A cornucopia of human polyomaviruses

DeCaprio, James A.; Garcea, Robert L.

doi:10.1038/nrmicro2992

Cited by 293 publications

(307 citation statements)

References 161 publications

(141 reference statements)

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“…However, only the Merkel cell polyomavirus has been linked to Merkel cell carcinoma and none of the others have been associated to cancer so far. [34][35][36] We found that the risk of CIN3/CIS and ICC linearly increased with increasing number of STIs the woman had had, including HPV, CT, and HHV-2. We do not know whether exposure to CT and/or HHV-2 truly contribute with HPV in ICC causation, or different STIs tend to cluster because of the common transmission route (reflecting thus a high-risk sexual behavior by the subject or her sexual partners), or whether this increase in the risk of CC reflect a decreased immunologic response to clear STIs.…”

Section: Epidemiologymentioning

confidence: 72%

Prospective seroepidemiologic study on the role of Human Papillomavirus and other infections in cervical carcinogenesis: Evidence from the EPIC cohort

et al. 2014

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To evaluate prospectively the association between serological markers of selected infections, including HPV, and risk of developing cervical cancer (CC) and precancer, we performed a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) study that included 184 cases of invasive CC (ICC), 425 cases of cervical intraepithelial neoplasia (CIN) grade 3 or carcinoma in situ (CIS), and 1,218 matched control women. At enrollment participants completed lifestyle questionnaires and provided sera. Subjects were followed‐up for a median of 9 years. Immunoassays were used to detect serum antibodies to Human Herpes Virus 2 (HHV‐2), Chlamydia trachomatis (CT), Chlamydia pneumoniae, L1 proteins of mucosal and cutaneous HPV types, E6/E7 proteins of HPV16/18, as well as to four polyomaviruses. Adjusted odds ratios (OR) [and 95% confidence intervals (CI)] for CIN3/CIS and ICC risk were respectively: 1.6 (1.2–2.0) and 1.8 (1.1–2.7) for L1 seropositivity to any mucosal HPV type, 1.0 (0.4–2.4) and 7.4 (2.8–19.7) for E6 seropositivity to HPV16/18, 1.3 (0.9–1.9) and 2.3 (1.3–4.1) for CT seropositivity, and 1.4 (1.0–2.0) and 1.5 (0.9–2.6) for HHV‐2 seropositivity. The highest OR for ICC was observed for HPV16 E6 seropositivity [OR = 10.2 (3.3–31.1)]. Increasing number of sexually transmitted infections (STIs) was associated with increasing risk. Non‐STIs were not associated with CC risk. In conclusion, this large prospective study confirms the important role of HPV and a possible contribution of CT and HHV‐2 in cervical carcinogenesis. It further identifies HPV16 E6 seropositivity as the strongest marker to predict ICC well before disease development.

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Section: Epidemiologymentioning

confidence: 72%

Prospective seroepidemiologic study on the role of Human Papillomavirus and other infections in cervical carcinogenesis: Evidence from the EPIC cohort

et al. 2014

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“…For example, infections caused by the human BK, JC, and Merkel cell PyVs can lead to PyV-associated nephropathy, progressive multifocal leukoencephalopathy, and Merkel cell carcinoma, respectively (1,2). Simian virus 40 (SV40) traditionally has been used as a model for studying this virus family and has structural and genetic similarities to human PyVs.…”

mentioning

confidence: 99%

The Endoplasmic Reticulum Membrane J Protein C18 Executes a Distinct Role in Promoting Simian Virus 40 Membrane Penetration

Bagchi

Walczak

Tsai

2015

J Virol

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The nonenveloped simian virus 40 (SV40) hijacks the three endoplasmic reticulum (ER) membrane-bound J proteins B12, B14, and C18 to escape from the ER into the cytosol en route to successful infection. How C18 controls SV40 ER-to-cytosol membrane penetration is the least understood of these processes. We previously found that SV40 triggers B12 and B14 to reorganize into discrete puncta in the ER membrane called foci, structures postulated to represent the cytosol entry site (C. P. Walczak, M. S. Ravindran, T. Inoue, and B. Tsai, PLoS Pathog 10:e1004007, 2014). We now find that SV40 also recruits C18 to the virus-induced B12/B14 foci. Importantly, the C18 foci harbor membrane penetration-competent SV40, further implicating this structure as the membrane penetration site. Consistent with this, a mutant SV40 that cannot penetrate the ER membrane and promote infection fails to induce C18 foci. C18 also regulates the recruitment of B12/B14 into the foci. In contrast to B14, C18's cytosolic Hsc70-binding J domain, but not the lumenal domain, is essential for its targeting to the foci; this J domain likewise is necessary to support SV40 infection. Knockdown-rescue experiments reveal that C18 executes a role that is not redundant with those of B12/B14 during SV40 infection. Collectively, our data illuminate C18's contribution to SV40 ER membrane penetration, strengthening the idea that SV40-triggered foci are critical for cytosol entry. IMPORTANCEPolyomaviruses (PyVs) cause devastating human diseases, particularly in immunocompromised patients. As this virus family continues to be a significant human pathogen, clarifying the molecular basis of their cellular entry pathway remains a high priority. To infect cells, PyV traffics from the cell surface to the ER, where it penetrates the ER membrane to reach the cytosol. In the cytosol, the virus moves to the nucleus to cause infection. ER-to-cytosol membrane penetration is a critical yet mysterious infection step. In this study, we clarify the role of an ER membrane protein called C18 in mobilizing the simian PyV SV40, a PyV archetype, from the ER into the cytosol. Our findings also support the hypothesis that SV40 induces the formation of punctate structures in the ER membrane, called foci, that serve as the portal for cytosol entry of the virus. While polyomaviruses (PyVs) are known to establish asymptomatic persistent infections in the kidney, blood, skin, and brain of healthy individuals, they carry the potential to cause debilitating diseases, especially during immunosuppression. For example, infections caused by the human BK, JC, and Merkel cell PyVs can lead to PyV-associated nephropathy, progressive multifocal leukoencephalopathy, and Merkel cell carcinoma, respectively (1, 2). Simian virus 40 (SV40) traditionally has been used as a model for studying this virus family and has structural and genetic similarities to human PyVs. SV40 and all other PyVs are nonenveloped icosahedral particles, approximately 45 nm in diameter, and contain a double-stranded DNA gen...

