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Biomedical subjects

A B Jenson

Publications and source records attributed to A B Jenson.

At least 19 recordsLinked to original sources
PubMed1998

Prevalence of antibodies against virus-like particles of Epidermodysplasia verruciformis-associated HPV8 in patients at risk of skin cancer.

There is increasing evidence for widespread occurrences of infection with Epidermodysplasia verruciformis-related human papillomaviruses, both in the general population and in immunosuppressed patients. In order to test for the prevalence of antibodies directed against the native L1 epitopes exposed on the surface of the virions, we have established an IgG-specific enzyme-linked immunosorbent assay with L1 virus-like particles of the Epidermodysplasia verruciformis-specific human papillomavirus 8 as antigen to screen 567 representative serum samples from the general population and immunosuppressed/dermatologic patients. Among healthy European donors (n = 210), 7.6% were found to be seropositive. In a group of renal transplant recipients (n = 185) the antibody prevalence was elevated to 21.1%, irrespective of the presence or absence of skin cancer. High positivity rates could be detected among (i) immunocompetent patients with nonmelanoma skin tumors (45.6%, n = 79) and (ii) Psoralene/UVA treated psoriasis patients (42.9%, n = 42). In contrast, anti-human papillomavirus 8-virus-like particle antibodies were found in only 6.8% of Hodgkin lymphoma patients (n = 44).

Antibodies, Viral↗
PubMed1998

Prospects for human papillomavirus vaccine development: emerging HPV vaccines.

This review concentrates on recent advances in human papillomavirus vaccine development. Strategies for prophylactic HPV subunit vaccines utilizing recombinantly synthesized, immunogenic virus-like particles are discussed. Therapeutic strategies focusing on the induction of cell-mediated immunity and gene manipulation for the treatment of established HPV-associated disease are also reviewed.

Drug Evaluation↗
PubMed1998

Mutant canine oral papillomavirus L1 capsid proteins which form virus-like particles but lack native conformational epitopes.

Recently, the L1 capsid protein of canine oral papillomavirus (COPV) has been used as an effective systemic vaccine that prevents viral infections of the oral mucosa. The efficacy of this vaccine is critically dependent upon native L1 conformation and, when purified from Sf9 insect cells, the L1 protein not only displays type-specific, conformation-dependent epitopes but it also assembles spontaneously into virus-like particles (VLPs). To determine whether VLP formation was coupled to the expression of conformation-dependent epitopes, we generated a series of N- and C-terminal L1 deletion mutants and evaluated their ability to form VLPs (by electron microscopy) and to react with conformation-dependent antibodies (by immunofluorescence microscopy). We found that (a) deletion of the 26 C-terminal residues generated a mutant protein which formed VLPs efficiently and folded correctly both in the cytoplasm and in the nucleus; (b) further truncation of the L1 C terminus (67 amino acids) resulted in a capsid protein which formed VLPs but which failed to express conformational epitopes; (c) deletion of the first 25 N-terminal amino acids also abolished expression of conformational epitopes (without altering VLP formation) but the native conformation of this deletion mutant could be restored by the addition of the human papillomavirus type 11 N terminus. These results demonstrate that VLP formation and conformational epitope expression can be dissociated and that the L1 N terminus has a critical role in protein folding. In addition, it appears that correct L1 protein folding is not dependent upon the nucleoplasmic environment.

Amino Acid Sequence↗
PubMed1997

Multiplicity of uses of monoclonal antibodies that define papillomavirus linear immunodominant epitopes.

During the last 10 yr, we have derived monoclonal antibodies from animals immunized with denatured bovine papillomaviruses type 1 major capsid (L1) protein, mapped their corresponding immunodominant epitopes to within a single amino acid (aa), and compared the reactivity of authentic L1 proteins to the predicted response by collinear analysis of the aa sequences of the same and other papillomaviruses (PVs). The data obtained from this approach has provided us with new insights into the sensitivity and specificity of the antibody response to viral proteins. We have included here some observations and conclusions that appear to be generic for the immune response, some of which might have applications for working with linear epitopes in other experimental systems.

