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  • 1
    Keywords: CELLS ; EXPRESSION ; Germany ; CLONING ; GENE ; PROTEIN ; PROTEINS ; transcription ; RELEASE ; DNA ; FAMILY ; DOMAIN ; CARCINOGENESIS ; CONTRAST ; PARTICLES ; virus ; DEGRADATION ; REPLICATION ; ANTIVIRAL ACTIVITY ; CONSTRUCTION ; IMMUNODEFICIENCY-VIRUS ; RE ; spumaretrovirus ; zoonosis ; cytidine deamination ; HIV-1 VIF ; HYPERMUTATION ; restriction factor ; virion infectivity factor
    Abstract: Genome hypermutation of different orthoretroviruses by cellular cytidine deaminases of the APOBEC3 family during reverse transcription has recently been observed. Lentiviruses like HIV-1 have acquired proteins preventing genome editing in the newly infected cell. Here we show that feline foamy virus (FFV), a typical member of the foamy retrovirus subfamily Spumaretrovirinae, is also refractory to genome deamination. APOBEC3-like FFV genome editing in APOBEC3-positive feline CRFK cells only occurs when the accessory FFV Bet protein is functionally inactivated. Editing of bet-deficient FFV genomes is paralleled by a strong decrease in FFV titer. In contrast to lentiviruses, cytidine deamination already takes place in APOBEC3-positive FFV-producing cells, because edited proviral DNA genomes are consistently present in released particles. By cloning the feline APOBEC3 orthologue, we found that its homology to the second domain of human APOBEC3F is 48%. Expression of feline APOBEC3 in APOBEC3-negative human 293T cells reproduced the effects seen in homologous CRFK cells: Bet-deficient FFV displayed severely reduced titers, high-level genome editing, reduced particle release, and suppressed Gag processing. Although WT Bet efficiently preserved FFV infectivity and genome integrity, it sustained particle release and Gag processing only when fe3 was moderately expressed. Similar to lentiviral Vif proteins, FFV Bet specifically bound feline APOBEC3. In particles from Bet-deficient FFV, feline APOBEC3 was clearly present, whereas its foamy viral antagonist Bet was undetectable in purified WT particles. This is the first report that, in addition to lentiviruses, the foamy viruses also developed APOBEC3-counteracting proteins
    Type of Publication: Journal article published
    PubMed ID: 15911774
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  • 2
    Keywords: CELLS ; CELL ; Germany ; INHIBITION ; PROTEIN ; PROTEINS ; COMPLEX ; MECHANISM ; DOMAIN ; FORM ; PARTICLES ; DEGRADATION ; ANTIVIRAL ACTIVITY ; HIV-1 VIF ; LEUKEMIA-VIRUS ; VIF ; 2 DISTINCT ; ANTIRETROVIRAL DEFENSE ; CYTIDINE DEAMINASES ; EDITING ENZYME APOBEC3G ; MURINE APOBEC3 ; SOCS-BOX ; TYPE-1 VIF
    Abstract: The APOBEC3 cytidine deaminases are part of the intrinsic defense of cells against retroviruses. Lentiviruses and spumaviruses have evolved essential accessory proteins, Vif and Bet, respectively, which counteract the APOBEC3 proteins. We show here that Bet of the Prototype foamy virus inhibits the antiviral APOBEC3C activity by a mechanism distinct to Vif: Bet forms a complex with APOBEC3C without inducing its degradation. Bet abolished APOBEC3C dimerization as shown by co-immunoprecipitation and cross-linking experiments. These findings implicate a physical interaction between Bet and the APOBEC3C. Subsequently, we identified the Bet interaction domain in human APOBEC3C in the predicted APOBEC3C dimerization site. Taken together, these data support the hypothesis that Bet inhibits incorporation of APOBEC3Cs into retroviral particles. Bet likely achieves this by trapping APOBEC3C protein in complexes rendering them unavailable for newly generated viruses due to direct immobilization
    Type of Publication: Journal article published
    PubMed ID: 19074429
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  • 3
    Abstract: BACKGROUND: In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC). METHODS AND FINDINGS: We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for 〉/=15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7). CONCLUSIONS: Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.
