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Infection with human papillomavirus (HPV) is almost universal and eventually asymptomatic, but pathologic infection with HPV is severe, recurrent, and recalcitrant to therapy. It is also an underappreciated manifestation of primary immunodeficiency. Mutations in EVER1, EVER2, GATA2, CXCR4, and dedicator of cytokinesis 8 (DOCK8) are typically associated with extensive HPV infections, whereas several other primary immune defects result in severe HPV much less frequently. We review immunodeficiencies with severe HPV infections and the mechanisms underlying them., (Published by Mosby, Inc.)

This study was performed to test the therapeutic efficacy of overlapping long E6 and E7 peptides, containing both CD4+ T-helper and CD8+ CTL epitopes, on CRPV-induced lesions, which is an appropriate pre-clinical model for HPV diseases, including recurrent respiratory papillomatosis (RRP). Therapeutic peptide vaccination was able to significantly control wart growth (p < 0.01) and abrogate latent CRPV infection (p = 0.0006) compared to controls. Vaccination was associated with a T(H)1 T cell response, as suggested by a strong DTH skin test, antigen-specific proliferation of PBMC and a minimal IgG antibody response. Thus, this study shows promise for treatment of RRP by vaccination with long peptides.

Papillomaviruses are species- and tissue-specific double-stranded DNA viruses. These viruses cause epithelial tumours in many animals, including man. Typically, the benign warts undergo spontaneous, immune-mediated regression, most likely effected by T-cells (especially CD4, but also CD8 subsets), whereas humoral immunity can prevent new infections. Some papillomavirus infections fail to regress spontaneously and others progress to malignant epithelial tumours. Additionally, the impact of these lesions is greater in immunosuppressed individuals. Many therapies are ineffective, and there is much interest in the potential for immunological intervention in papillomavirus infections of man and animals. Vaccination can be achieved with 'live' virus, formalin-inactivated virus, synthetic virus-like particles, and DNA vaccination. There has been much recent progress in the development of such vaccines for papillomavirus infections in the rabbit, ox and dog. Success in these animal models suggests that similar approaches may prove useful for prophylactic or therapeutic vaccination against the important human papillomaviruses involved in the development of cutaneous and anogenital warts, laryngeal papillomatosis, and cervical cancer.

Papillomaviruses occasionally cause severe, nonregressing or recurrent infections in their human and animal hosts. The mechanisms underlying these atypical infections are not known. Canine oral papillomavirus (COPV) typically regresses spontaneously and is an important model of mucosal human papillomavirus infections. A severe, naturally occurring, nonregressing COPV infection provided an opportunity to investigate some aspects of viral pathogenicity and host immunity. In this case, the papillomas proved refractory to surgical and medical treatments, including autogenous vaccination and vaccination with capsid (L1) virus-like particles. High levels of induced anti-L1 antibodies appeared to have no effect on the infection. The papillomas spread to oesophageal mucosa, perioral haired skin, and remote cutaneous sites. Isolation of COPV from the animal and sequencing of several regions of the viral genome showed no differences to the COPV prototype. Experimental infection of beagle dogs with this viral isolate resulted in the uncomplicated development and regression of oral warts within the usual period, indicating that the virus was not an unusual pathogenic variant. These findings support the hypothesis that the recurrent lesions seen in some human papillomavirus infections, such as recurrent laryngeal papillomatosis, are associated with specific defects in host immunity rather than variations in viral pathogenicity., (Copyright 1999 Academic Press.)

Background: We describe a patient with generalized verrucosis secondary to human papillomavirus (HPV) type 2 infection and a primary immunodeficiency and cyclic neutropenia. Treatment, which was well tolerated, included granulocyte-macrophage colony-stimulating factor and interferon gamma (IFN-gamma). In vitro assays to assess responses of T lymphocytes to mitogens (ie, proliferation assay and IFN-gamma enzyme-linked immunosorbent assay) were performed. In situ hybridization and polymerase chain reaction were used to detect HPV DNA in skin biopsy specimens., Observations: The T lymphocytes of the patient showed a significant (P < .05, unpaired Student t test) defect in IFN-gamma production (the basis for initiating IFN-gamma therapy). The response to immunotherapy was confirmed by using molecular methods. Six months after the completion of immunotherapy, HPV DNA was undetectable in skin samples from clinically regressed warts (according to the results of in situ hybridization and polymerase chain reaction)., Conclusions: Our patient had treatment-resistant generalized verrucosis for 13 years. Treatment with granulocyte-macrophage colony-stimulating factor and IFN-gamma may have reconstituted an immune response against HPV, resulting in the dramatic regression of her widespread warts.