Amino Acid Sequence↗
PubMed1997

Development and progression of psoriasiform dermatitis and systemic lesions in the flaky skin (fsn) mouse mutant.

Flaky skin (fsn) mutant mice were originally described as a mouse model for psoriasis accompanied by hematological abnormalities. However, homozygous (fsn/fsn) mice develop a number of other pathological changes. Systematic evaluation of over 300 fsn/fsn and normal littermate control (+/+ or +/fsn) mice was carried out to characterize these changes. Psoriasiform skin lesions were first evident as focal epidermal hyperplasia and inflammation at 2 weeks of age. These lesions became confluent and diffuse by 3-4 weeks of age and were associated with marked dermal infiltration of lymphocytes and small numbers of neutrophils and macrophages. Mast cell numbers increased significantly in the dermis from 2 weeks of age onward. Diffuse dermal neovascularization accompanied these cutaneous changes. Systemic lesions included progressive and massive papillomatosis of the stratified squamous epithelium of the forestomach, hyperplasia and dysplasia of the glandular stomach, increased apoptosis of cecal enterocytes, renal glomerulopathy associated with immune complex and complement deposition, testicular degeneration, mixed inflammatory cell infiltrates and fibrosis around portal triads in the liver, splenomegaly due to massive erythropoiesis, and granulomatous lymphadenitis. This spontaneous mouse mutation provides a useful model for modulating neovascularization and keratinocyte hyperproliferation, especially since the cutaneous changes resemble some forms of psoriasis in humans.

Aging↗
PubMed1996

Tissue effects and host response. The key to the rational triage of cervical neoplasia.

Genital HPV infections are associated with a spectrum of lesions ranging from benign condylomata to invasive cancer and its precursor lesions. The transformation zone of the cervix is the most frequent target of the high-risk HPV types. Depending on the nomenclature used, cancer precursors are subdivided on the basis of their morphologic presentation into dysplasias (mild, moderate, and severe); cervical intraepithelial neoplasias (CIN I, II, and III); or low-grade and high-grade squamous intraepithelial lesions (LGSILs and HGSILs). The HGSILs (i.e., moderate and severe dysplasias, CIN II and III lesions) are recognized universally as cancer precursors. The LGSILs (i.e., very mild dysplasia and mild dysplasias, condylomata and CIN I lesions), have shown that one of the most important denominators of their cancer potential is the presence of intermediate and particularly high-risk HPV types. HPV typing provides the most rational basis for selecting women with LGSILs to be colposcoped and treated or given follow-up treatment with Pap smears. Until the clinical significance of HPV typing is known, management decisions may be based on an individual's risk factors such as age, compliance, past history of abnormal Pap smears, sexual habits, and access to adequate cytologic diagnosis.

Colposcopy↗
PubMed1996

Antigenicity of bovine papillomavirus type 1 (BPV-1) L1 virus-like particles compared with that of intact BPV-1 virions.

Virus-like-particles (VLPs) of various papillomavirus (PV) types have been produced by expressing recombinant L1 proteins in eukaryotic cells. Although VLPs have the same ultrastructural appearance as native virions and their immunogenicity appears to be similar, their antigenicity has not been carefully evaluated. For this reason, the antigenicity of intact bovine PV type 1 (BPV-1) virions was compared with that of BPV-1 recombinant L1 VLPs by ELISA using a well-characterized panel of polyclonal and monoclonal antibodies generated against intact and denatured BPV-1 particles. The structural integrity of the authentic virions and recombinant VLPs was verified by electron microscopy. The specificity of antibodies raised against intact BPV-1 virions and their reactivity with VLPs revealed that the immunodominant, type-specific, conformational epitopes of intact virions were reproduced on VLPs. However, many monoclonal antibodies that define cross-reactive, non-conformational (linear) epitopes cryptic to the authentic BPV-1 virion tested positively when reacted with intact VLPs. One monoclonal antibody, which recognizes a BPV-1 and deer PV surface conformational epitope, did not react with VLPs. Therefore, although VLPs can be used to immunize animals against infection, the external exposure of broadly cross-reactive epitopes of intact L1 VLPs suggests that the use of L1 VLPs in antigenicity studies such as serological screening should be done with caution.

