Reactivation of human herpesvirus 6 (HHV-6) infection in patients with connective tissue diseases

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Abstract

Background

Little is known about the involvement of human herpesviruses 6 and 7 (HHV-6 and HHV-7) in autoimmune connective tissue diseases (ACTD).

Objective

To determine the prevalence of active infection with HHV-6 and HHV-7 in patients with ACTD.

Study design

The presence and quantity of HHV-6 DNA was determined by quantitative real-time PCR in a cross-sectional study of serum, peripheral blood mononuclear cells, and tissues obtained from 58 ACTD patients and 38 healthy subjects (HS). Specific anti-HHV-6 antibody titer was also measured.

Results

HHV-6 serum viremia occurred in a significantly higher proportion of ACTD patients compared to HS [26/58 (44.8%) vs. 1/38 (2.6%), p = 0.001] with the highest reactivation frequency [7/10 (70%)] observed in patients with scleroderma. Moreover, HHV-6 in serum was associated with ACTD activity (22/38 vs. 4/20, p < 0.05). Higher titers of HHV-6 antibodies were found in ACTD patients than in HS, although HHV-6 seroprevalence among patients with ACTD and HS was similar. HHV-7 viremia was not detected in any patients or HS controls.

Conclusion

The frequent reactivation of HHV-6 in scleroderma and other ACTD, especially when active, suggests that HHV-6 may play a role in the pathogenesis of these diseases.

Introduction

Autoimmune connective tissue diseases (ACTD) encompass many diseases, including systemic sclerosis or scleroderma (SSc), systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE), dermatomyositis (DM), vasculitis and other conditions causing chronic inflammation that can affect many organs and systems. Although the etiologies of ACTD remain unclear, clinical, epidemiological, and laboratory findings suggest that several viral infections may be involved.1

Reactivation of human herpesvirus 6 (HHV-6), as suggested by the high rates of viral isolation, occurs frequently in patients with collagen vascular diseases.2 Moreover, Hoffmann and coauthors demonstrated active HHV-6 infection in a 37-year-old woman affected by SLE and histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease).3 More recently, HHV-7 replication has been documented in the salivary glands of patients with adult-onset Still disease.4 Beside these two reports, little is known about the involvement of HHV-6 and 7 in the pathogenesis of ACTD. In the present study the presence and burden of these two viruses in ACTD were investigated.

Section snippets

Subjects and clinical samples

Blood and skin biopsies were obtained from 58 patients with ACTD recruited at the Section of Dermatology, University of Genoa. Their characteristics, details of their therapy, and disease activity are included in Table 1. Disease activity in patients with SLE, LED, DM were assessed using different validated clinical activity tests (SLEDAI, CLASI, DSSI) based on involvement of organs systems.5, 6, 7

Blood samples from 38 healthy subjects (HS) were included as the control group. The Medical

Detection and quantification of HHV-6 and HHV-7 DNA load in serum

HHV-6 viremia was detected in a significantly higher proportion of ACTD patients than in HS (26/58 [44.8%] vs. 1/38 [2.6%], p = 0.001; χ2 test). HHV-7 DNA was not detected in sera from any of the patients or HS controls (Table 2).

The detection rates of HHV-6 DNA in patients affected by SSc, DLE, SLE and DM were 70%, 40%, 45%, 25%, respectively (Fig. 1). The levels of HHV-6 DNA load were low in the majority of cases, ranging from 7 to 165 GEq/ml (Fig. 2), with the exception of 1 patient that had

Discussion

The measurement of HHV-6 and HHV-7 in serum combined with measurement of the latently infected PBMC proved that HHV-6, but not HHV-7, is actively replicating in patients affected by ACTD. This is shown by the significantly higher percentage of HHV-6 DNA detected in sera from patients with ACTD, which is an accurate marker of active HHV-6 infection.13, 14 The measurement of HHV-6 in serum is not sufficient to prove that the viral DNA detected is not derived from passive lysis of latently

References (21)

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1

Present address: Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland.

2

These authors equally contributed to this work.

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