We previously found that regression of skin warts induced by the Shope cottontail rabbit papillomavirus in New Zealand White rabbits, as well as malignant conversion of persistent warts, are linked to a restriction fragment length polymorphism of the major histocompatibility complex class II DR alpha and DQ alpha genes. To find out whether this immunogenetic control could be connected with the antigen binding and presentation function of the alpha 1 domain of class II molecules, we have sequenced the exon 2 of the four DR alpha EcoRI and six of the seven DQ alpha PvuII restriction fragment length polymorphism alleles identified, and deduced the encoded amino acid sequences. We found no amino acid polymorphism among DR alpha alleles, indicating that the alpha 1 domain of the DR alpha chain does not condition wart regression or cancer development. In contrast, 27 of the 82 amino acids of the DQ alpha 1 domain were found variable, defining five amino acid sequence alleles. The restriction fragment length polymorphism allele linked to regression and another allele not linked to regression share the same alpha 1 domain, indicating that wart regression is rather conditioned by a closely linked gene. The most divergent DQ alpha 1 allele, however, was that associated with a higher risk of cancer. Alignment of rabbit and human DQ alpha exon 2 alleles disclosed that amino acid charge variations occur at positions assumed to be important for peptide binding in humans. By modulating the affinity for tumor-specific antigenic peptides, such transitions could affect immune surveillance and, thus, condition the risk for progression to carcinoma of papillomavirus-associated lesions.

Severe papillomatosis developed in the oral cavity and spread throughout the haired skin of the trunk and limbs of an 8-month-old female Chinese Shar Pei dog. The dog had received corticosteroids prior to referral, which was associated with the onset of demodecosis and papillomatosis. Papillomavirus structural antigens were detected in biopsies by immunohistochemistry using a panel of monoclonal and polyclonal antibodies. An 8.2-kilobase papillomavirus-specific DNA molecule was detected in the cutaneous lesions by high stringency Southern blot hybridization using a cloned canine oral papillomavirus DNA probe. Restriction enzyme analysis revealed that the virus in the cutaneous lesions was identical to the canine oral papillomavirus. Discontinuation of the steroids combined with the use of a mitocide, antibiotics, and an autogenous vaccine resolved the demodecosis and papillomatosis. This case report suggests that corticosteroid-induced immunosuppression can expand the tissue tropism of papillomaviruses.

The expression of immune associated surface antigens of keratinocytes was studied in human papillomavirus (HPV) derived lesions in order to determine whether HPV types have a regulatory role in the pathogenesis of papillomas. A series of cutaneous and mucosal lesions were immunolabeled with monoclonal antibodies to the major histocompatibility complex class 1 (beta 2-microglobulin) and 2 (HLA-DR antigens), intercellular adhesion molecule (ICAM-1) and glycoprotein CD36 (OKM5) as well as CD1a (Langerhans cells), CD4, CD8 (T cells) and CD11a (LFA1 antigen). Testing for the presence of HPV was carried out by in situ hybridization with biotinylated probes for viral DNA detection and typing. We observed a drastic reduction or a loss of beta 2-microglobulin by keratinocytes from cutaneous lesions in correlation with the disappearance of Langerhans cells. Only mild alterations were observed in mucosal lesions. HLA-DR expressed by keratinocytes was only detected in condylomas and laryngeal papillomas and was usually associated with a dense inflammatory reaction. This HLA-DR expression may be correlated with an up-regulation of ICAM-1 and the presence of LFA1 positive leukocytes, mainly of CD8 phenotype, in the epithelium. CD36 was detected on differentiated keratinocytes of all lesions; its expression seems related to the proliferation state of the lesions and probably does not represent an immune marker. The different reactivity patterns observed in cutaneous and mucosal lesions may reflect: 1. different roles for mucosal and cutaneous HPV types in the induction of immunoregulatory surface antigens of keratinocytes, or 2. the changing nature of the cytokines released by mononuclear cells and infected keratinocytes in these lesions.