Animals↗
PubMed1995

Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas.

Infection of mucosal epithelium by papillomaviruses is responsible for the induction of genital and oral warts and plays a critical role in the development of human cervical and oropharyngeal cancer. We have employed a canine model to develop a systemic vaccine that completely protects against experimentally induced oral mucosal papillomas. The major capsid protein, L1, of canine oral papillomavirus (COPV) was expressed in Sf9 insect cells in native conformation. L1 protein, which self-assembled into virus-like particles, was purified on CsCl gradients and injected intradermally into the foot pad of beagles. Vaccinated animals developed circulating antibodies against COPV and became completely resistant to experimental challenge with COPV. Successful immunization was strictly dependent upon native L1 protein conformation and L1 type. Partial protection was achieved with as little as 0.125 ng of L1 protein, and adjuvants appeared useful for prolonging the host immune response. Serum immunoglobulins passively transferred from COPV L1-immunized beagles to naive beagles conferred protection from experimental infection with COPV. Our results indicate the feasibility of developing a human vaccine to prevent mucosal papillomas, which can progress to malignancy.

Animals↗
PubMed1995

Prospects for a vaccine against human papillomavirus.

OBJECTIVE: To summarize existing data regarding the feasibility of developing strategies for prophylactic and therapeutic vaccination against human papillomavirus (HPV) infection. DATA SOURCES: We used the Medline data base and reference lists of articles to identify English-language papers that evaluate strategies for prophylactic and therapeutic vaccination against HPV infection. METHODS OF STUDY SELECTION: Our search uncovered several reports of systems that produce recombinant HPV major capsid proteins as antigens for biochemical, molecular, and immunologic studies and investigations that evaluate cell-mediated immune responses to HPV-induced, tumor-associated peptides. DATA EXTRACTION AND SYNTHESIS: Recombinant HPV major capsid proteins, which self-assemble into virus-like particles, are produced in quantity, mimic the conformation of native virions, react with neutralizing antibodies, and are type-specific. Human papillomavirus early viral peptides induce cytotoxic T lymphocyte responses that retard tumor progression and protect against tumor development after challenge in animal models. CONCLUSIONS: Recombinant papillomavirus virus-like particles are highly antigenic, protective in animal models, lack potentially carcinogenic viral DNA, and are, therefore, ideal candidates for a prophylactic vaccine against HPV infection. Immunization with HPV tumor peptides may be beneficial in tumor prevention, regression, and rejection. Vaccines against HPV infection can be important in reducing the incidence of cervical dysplasia and carcinoma worldwide, particularly in developing countries.

Animals↗
PubMed1995

Papillomavirus capsid binding and uptake by cells from different tissues and species.

The inability of papillomaviruses (PV) to replicate in tissue culture cells has hampered the study of the PV life cycle. We investigated virus-cell interactions by the following two methods: (i) using purified bovine PV virions or human PV type 11 (HPV type 11) virus-like particles (VLP) to test the binding to eukaryotic cells and (ii) using different VLP-reporter plasmid complexes of HPV6b, HPV11 L1 or HPV11 L1/L2, and HPV16 L1 or HPV16 L1/L2 to study uptake of particles into different cell lines. Our studies showed that PV capsids bind to a broad range of cells in culture in a dose-dependent manner. Binding of PV capsids to cells can be blocked by pretreating the cells with the protease trypsin. Penetration of PV into cells was monitored by using complexes in which the purified PV capsids were physically linked to DNA containing the gene for beta-galactosidase driven by the human cytomegalovirus promoter. Expression of beta-galactosidase occurred in < 1% of the cells, and the efficiency of PV receptor-mediated gene delivery was greatly enhanced (up to 10 to 20% positive cells) by the use of a replication-defective adenovirus which promotes endosomal lysis. The data generated by this approach further confirmed the results obtained from the binding assays, showing that PV enter a wide range of cells and that these cells have all functions required for the uptake of PV. Binding and uptake of PV particles can be blocked by PV-specific antisera, and different PV particles compete for particle uptake. Our results suggest that the PV receptor is a conserved cell surface molecule(s) used by different PV and that the tropism of infection by different PV is controlled by events downstream of the initial binding and uptake.

