Background
A virus was isolated in the 1950ies from mouse and because of its ability to induce multiple tumors in animal models named polyomavirus (PyV) [
1]. Since then, PyVs have been described in other mammals, including humans, birds, and fish [
2,
3]. Members of the
Polyomaviridae family are characterized by non-enveloped virus particles containing a circular double-stranded DNA genome of approximately 5000 base-pairs (bp). A typical PyV genome codes for the regulatory proteins large T-antigen (LT) and small T-antigen (sT) and at least two capsid proteins, VP1 and VP2. The T-antigens are expressed early during the infection cycle, and are required for viral transcription and replication [
4]. These proteins possess oncogenic properties [
5‐
7]. The capsid proteins are expressed after viral replication has initiated and therefore later during infection of the host cell. A non-coding region (NCCR), which encompasses the origin of replication and the transcription regulatory sequences for both the T-antigens and the VPs, separates the coding regions for the T-antigens and capsid proteins [
4].
So far, 15 polyomavirus genomes have been isolated from humans. In 1971, BKPyV and JCPyV were the first human PyVs to be described in literature. They were isolated from urine of a renal transplant patient and the brain from a patient with progressive multifocal encephalopathy (PML), respectively [
8,
9]. Since then, novel PyVs were originally described in nasopharyngeal aspirates (KIPyV; [
10]), bronchoalveolar lavage (WUPyV; [
11]), Merkel cell carcinoma (MCPyV; [
12]), skin (HPyV6, HPyV7, TSPyV, LIPyV; [
13‐
15]), serum (HPyV9; [
16]), genital warts (HPyV10; [
17]), feces (STLPyV, QPyV; [
18,
19]), liver (HPyV12; [
20]), and muscle (NJPyV; [
21]). Although HPyVs seem to establish a harmless persistent infection in healthy individuals [
22,
23], they may cause diseases in immunocompromised patients. BKPyV is associated with nephropathy in renal transplant recipients and hemorrhagic cystitis in hematopoietic stem cell transplantation [
24,
25]. JCPyV causes PML and few cases of JCPyV-associated nephropathy in renal transplant patients have been observed [
26‐
28]. MCPyV is the cause of Merkel cell carcinoma, a neuroendocrine skin cancer [
12], and TSPyV is the etiological factor of trichodysplasia spinulosa in immunodeficient patients [
29].
Serological studies have demonstrated that HPyV6 and HPyV7 infections are ubiquitous in the healthy adult human population, with a seroprevalence ranging between 74 and 93% for HPyV6 and between 56 and 80% for HPyV7 [
30‐
34]. The presence of HPyV6 and HPyV7 DNA has been examined in different biological samples of healthy controls and different patient groups in a quest to determine the cell tropism and the possible association of these viruses with diseases. HPyV6 and HPyV7 are natural inhabitants of the healthy skin virome [
13,
35‐
39]. These viruses have been detected in other specimens. HPyV6 was present in the urine from one out of 70 patients with hemorrhagic cystitis [
40], and HPyV7 was found in urine from one out of 100 liver transplant patients [
41] and from five out of 43 hematopoietic stem cell transplant patients [
40]. HPyV6, but not HPyV7, was detected in cerebrospinal fluid (CSF) from one out of 243 neurological patients [
42] and from one HIV-positive patient with JCPyV-negative progressive multifocal leukoencephalopathy [
43]. HPyV6 DNA could be amplified from two out 110 serum samples from HIV-negative patients [
44], and from nasopharyngeal aspirates [
45] and lymph nodes [
46]. HPyV7 DNA was present in the blood from a patient with dyskeratotic dermatosis [
47]. Both viruses are also present in eyebrow hair from healthy men [
38], and in cervical specimens of women [
48].
Clear associations with diseases have not been established, except in severely immunocompromised patients, where HPyV6 and HPyV7 can cause pruritic dermatoses characterized by hyperproliferation of dyskeratotic (with premature or altered differentiation) keratinocytes that result in brownish skin plaques [
49‐
53]. The presence of HPyV6 has sporadically been detected in the skin from lichen simplex chronicus, eosinophilic pustular folliculitis and suppurative foliculitis patients [
39,
54]. HPyV6 has also been associated with Kimura disease and patients with dermatopathic lymphadenitis [
46,
55]. HPyV6, but not HPyV7 DNA was present in anal/rectal swabs of some men who had sex with men that were HIV-negative, but neither HPyV6 nor HPyV7 were detected in throat/oral swabs and in urethral specimens from these subjects [
56].