In human papillomavirus (HPV) infections, Langerhans cells (LC) are essential in the control of viral infection. The evolution of HPV-derived lesions in the normal population and in graft patients is drastically different, since a high proportion of papillomas progress towards malignancy in transplant recipients. We analyzed the distribution of markers of LC and T lymphocytes, the level of keratinocyte activation and the prevalence of HPV in a series of epithelial lesions obtained from the normal population and from graft patients. The local immune response of warts, condyloma acuminata, Bowen, basal and squamous cell carcinomas (SCC) showed a moderate to intense inflammatory reaction of HLA-DR positive cells, the intensity of the immune reaction being correlated with the degree of malignancy. In the normal population, CD4-positive cells were mainly overexpressed in the dermal infiltrate of condyloma and malignant lesions, whereas in grafted patients such infiltrates were CD4- and CD8-positive without significant predominance of a single T cell subset. The epidermis of most lesions was characterized by a reduced number of CD1a-positive LC with an altered morphology. This was concomitant with the decrease or loss of beta 2-microglobulin by epithelial cells. HLA-DR antigen was sometimes expressed by keratinocytes in genital lesions and SCC from the normal population but has not been detected in immunosuppressed patients. Whereas in the normal population HPV infection was only detected in benign papillomas, both benign and oncogenic HPV DNA may be present in carcinomas from graft patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Series of frozen or paraffin-embedded tissues from various body sites, taken from non-immunosuppressed or immunosuppressed patients with persistent papilloma lesions were examined for the presence of group specific antigen from human papillomavirus (HPV) by indirect immunofluorescence or HPV DNA by in situ hybridization with biotinylated probes. We have shown that it is possible to detect HPV DNA after fixation of tissues in neutral formalin, Bouin's or Baker's solution. However, the sensitivity was reduced as compared to frozen tissues. The HPV DNA was detected in nuclei of heavily infected epithelial cells such as plantar or hand warts or in dispersed cells containing high copy numbers of HPV DNA from lesions such as squamous cell carcinomas or keratoacanthomas. In premalignant or malignant lesions of both immunosuppressed or non-immunosuppressed patients, HPV DNA was rarely detected after fixation. HPV types commonly described for skin and genital samples were identified in non-immunosuppressed patients, whereas in transplant recipients oncogenic HPV type 16 was identified in benign warts as well as in premalignant or malignant lesions. Positive reactions with several HPV types were more frequent in lesions from grafted patients than from the normal population. Virus antigen was detectable more frequently in frozen sections than in fixed tissues. Our findings indicate that in situ hybridization is an appropriate and rapid technique to study the presence of HPV infection. However, numerous controls are needed to avoid misinterpretations.

Our knowledge of warts dates thousands of years. Most warts represent no more than a transient infection in the hands and feet of children and adults. With the relatively recent medical advances permitting the prolonged survival of immunocompromised hosts, however, HPV-induced lesions have become an important problem. In these patients, lesions represent a recurring, intractable infection that predisposes the patient to the development of skin cancer. Such problems have been appreciated for some time in patients with EV. Newer laboratory techniques have led to an increasing number of clinical entities linked with an HPV cause in the nonimmunosuppressed host. Although evidence incriminating HPV as a causative factor for genital cancers of the cervix and the skin continues to mount, such evidence for nongenital Bowen's disease, certain squamous cell carcinomas of the skin, keratoacanthomas, and other tumors of the skin also has begun to grow. It is to be hoped that continued advances in molecular biologic techniques will further delineate the relationship between HPV and these conditions, lead to an HPV classification scheme that is more utilitarian from a clinical point of view, and ultimately lead to improved treatment.

A study of antibodies to human papillomavirus (HPV) 1 is reported in a series of sera from 126 patients with papilloma lesions of different clinical types (verruca plantaris, vulgaris, plana, condyloma acuminata, laryngeal papilloma) using a sensitive solid-phase enzyme-linked immunosorbent assay (ELISA). Our findings showed a significant prevalence of specific HPV 1 IgG antibodies in patients with plantar warts (65%). This incidence was considerably lower in patients with other papilloma lesions, in which positive sera may reflect a past infection with HPV 1. The ELISA test was evaluated as nearly 100 times more sensitive than the indirect immunofluorescence test, and IgG titers to HPV 1 in patients' sera were usually low. Serum samples taken at different times during the course of HPV infection in a few patients with refractory lesions did not show any significant change in their antibody titer.