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“…HPyV seroprevalence data obtained using the major capsid protein Vp1 as pentamers or virus-like particles indicate that HPyVs infect 50% to 90% of the general human population without known specific signs or symptoms of disease (2)(3)(4)(5)(6)(7). As information about the virology and pathology of the 13 human PyVs is only emerging (8,9), we focused on BK polyomavirus (BKPyV) as a model (10).…”

mentioning

confidence: 99%

Imperfect Symmetry of Sp1 and Core Promoter Sequences Regulates Early and Late Virus Gene Expression of the Bidirectional BK Polyomavirus Noncoding Control Region

Bethge

Ajuh

Hirsch

2016

J Virol

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Rearrangements or point mutations in the noncoding control region (NCCR) of BK polyomavirus (BKPyV) have been associated with higher viral loads and more pronounced organ pathology in immunocompromised patients. The respective alterations affect a multitude of transcription factor binding sites (TFBS) but consistently cause increased expression of the early viral gene region (EVGR) at the expense of late viral gene region (LVGR) expression. By mutating TFBS, we identified three phenotypic groups leading to strong, intermediate, or impaired EVGR expression and corresponding BKPyV replication. Unexpectedly, Sp1 TFBS mutants either activated or inhibited EVGR expression when located proximal to the LVGR (sp1-4) or the EVGR (sp1-2), respectively. We now demonstrate that the bidirectional balance of EVGR and LVGR expression is dependent on affinity, strand orientation, and the number of Sp1 sites. Swapping the LVGR-proximal high-affinity SP1-4 with the EVGR-proximal low-affinity SP1-2 in site strand flipping or inserting an additional SP1-2 site caused a rearranged NCCR phenotype of increased EVGR expression and faster BKPyV replication. The 5= rapid amplification of cDNA ends revealed an imperfect symmetry between the EVGR-and LVGR-proximal parts of the NCCR, consisting of TATA and TATA-like elements, initiator elements, and downstream promoter elements. Mutation or deletion of the archetypal LVGR promoter, which is found in activated NCCR variants, abrogated LVGR expression, which could be restored by providing large T antigen (LTag) in trans. Thus, whereas Sp1 sites control the initial EVGR-LVGR expression balance, LTag expression can override inactivation of the LVGR promoter and acts as a key driver of LVGR expression independently of the Sp1 sites and core promoter elements. IMPORTANCEPolyomaviridae currently comprise more than 70 members, including 13 human polyomaviruses (PyVs), all of which share a bidirectional genome organization mediated by the NCCR, which determines species and host cell specificity, persistence, replication, and virulence. Here, we demonstrate that the BKPyV NCCR is fine-tuned by an imperfect symmetry of core promoter elements centered around TATA and TATA-like sequences close to the EVGR and LVGR, respectively, which are governed by the directionality and affinity of two Sp1 sites. The data indicated that the BKPyV NCCR is poised toward EVGR expression, which can be readily unlatched by a simple switch affecting Sp1 binding. The resulting LTag, which is the major EVGR protein, drives viral genome replication, renders subsequent LVGR expression independently of archetypal promoter elements, and can overcome enhancer/promoter mutations and deletions. The data are pivotal for understanding how human PyV NCCRs mediate secondary host cell specificity, reactivation, and virulence in their natural hosts. The Polyomaviridae comprise more than 70 polyomavirus (PyV) members, including at least 13 human PyV (HPyV) species (1). HPyV seroprevalence data obtained using the major capsid prote...

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A cornucopia of human polyomaviruses

Cited by 293 publications

References 161 publications

Prospective seroepidemiologic study on the role of Human Papillomavirus and other infections in cervical carcinogenesis: Evidence from the EPIC cohort

Prospective seroepidemiologic study on the role of Human Papillomavirus and other infections in cervical carcinogenesis: Evidence from the EPIC cohort

The Endoplasmic Reticulum Membrane J Protein C18 Executes a Distinct Role in Promoting Simian Virus 40 Membrane Penetration

Imperfect Symmetry of Sp1 and Core Promoter Sequences Regulates Early and Late Virus Gene Expression of the Bidirectional BK Polyomavirus Noncoding Control Region

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