    Type of Publication: Journal article published
    PubMed ID: 26808155
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  • 4
    Keywords: IN-VIVO ; GENE ; PROTEIN ; PROTEINS ; INFECTION ; MECHANISM ; ADAPTIVE EVOLUTION ; RESTRICTION ; AID/APOBEC FAMILY ; POLYNUCLEOTIDE (DEOXY)CYTIDINE DEAMINASES ; VIF
    Type of Publication: Journal article published
    PubMed ID: 18987154
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  • 5
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; CELL ; Germany ; SYSTEM ; PROTEIN ; PROTEINS ; CONTRAST ; TYPE-1 ; virus ; resistance ; HUMAN IMMUNODEFICIENCY VIRUS ; REPLICATION ; sensitivity ; HUMAN-IMMUNODEFICIENCY-VIRUS ; virion infectivity factor ; TRANSMISSION ; DEPLETION ; ENZYME APOBEC3G ; CYTIDINE DEAMINASES ; TYPE-1 VIF ; Type ; DOMESTIC CAT ; ANEMIA VIRUS ; ANTIRETROVIRAL ACTIVITY ; HIV-1 REVERSE TRANSCRIPTION ; PUMA-CONCOLOR
    Abstract: To get more insight into the role of APOBEC3 (A3) cytidine deaminases in the species-specific restriction of feline immunodeficiency virus (FIV) of the domestic cat, we tested the A3 proteins present in big cats (puma, lion, tiger, and lynx). These A3 proteins were analyzed for expression and sensitivity to the Vif protein of FIV. While A3Z3s and A3Z2-Z3s inhibited Delta vif FIV, felid A3Z2s did not show any antiviral activity against Delta vif FIV or wild-type (wt) FIV. All felid A3Z3s and A3Z2-Z3s were sensitive to Vif of the domestic cat FIV. Vif also induced depletion of felid A3Z2s. Tiger A3s showed a moderate degree of resistance against the Vif-mediated counter defense. These findings may imply that the A3 restriction system does not play a major role to prevent domestic cat FIV transmission to other Felidae. In contrast to the sensitive felid A3s, many nonfelid A3s actively restricted wt FIV replication. To test whether Vif(FIV) can protect also the distantly related human immunodeficiency virus type 1 (HIV-1), a chimeric HIV-1. Vif(FIV) was constructed. This HIV-1. VifFIV was replication competent in nonpermissive feline cells expressing human CD4/CCR5 that did not support the replication of wt HIV-1. We conclude that the replication of HIV-1 in some feline cells is inhibited only by feline A3 restriction factors and the absence of the appropriate receptor or coreceptor
    Type of Publication: Journal article published
    PubMed ID: 20444897
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  • 6
    Keywords: CANCER ; RISK ; RESPONSES ; antibodies ; NESTED CASE-CONTROL ; EARLY PROTEINS ; glutathione-S-transferase ; CELL-CARCINOMA ; human polyomaviruses ; CHLAMYDIA-TRACHOMATIS INFECTION
    Abstract: 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. What's New? Limited data are available from prospective studies concerning the role of past exposure to human papillomavirus (HPV) and other infections in cervical carcinogenesis. This study assessed associations between cervical cancer and pre-cancer and serological markers of exposure to mucosal and cutaneous HPVs, Chlamydia trachomatis (CT), Chlamydia pneumonia, human herpes virus-2 (HHV-2), and polyomaviruses using a nested case-control design within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Associations were found for mucosal HPVs, CT, and HHV-2. A greater number of sexually transmitted diseases further raised the risk of cervical cancer.
    Type of Publication: Journal article published
    PubMed ID: 24338606
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  • 7
    Abstract: BACKGROUND: Hosts are able to restrict viral replication to contain virus spread before adaptive immunity is fully initiated. Many viruses have acquired genes directly counteracting intrinsic restriction mechanisms. This phenomenon has led to a co-evolutionary signature for both the virus and host which often provides a barrier against interspecies transmission events. Through different mechanisms of action, but with similar consequences, spumaviral feline foamy virus (FFV) Bet and lentiviral feline immunodeficiency virus (FIV) Vif counteract feline APOBEC3 (feA3) restriction factors that lead to hypermutation and degradation of retroviral DNA genomes. Here we examine the capacity of vif to substitute for bet function in a chimeric FFV to assess the transferability of anti-feA3 factors to allow viral replication. RESULTS: We show that vif can replace bet to yield replication-competent chimeric foamy viruses. An in vitro selection screen revealed that an engineered Bet-Vif fusion protein yields suboptimal protection against feA3. After multiple passages through feA3-expressing cells, however, variants with optimized replication competence emerged. In these variants, Vif was expressed independently from an N-terminal Bet moiety and was stably maintained. Experimental infection of immunocompetent domestic cats with one of the functional chimeras resulted in seroconversion against the FFV backbone and the heterologous FIV Vif protein, but virus could not be detected unambiguously by PCR. Inoculation with chimeric virus followed by wild-type FFV revealed that repeated administration of FVs allowed superinfections with enhanced antiviral antibody production and detection of low level viral genomes, indicating that chimeric virus did not induce protective immunity against wild-type FFV. CONCLUSIONS: Unrelated viral antagonists of feA3 cellular restriction factors can be exchanged in FFV, resulting in replication competence in vitro that was attenuated in vivo. Bet therefore may have additional functions other than A3 antagonism that are essential for successful in vivo replication. Immune reactivity was mounted against the heterologous Vif protein. We conclude that Vif-expressing FV vaccine vectors may be an attractive tool to prevent or modulate lentivirus infections with the potential option to induce immunity against additional lentivirus antigens.
