scholarly journals Human papillomavirus 16 L2 inhibits the transcriptional activation function, but not the DNA replication function, of HPV-16 E2

2005 ◽  
Vol 108 (1-2) ◽  
pp. 1-14 ◽  
Author(s):  
A. Okoye ◽  
P. Cordano ◽  
E.R. Taylor ◽  
I.M. Morgan ◽  
R. Everett ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Dna Replication ◽  
Transcriptional Activation ◽  
Activation Function ◽  
Hpv 16 ◽  
Human Papillomavirus 16 ◽  
Replication Function

scholarly journals A Fifteen-Amino-Acid Peptide Inhibits Human Papillomavirus E1-E2 Interaction and Human Papillomavirus DNA Replication In Vitro

1998 ◽  
Vol 72 (10) ◽  
pp. 8166-8173 ◽  
Author(s):  
Hiroaki Kasukawa ◽  
Peter M. Howley ◽  
John D. Benson
Keyword(s):  
Human Papillomavirus ◽  
Amino Acid ◽  
Dna Replication ◽  
Transcriptional Activation ◽  
Hpv 16 ◽  
Hpv Dna ◽  
Amino Acid Peptide ◽  
In Vitro Replication ◽  
Papillomavirus Dna

ABSTRACT Mutation of the conserved glutamic acid residue at position 39 of human papillomavirus type 16 (HPV-16) E2 to alanine (E39A) disrupts its E1 interaction activity and its replication function in transient replication assays but does not affect E2 transcriptional activation. This E39A mutation also disrupts replication activity of HPV-16 E2 in HPV-16 in vitro DNA replication. On this basis, we designed 23- and 15-amino-acid peptides derived from HPV-16 E2 sequences flanking the E39 residue and tested the ability of these peptides to inhibit interaction between HPV-16 E1 and E2 in vitro. The inhibitory activity of these peptides was specific, since analogous peptides in which alanine was substituted for the E39 residue did not inhibit interaction. The 15-amino-acid peptide E2N-WP15 was the smallest peptide tested that effectively inhibited HPV-16 E1-E2 interaction. This peptide also inhibited in vitro replication of HPV-16 DNA. The efficacy of E2N-WP15 was not exclusive to HPV-16: this peptide also inhibited interaction of HPV-11 E1 with the E2 proteins of both HPV-11 and HPV-16 and inhibited in vitro replication with these same combinations of E1 and E2 proteins. These results provide further evidence that E1-E2 interaction is required for papillomavirus DNA replication and constitute the first demonstration that inhibition of this interaction is sufficient to prevent HPV DNA replication in vitro.

scholarly journals DNA Damage Reduces the Quality, but Not the Quantity of Human Papillomavirus 16 E1 and E2 DNA Replication

Viruses ◽  
2016 ◽  
Vol 8 (6) ◽  
pp. 175 ◽  
Author(s):  
Molly Bristol ◽  
Xu Wang ◽  
Nathan Smith ◽  
Minkyeong Son ◽  
Michael Evans ◽  
...  
Keyword(s):  
Dna Damage ◽  
Human Papillomavirus ◽  
Dna Replication ◽  
Human Papillomavirus 16

scholarly journals Transcriptional Activation of the Telomerase hTERT Gene by Human Papillomavirus Type 16 E6 Oncoprotein

2001 ◽  
Vol 75 (9) ◽  
pp. 4467-4472 ◽  
Author(s):  
Tim Veldman ◽  
Izumi Horikawa ◽  
J. Carl Barrett ◽  
Richard Schlegel
Keyword(s):  
Human Papillomavirus ◽  
Transcriptional Activation ◽  
Transcriptional Control ◽  
Regulatory Region ◽  
Rnase Protection ◽  
Hpv 16 ◽  
Htert Gene ◽  
Human Papillomavirus Type 16 ◽  
E6 Gene

ABSTRACT The E6 and E7 oncogenes of human papillomavirus type 16 (HPV-16) are sufficient for the immortalization of human genital keratinocytes in vitro. The products of these viral genes associate with p53 and pRb tumor suppressor proteins, respectively, and interfere with their normal growth-regulatory functions. The HPV-16 E6 protein has also been shown to increase the telomerase enzyme activity in primary epithelial cells by an unknown mechanism. We report here that a study using reverse transcription-PCR and RNase protection assays in transduced primary human foreskin keratinocytes (HFKs) shows that the E6 gene (but not the E7 gene) increases telomerase hTERT gene transcription coordinately with E6-induced telomerase activity. In these same cells, the E6 gene induces a 6.5-fold increase in the activity of a 1,165-bp 5′ promoter/regulatory region of the hTERT gene, and this induction is attributable to a minimal 251-bp sequence (−211 to +40). Furthermore, there is a 35-bp region (+5 to +40) within this minimal E6-responsive promoter that is responsible for 60% of E6 activity. Although the minimal hTERT promoter contains Myc-responsive E-box elements and recent studies have suggested a role for Myc protein in hTERT transcriptional control, we found no alterations in the abundance of either c-Myc or c-Mad in E6-transduced HFKs, suggesting that there are other or additional transcription factors critical for regulating hTERT expression.

scholarly journals Identification of Peptides That Inhibit the DNA Binding, trans-Activator, and DNA Replication Functions of the Human Papillomavirus Type 11 E2 Protein

