The serologic response against virus-like particles (VLP) from 7 high risk genital papillomaviruses was investigated by ELISA in 147 Colombian women with invasive cervical cancer and 147 age-matched cytologically normal and HPV-DNA negative women. Anti-VLP antibodies were detected in 82% of the invasive cervical cancer patients and in 56% of the controls. Detection of antibodies against multiple HPV types is the rule and the presence of high antibody titers was associated with higher survival of cancer patients. Higher anti-VLP seroprevalence was observed in younger cancer patients. In those followed serologically for 1 year, antibodies generally remained at the same level. However, in some patients an increase or decrease in antibody levels occurred simultaneously for multiple HPV types, suggesting cross-reactivity between the HPV types investigated. Investigation of seroreactivity between 8 high risk HPVs suggested that there is some cross-reactivity between phylogeneticaly-related types such as 16, 31, 33 and 58; and 18, 45 and 59. In conclusion, our results confirmed (i) the high rate of HPV infections in Colombia, both in patients with cervical cancer and in the general population, and the particularly high rate of infections due to HPV 31 and 58; and (ii) the validity of anti-VLPs as a marker of present or past HPV infection. The simultaneous appearance or disappearance of antibodies against multiple HPV VLPs suggests that the antibodies detected by ELISA are not always type specific. © 2002 Wiley-Liss, Inc. Key words: HPV; virus-like particles; cervical cancer; anti-VLP antibodiesCancer of the uterine cervix is one of the most common malignancies in women world wide. 1,2 and the contribution of high risk or oncogenic genital human papillomaviruses (HPVs) in the development of such cancers is well established. [3][4][5][6] Cohort studies indicate that HPV infection with oncogenic types is mostly transient and that only a small proportion of those infected become carriers and then develop cervical intraepithelial neoplasia. [7][8][9][10][11][12] Over 100 HPV genotypes have been identified, 6,13 of which approximately 40 types infect the anogenital tract. The etiologic role of papillomavirus in cervical cancer has been recognized for only a limited number of them, including in decreasing order. 14 The geographical distribution of oncogenic HPV types in cervical cancers shows that HPV-16 is the most common type in all regions, followed by HPV-18. However, there are some geographical differences. For example HPV-33, -39, -58 and -59 are more common in Latin America than in other regions. 4,12,15 Colombia has one of the highest incidences of cervical cancer in the world (48 cases/ 100,000 women/year 1 ) and the most common types detected in Colombia are HPV-16, followed by HPV 58. 16,17 Numerous serologic studies using mainly HPV-16 VLPs 18 -27 have demonstrated that infection with genital HPVs is followed by a serologic immune response to viral capsid proteins and that anti-VLP antibodies can be an indicat...
Human papillomavirus type 16 (HPV-16) represents the major cervical carcinoma associated virus among women, especially in Colombia. It has thus become important to develop reliable inexpensive tests for detecting the presence of this virus. It has been shown that HPV16-E7 oncoprotein structural features have three alpha-helical structures and a loop-like structure. The hydrazone link approach was used to mimic helix secondary substructures. Sera from women with invasive cervical carcinoma were tested against conformationally restricted peptides and their respective linear peptides to identify conformational epitopes. One peptide that was conformationally restricted to an alpha-helix showed very strong positive reaction with sera from women having invasive cervical carcinoma; there was no reaction with sera from patients with other carcinomas, children, or healthy women. NMR studies confirmed this peptide's alpha-helical structure. The observation that constrained protein substructure peptidomimetics can identify new conformationally sensitive antibodies in cervical carcinoma patients' sera is very important, since these antibodies are almost all generated by native proteins, providing a new selection of antibodies for diagnostic and vaccine studies.
Cervical cancer is the fifth most common type of cancer worldwide (around 500,000 new cases diagnosed each year) and the second major cause of cancer related to women's deaths. 1,2 It has been estimated that over 95% of cervical cancer is associated with HPV infection, 3 since many cervical carcinomas and pre-invasive lesions contain human papillomavirus DNA sequences. 4 Papillomaviruses are classified as being low-risk or high-risk, depending on their preferential association with benign or malignant lesions. HPV-16 DNA is found in about 50 -60% of human anogenital carcinomas, HPV 18 in about 20% and other HPV genotypes in a further 15%. There are as yet undefined papillomavirus sequences in about 15% of anogenital carcinomas. 5,6 Papillomaviruses (PVs) are nonenveloped particles, characterized by having an icosahedral capsid of about 55 nm diameter. The capsids are composed of 2 virally encoded proteins (the L1 major and the L2 minor capsid proteins) that migrate on SDS-PAGE at about 55 and 75 kDa, respectively. The papillomavirus L1 major capsid protein (L1) is the most abundant virus-encoded protein, being highly conserved amongst different HPV types, having amino-acid homology as high as 80%. L1 presents the ability to self-assemble in virus-like particles (VLPs). 7,8 Different PVs seem to use the same receptor to enter their host cells. 7,9,10 Trypsin treatment of cells markedly reduced their ability to bind to VLPs, suggesting that a surface cell protein was involved in VLP binding. 11,12 Red blood cell invasion by Plasmodium falciparum merozoites, 13-15 reticulocytes by Plasmodium vivax merozoites 14 and hepatic cells by Hepatitis C virus 16 has shown that specific receptorligand interactions mediate microbe binding to host cells. Using a similar methodology, synthetic 125 I-radio-labeled peptides were thus used in receptor-ligand type binding assays to better pin/point VERO and HeLa cell binding activity from high-risk 16 and 18 type L1 amino acid sequences. VERO and HeLa cell high activity binding peptides (HABPs) showed saturable binding, cell receptors being sensitive to enzyme treatment and the majority of bound peptide being surface-exposed. HABPs specifically bound to 69 and 54 kDa HeLa cell surface membrane protein and inhibited HPV-16 VLP binding to both cells. Furthermore, several HABP residues formed part of the VLP surface, becoming the target for neutralizing antibodies. METHODS Peptide synthesisTwenty-seven sequential 20-mer peptides, corresponding to HPV type 16 L1, 17 and 29 sequential 20-mer peptides, corresponding to HPV 18 L1, 18 were synthesized by solid-phase multiple peptide system. 19,20 MBHA resin (0.7 meq/g), t-Boc amino-acid and low-high cleavage techniques were used. 21 Peptides were analyzed by MALDI-TOF mass spectrometry and reverse phasehigh performance liquid chromatography (RP-HPLC). These synthesized peptides are shown in 1-letter code in Figures 1a,b. An extra Tyr residue was added to a peptide's C-terminus for radiolabeling purposes when such peptide did not contain Tyr...
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