk of NHL was strongest for cases diagnosed 10 or more years after blood collection.

The group also found that patients with the highest levels of antibodies against ZEBRA and EA-D, two EBV-specific proteins, had an increased risk of NHL. Additionally, overall HBV seropositivity was associated with an increased risk of NHL, while only 5 patients were seropositive for HCV (2 controls, 3 cases). Of the 4 polyomaviruses tested, only higher antibody levels against trichodysplasia spinulosa polyomavirus in one cohort were linked to a higher risk of NHL. No association with NHL risk was observed for HHV-6B, HSV1, HSV2, CMV, and HHV-8, and HHV-7 was insignificantly associated with the disease.

Currently, the strongest evidence in favor of a role for HHV-6 in lymphomas is found for the nodular sclerosis subset of Hodgkin lymphoma (Lacroix 2007, Lacroix 2010, Siddon 2012). The finding of an increased risk of NHL after detection of antibodies against IE1A antigen indicates that active HHV-6A infection may also play a part in the early stages of NHL, perhaps by spurring changes to the immune system that favor NHL development. It is also possible that suppression of the immune system resulting from changes associated with NHL allow for opportunistic reactivation of HHV-6A that does not affect the course of the disease, although increased antibodies against HHV-6B-specific IE1 antigen might also be expected in this case. Either way, elevated antibodies against IE1A could prove useful as early biomarkers for NHL, and monitoring patients with high levels may aid in the early detection of NHL.

This is the first study using a serological assay that can differentiate HHV-6A from HHV-6B, and the first utilizing an immediate early 1 antigen. The prevalence of HHV-6A is largely unknown, since there has been no serology assay that can differentiate between the two closely related viruses. HHV-6 reactivation after transplantation is almost exclusively HHV-6B. Disease associations suggested for HHV-6A include Hashimoto’s thyroiditis (Caselli 2012) and unexplained infertility (Marci 2016).

Find the full paper here: Bassig 2018.