2004 ◽  
Vol 78 (5) ◽  
pp. 2637-2641 ◽  
Author(s):  
Su-Jun Deng ◽  
Kenneth H. Pearce ◽  
Eric P. Dixon ◽  
Kelly A. Hartley ◽  
Thomas B. Stanley ◽  
...  
Keyword(s):  
Cell Culture ◽  
Human Papillomavirus ◽  
Dna Replication ◽  
Transcriptional Activation ◽  
Synthetic Peptides ◽  
Dna Interaction ◽  
Peptide Library ◽  
Random Peptide Library ◽  
Random Peptide

ABSTRACT Peptide antagonists of the human papillomavirus type 11 (HPV-11) E2-DNA association were identified using a filamentous bacteriophage random peptide library. Synthetic peptides antagonized the E2-DNA interaction, effectively blocked E2-mediated transcriptional activation of a reporter gene in cell culture, and inhibited E1-E2-mediated HPV-11 DNA replication in vitro. These peptides may prove to be useful tools for characterizing E2 function and for exploring the effectiveness of E2-inhibitor-based treatments for HPV-associated diseases.

scholarly journals Acquisition and Persistence of Human Papillomavirus 16 (HPV-16) and HPV-18 Among Men With High-HPV Viral Load Infections in a Circumcision Trial in Kisumu, Kenya

2014 ◽  
Vol 211 (5) ◽  
pp. 811-820 ◽  
Author(s):  
Virginia Senkomago ◽  
Danielle M. Backes ◽  
Michael G. Hudgens ◽  
Charles Poole ◽  
Kawango Agot ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Viral Load ◽  
Hpv 16 ◽  
Human Papillomavirus 16 ◽  
Hpv Viral Load ◽  
Hpv 18

scholarly journals Evidence Supporting a Role for TopBP1 and Brd4 in the Initiation but Not Continuation of Human Papillomavirus 16 E1/E2-Mediated DNA Replication

2015 ◽  
Vol 89 (9) ◽  
pp. 4980-4991 ◽  
Author(s):  
Elaine J. Gauson ◽  
Mary M. Donaldson ◽  
Edward S. Dornan ◽  
Xu Wang ◽  
Molly Bristol ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Dna Replication ◽  
Viral Proteins ◽  
Future Generations ◽  
Cellular Proteins ◽  
Origin Of Replication ◽  
Viral Dna ◽  
Viral Origin ◽  
Viral Dna Replication ◽  
Human Papillomavirus 16

ABSTRACTTo replicate the double-stranded human papillomavirus 16 (HPV16) DNA genome, viral proteins E1 and E2 associate with the viral origin of replication, and E2 can also regulate transcription from adjacent promoters. E2 interacts with host proteins in order to regulate both transcription and replication; TopBP1 and Brd4 are cellular proteins that interact with HPV16 E2. Previous work with E2 mutants demonstrated the Brd4 requirement for the transactivation properties of E2, while TopBP1 is required for DNA replication induced by E2 from the viral origin of replication in association with E1. More-recent studies have also implicated Brd4 in the regulation of DNA replication by E2 and E1. Here, we demonstrate that both TopBP1 and Brd4 are present at the viral origin of replication and that interaction with E2 is required for optimal initiation of DNA replication. Both cellular proteins are present in E1-E2-containing nuclear foci, and the viral origin of replication is required for the efficient formation of these foci. Short hairpin RNA (shRNA) against either TopBP1 or Brd4 destroys the E1-E2 nuclear bodies but has no effect on E1-E2-mediated levels of DNA replication. An E2 mutation in the context of the complete HPV16 genome that compromises Brd4 interaction fails to efficiently establish episomes in primary human keratinocytes. Overall, the results suggest that interactions between TopBP1 and E2 and between Brd4 and E2 are required to correctly initiate DNA replication but are not required for continuing DNA replication, which may be mediated by alternative processes such as rolling circle amplification and/or homologous recombination.IMPORTANCEHuman papillomavirus 16 (HPV16) is causative in many human cancers, including cervical and head and neck cancers, and is responsible for the annual deaths of hundreds of thousands of people worldwide. The current vaccine will save lives in future generations, but antivirals targeting HPV16 are required for the alleviation of disease burden on the current, and future, generations. Targeting viral DNA replication that is mediated by two viral proteins, E1 and E2, in association with cellular proteins such as TopBP1 and Brd4 would have therapeutic benefits. This report suggests a role for these cellular proteins in the initiation of viral DNA replication by HPV16 E1-E2 but not for continuing replication. This is important if viral replication is to be effectively targeted; we need to understand the viral and cellular proteins required at each phase of viral DNA replication so that it can be effectively disrupted.

scholarly journals Efficacy of Human Papillomavirus 16 and 18 (HPV-16/18) AS04-Adjuvanted Vaccine against Cervical Infection and Precancer in Young Women: Final Event-Driven Analysis of the Randomized, Double-Blind PATRICIA Trial

2015 ◽  
Vol 22 (4) ◽  
pp. 361-373 ◽  
Author(s):  
Dan Apter ◽  
Cosette M. Wheeler ◽  
Jorma Paavonen ◽  
Xavier Castellsagué ◽  
Suzanne M. Garland ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Young Women ◽  
Sexual Debut ◽  
Vaccine Dose ◽  
Hpv 16 ◽  
Substantial Impact ◽  
Hpv Dna ◽  
Human Papillomavirus 16 ◽  
Adjuvanted Vaccine ◽  
Event Driven

ABSTRACTWe report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine,n= 9,319; control,n= 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine,n= 5,822; control,n= 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (−1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered atClinicalTrials.govunder registration no. NCT001226810.)

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