Animals↗
PubMed1995

Human papillomaviruses: their clinical significance in the management of cervical carcinoma.

Studies have shown a strong association between certain human papillomaviruses and the development of cervical carcinoma and its precursor lesions. The oncogenic potential of papillomaviruses has been clearly demonstrated in both laboratory animals and cultured cells. Recent advances in our understanding of viral pathogenesis have provided insights into the natural history of papillomavirus infection and subsequent development of neoplasia. A more thorough understanding of the molecular mechanisms responsible for viral oncogenesis will facilitate the development of novel preventive and therapeutic strategies to prevent and treat papillomavirus-associated cervical neoplasias. Strategies under current investigation are focusing on the induction of effective humoral and cell-mediated immunity, the expression of HPV gene products, and cofactors that interact with HPV gene products to affect cell transformation. As a result of these investigative efforts, prophylactic HPV capsid vaccines and other gene therapies may soon become clinically available.

Cell Transformation, Neoplastic↗
PubMed1994

Human papillomavirus types 6 and 11 have antigenically distinct strongly immunogenic conformationally dependent neutralizing epitopes.

Antibodies reactive to HPV types 6 and 11 were tested in ELISA and HPV-11 neutralization assays to determine whether these closely related types shared cross-reactive neutralizing epitopes. A series of HPV-11 neutralizing monoclonal antibodies (N-MAbs) that targeted conformational epitopes on infectious HPV-11 and HPV-11 L1 virus-like particles (VLPs) were tested for type-specificity of reactivity using intact HPV-6 L1 VLPs. Polyclonal antisera generated against intact HPV-6 L1 VLPs were also tested for HPV-11 neutralizing capacity using the athymic mouse xenograft system. The results demonstrated that conformationally dependent neutralizing epitopes on HPV-11 were very type-specific. Three of the four HPV-11 N-MAbs were negative for binding to HPV-6 L1 VLP, and the fourth demonstrated binding to HPV-6 L1 VLPs that was several orders of magnitude weaker than its binding to HPV-11 L1 VLP. The polyclonal anti-HPV-6 L1 VLP antiserum was only partially protective against HPV-11 infectivity even at a low dilution of 1:100. In contrast, polyclonal anti-HPV-11 L1 VLP antiserum was completely protective at dilutions greater than 1:10,000.

Animals↗
PubMed1994

Role of conformational epitopes expressed by human papillomavirus major capsid proteins in the serologic detection of infection and prophylactic vaccination.

Human papillomaviruses (HPVs) cause a variety of cutaneous warts, mucosal condylomata, and dysplasias and are etiologic in cervical cancer. Papillomavirus (PV) conformational epitopes on the surface of virions are type-specific and are the target of neutralizing antibodies. In this study, we describe two methods of in vitro expression of HPV major capsid (L1) proteins which mimicked conformational epitopes and demonstrate their type specificity and ability to react with neutralizing and/or conformation-dependent antibodies. The L1 open reading frames (ORFs) for HPV-1, 6, 11, and 16 were molecularly cloned into a SV 40 expression vector and the encoded gene products were expressed in mammalian (cos) cells. Similarly, the L1 ORFs for HPV-6, 11, 16, and 18 were molecularly cloned into recombinant baculovirus and the encoded gene products were expressed in insect (SF9) cells. The expressed L1 proteins reacted by immunofluorescence and immunoprecipitation with polyclonal and monoclonal antibodies generated against their corresponding native virions and by Western blotting with antibodies that recognized nonconformational epitopes of denatured virions. The recombinant L1 proteins expressed conformational epitopes in both cos and Sf9 cells that were type-specific and displayed neutralizing epitopes. The ability to express, purify, and qualitate the reactivity of recombinant L1 proteins will now permit the serologic analysis of host response to HPV infection and the development of prophylactic PV subunit vaccines.