    Type of Publication: Journal article published
    PubMed ID: 29769087
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  • 8
    Keywords: carcinoma ; cohort study ; ASSOCIATION ; TRIAL ; PLASMA ; WOMEN ; cervical cancer ; intraepithelial neoplasia ; ABNORMALITIES ; NATURAL-HISTORY ; VITAMIN-C ; DYSPLASIA ; HUMAN-PAPILLOMAVIRUS INFECTION ; foods and nutrients intake ; NUTRIENT STATUS
    Abstract: Some dietary factors could be involved as cofactors in cervical carcinogenesis, but evidence is inconclusive. There are no data about the effect of fruits and vegetables intake (F&V) on cervical cancer from cohort studies. We examined the association between the intake of F&V and selected nutrients and the incidence of carcinoma in situ (CIS) and invasive squamous cervical cancer (ISC) in a prospective study of 299,649 women, participating in the European Prospective Investigation into Cancer and Nutrition study. Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CI). A calibration study was used to control measurement errors in the dietary questionnaire. After a mean of 9 years of follow-up, 253 ISC and 817 CIS cases were diagnosed. In the calibrated model, we observed a statistically significant inverse association of ISC with a daily increase in intake of 100 g of total fruits (HR 0.83; 95% CI 0.72-0.98) and a statistically nonsignificant inverse association with a daily increase in intake of 100 g of total vegetables (HR 0.85: 95% CI 0.65-1.10). Statistically nonsignificant inverse associations were also observed for leafy vegetables, root vegetables, garlic and onions, citrus fruits, vitamin C, vitamin E and retinol for ISC. No association was found regarding beta-carotene, vitamin D and folic acid for ISC. None of the dietary factors examined was associated with CIS. Our study suggests a possible protective role of fruit intake and other dietary factors on ISC that need to be confirmed on a larger number of ISC cases.
    Type of Publication: Journal article published
    PubMed ID: 20853322
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  • 9
    Keywords: CIGARETTE-SMOKING ; intraepithelial neoplasia ; TOBACCO SMOKING ; glutathione-S-transferase ; ORAL-CONTRACEPTIVE USE ; pooled analysis ; COLLABORATIVE REANALYSIS ; PASSIVE SMOKING ; INDIVIDUAL DATA ; ONCOGENIC HUMAN-PAPILLOMAVIRUS
    Abstract: A total of 308,036 women were selected from the European Prospective Investigation into Cancer and Nutrition (EPIC) study to evaluate the association between tobacco smoking and the risk of cervical intraepithelial neoplasia of grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC). At baseline, participants completed a questionnaire and provided blood samples. During a mean follow-up time of 9 years, 261 ICC cases and 804 CIN3/CIS cases were reported. In a nested case-control study, the baseline sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11, 16, 18, 31, 33, 35, 45, 52, 58, and antibodies against Chlamydia trachomatis (CT), and Human Herpes Virus 2 (HHV-2). Cervical samples were not available for HPV-DNA analysis in this study. Multivariate analyses were used to estimate associations between smoking and risk of CIN3/CIS and ICC in the cohort and the case-control studies. In the cohort analyses smoking status, duration and intensity showed a two-fold increased risk of CIN3/CIS and ICC, while time since quitting was associated with a two-fold reduced risk. In the nested case-control study, consistent associations were observed after adjustment for HPV, CT and HHV-2 serostatus, in both HPV seronegative and seropositive women. Results from this large prospective study confirm the role of tobacco smoking as an important risk factor for both CIN3/CIS and ICC, even after taking into account HPV exposure as determined by HPV serology. The strong beneficial effect of quitting smoking is an important finding that will further support public health policies for smoking cessation. What's new? Tobacco smoking is a cited cause of cervical cancer, but whether it causes cervical malignancy independent of human papillomavirus (HPV) infection is unclear. Here, strong associations were found between most measures of tobacco smoking and the risk of cervical intraepithelial neoplasia of grade 3/carcinoma in situ and invasive cervical cancer, after taking into account past exposure to HPV infection. Quitting smoking was associated with a 2-fold risk reduction. The findings confirm the role of tobacco smoking in cervical carci
    Type of Publication: Journal article published
    PubMed ID: 24338632
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