A role for HPyV6 and HPyV7 in human cancers is lacking although low viral genome copy numbers have been found in few samples of different tumor tissue types [
39,
44,
57‐
69].
To further exploit a possible causative role of HPyV6 and HPyV7 in immunocompromised patients, we examined the presence of DNA from these viruses in urine from systemic lupus erythematosus (SLE), HIV positive, psoriasis, and multiple sclerosis patients, as well as in urine from pregnant women and healthy blood donors. HPyV6 viruria was found in SLE patients, HIV-positive patients and pregnant women, whereas HPyV7 DNA was only detected in SLE and HIV-positive patients. The prevalence of HPyV6 was higher than HPyV7 in these two patient groups. Longitudinal study of the SLE patients showed intermittent viruria.
Discussion
HPyV6 and HPyV7 DNA has been detected in different body samples of immunocompromised patients [
39,
43,
49‐
53], but viruria of these viruses has not been examined in SLE and MS patients and in pregnant women. We found that DNA of both viruses was detected in the urine from some SLE patient and pregnant women, with a higher prevalence of HPyV6 compared to HPyV7. A previous study failed to detect HPyV6 and HPyV7 DNA in skin from two SLE patients [
39]. Similar to HPyV6 and HPyV7, intermittent episodes of urine shedding of BKPyV and JCPyV and simultaneous viruria of BKPyV and JCPyV was observed in SLE patients [
70‐
75].
We could not detect HPyV6 or HPyV7 urine shedding in MS patients treated with natalizumab. CSF from 10 MS patients were negative for HPyV6 and HPyV7 DNA [
42], suggesting that reactivation of these two HPyVs may be a rare event in MS patients. Studies by several groups have shown that BKPyV, JCPyV or both can be detected in urine from MS patients receiving natalizumab or β-interferon [
76‐
81], indicating that HPyV viruria is not uncommon in these patients.
We did not discover HPyV6 and HPyV7 DNA in the urine samples of healthy blood donors. This is in agreement with a previous study that also failed to detect HPyV6 in the urine from 50 healthy volunteers [
82] or in 189 urine specimens from symptomatic children and adults undergoing routine diagnostic testing [
83]. A longitudinal study on 169 urine samples obtained from 32 organ transplant patients showed only one urine sample positive for HPyV7 DNA. This sample was obtained from a liver transplant child 8 months after transplantation [
41].
The presence of HPyV6, but not HPyV7 DNA has been described in CSF, serum, and anal/rectal swabs from HIV-positive individuals [
42,
43,
56], but neither HPyV6 nor HPyV7 were found in urethral samples or urine [
56,
84]. We found that 6 of our 66 HIV-positive subjects displayed HPyV6 viruria, whereas Torres et al
., examined only 19 urine samples [
84]. The relative small number of subjects in the latter study may explain the different findings with our results.
Hashida and colleagues examined nonlesional and lesional skin swabs from 30 psoriasis patients and reported that 58% (nonlesional) and 54% (lesional) samples were HPyV6 positive, while the HPyV7 prevalence was 42% and 25%. Of the skin swabs from healthy individuals, 14% were positive for HPyV6 and 6% were positive for HPyV7. The viral loads were also higher in both nonlesional and lesional samples of the psoriasis patients compared to the healthy individuals, indicating that HPyV6 and HPyV7 infection is higher in this inflammatory skin condition [
85].
While PCR-based studies have shown that BKPyV and JCPyV viruria is common in pregnant women [
86‐
89], less is known about urinal excretion of the novel HPyV. Cosma et al. [
90] examine KIPyV, WUPyV and HPyV9 viruria in 100 non-pregnant and 100 pregnant women and found HPyV9 viruria in 2 non-pregnant and 3 pregnant women, whereas no KIPyV and WUPyV was detected in either cohorts. To the best of our knowledge, HPyV6 and HPyV7 viruria has not been investigated in pregnant women. We found that 40.4% of the women were positive for HPyV6 and 8.5% were positive for HPyV7. Two of the women (4.3%) had a urine sample that contained DNA of both viruses.
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