Animals↗
PubMed1994

Canine oral papillomavirus genomic sequence: a unique 1.5-kb intervening sequence between the E2 and L2 open reading frames.

The canine oral papillomavirus (COPV) is associated with oropharyngeal papillomatosis in dogs, coyotes, and wolves. We have determined the complete nucleotide sequence of COPV, the largest of all known PV genomes (8607 bp). The genomic architecture of the COPV genome is similar to that of other PVs except for a unique and large noncoding region of 1.5 kb between the end of the early region (E2) and the beginning of the late region (L2) and a small (345 bp) upstream regulatory region between the end of L1 and the beginning of E6. Although COPV displays a primarily mucosal tropism, the COPV nucleotide sequence showed the highest overall similarity to cutaneous papillomaviruses such as HPV-1, HPV-63, CRPV (cottontail rabbit PV), FdPV (Felis domesticus PV), and MnPV (Mastomys natalensis PV).

Amino Acid Sequence↗
PubMed1994

Interaction of papillomaviruses with the cell surface.

To initiate an investigation of the initial step in papillomavirus infection, we have examined the interaction of bovine papillomavirus type 1 (BPV) virions with C127 cells by two assays, binding of radioiodinated BPV virions to cell monolayers and BPV-induced focal transformation. Under physiological conditions, the labeled virions bound to the cell surface in a dose-dependent manner within 1 h. Antibody studies indicated that the interaction was specific and related to infectivity: polyclonal sera raised to BPV virions or to baculovirus-expressed BPV L1 virus-like particles (VLPs) inhibited BPV binding and focal transformation, while sera to denatured BPV virions, to denatured BPV L1, or to human papillomavirus type 16 (HPV-16) VLPs were not inhibitory. An exception was that antisera to BPV L2 were neutralizing but did not inhibit binding. Unlabeled BPV virions and BPV VLPs competed with binding to the cell surface in a concentration-dependent manner. Binding to the cell surface appeared to depend primarily on L1, since BPV VLPs composed of L1 alone or of L1/L2 were equally effective in inhibiting binding and focal transformation. VLPs of HPV-16 also inhibited BPV binding and BPV transformation of C127 cells, suggesting that they interact with the same cell surface molecule(s) as BPV virions. Radiolabeled BPV bound specifically to several mammalian cell lines of fibroblastic and epithelial origin, as well as to a human schwannoma and melanoma lines, although some lines bound up to 10 times as many counts as others. Radiolabeled HPV-16 VLPs bound to both human keratinocytes and mouse C127 cells. The results suggest that papillomaviruses bind a widely expressed and evolutionarily conserved cell surface receptor.

Animals↗
PubMed1994

The expressed L1 proteins of HPV-1, HPV-6, and HPV-11 display type-specific epitopes with native conformation and reactivity with neutralizing and nonneutralizing antibodies.

Previous studies demonstrated that the human papillomavirus (HPV) type 1 L1 protein, expressed in cos cells by an SV40-based vector, displays conformational epitopes characteristic of native virions. In this study, we analyzed the expression of HPV-1, HPV-6, and HPV-11 L1 proteins in order to determine the forms of conformational epitopes expressed by recombinant L1 proteins. Using both immunofluorescence and immunoprecipitation techniques, polyclonal and monoclonal antibodies (MAbs) generated against native HPV-11 virions reacted with expressed L1 proteins of HPV-6 and/or HPV-11, but not HPV-1. Similarly, polyclonal antibodies and MAbs generated against HPV-1 virions reacted with the expressed L1 protein of HPV-1, but not HPV-6 or HPV-11. Of two MAbs that neutralized HPV-11 infection of murine fetal foreskin xenografts, one reacted with the expressed L1 protein of both HPV-6 and HPV-11, and the other reacted with HPV-11 only. A nonneutralizing conformationally dependent MAb reacted with the expressed L1 protein of both HPV-6 and HPV-11. These results demonstrate that expressed HPV L1 proteins retain type-specific, neutralizing, and nonneutralizing conformational epitopes and that cos cells may be utilized to evaluate host immune responses to such epitopes.

Animals↗