The human papillomavirus, well known as the etiologic agent of warts, has recently received much attention in the medical literature for its association with various cancers. This article discusses the virology, epidemiology, pathogenesis, immunology, clinical manifestations, and therapy for human papillomavirus infection. Some newer techniques for identifying human papillomavirus in tissue, based on recent advances in molecular biology, are also covered. Two final topics addressed are human papillomavirus infection in the immunocompromised host, including patients with acquired immunodeficiency syndrome, and the possible role of human papillomavirus in several different carcinomas.

Great progress has been made over the last five years in our understanding of papillomavirus (PV) biology. New technology has enabled investigators to understand the relationship between the PV and its host. The PV cannot be cultured in vitro, and this has led to limitations for those wishing to study the biology of this virus. However, utilizing recombinant DNA technology, investigators now have abundant quantities of human papillomavirus (HPV) DNA for study. Such HPV genomes may be labeled with a radioisotope such as P32 and used as a "probe" in hybridization studies to see if a given tissue contains HPV DNA. No longer are we limited to electron microscopy and immune studies in our efforts to identify HPV within benign or malignant tissues. Ultimately, we hope to understand the relationship between the virus and its host. This paper will concentrate on one aspect of this relationship--the immunology of HPV.

244 cervical tissue specimens with different diagnoses were stained by peroxidase-anti-peroxidase technique (PAP) for assay of the human papillomavirus (HPV) genus-specific antigen, the first of its kind performed in China. HPV antigen was detected in 41.93% of simple condyloma group, in 35.29% of dysplasia with condyloma and in 27.27% of carcinoma with condyloma. There was no positive in the control, dysplasia or carcinoma groups. The antigen positive nuclei were found in the koilocytes or parakeratosis cells in the upper layers of the epithelium. The severer the condyloma, the higher the positive rate of antigen. In the severe condyloma group, the positive rate was as high as 64.71%. The koilocytes were observed in every HPV antigen positive section. In view of the coexistence and continuous transformation of condyloma, dysplasia and carcinoma in pathomorphology, these results provide an important evidence to the further studies on the relation between HPV infection and carcinogenesis of cancer of uterine cervix.

The cell-mediated and humoral immune responses to human papillomavirus (HPV) were tested in groups of patients with various degrees of cervical intraepithelial neoplasia (CIN) using a lymphocyte proliferation assay (LPA) as a measure of circulating sensitised T-cells and an enzyme-linked immunosorbent assay (ELISA) for antibodies. Twenty-three of 92 patients (25%) gave stimulation indices (S.I.) greater than two to at least one of the several antigen preparations tested in the LPA. Of 282 patients, 144 (50.1%) showed ELISA indices (E.I.) greater than one to HPV-1 and/or HPV-2 antigens prepared by disruption of purified virions. No correlation was found between positive responses in either test and the presence in cervical biopsies of koilocytes (considered pathognomonic for HPV infections), or between positive responses and the degree of dysplasia observed. Rather, positive antibody and T-cell responses corresponded with a history of past or present skin warts. Although antibody was detected in 42/86 (48.8%) women who thought they had never had warts, only 2/24 (8.3%) with no known history gave a positive S.I. in LPA.

HPV infections are associated with many proliferative lesions of cutaneous and mucosal squamous epithelium. PV genus-specific (common) antigens can be detected by immunocytochemical techniques in approximately 50% of lesions (warts and papillomas) without dysplastic changes. Dysplastic lesions of squamous epithelium are less likely to be permissive for viral expression; squamous neoplasias are rarely, if ever, productively infected. Almost any tissue that has been processed for pathology or exfoliative cytologic preparations can be reliably stained for the presence of papillomavirus common antigens. A positive staining reaction is interpreted as meaning that the lesion is associated with HPV infection and that it has a potential for being contagious.

Forty five oral papillary lesions classified clinically and histologically as condylomatous papilloma, hyperkeratotic papilloma and oral wart were subjected to histopathological evaluation and tested with Human Papilloma Virus (HPV) antiserum, in order to detect HPV group-specific antigens. The immunoperoxidase labelling technique was positive in 10% of 31 condylomatous papillomas, 22% of 9 hyperkeratotic papillomas, and 60% of 5 oral warts. No viral antigens could be detected in 4 oral fibromas used as negative controls. The study of presumed HPV cytopathogenic effects showed that koilocytosis of varying extent was regularly observed and quantified, while three types of koilocytotic cells could be identified. As it is now evident that HPVs play an important role in oral epithelial lesions, the recognition of their cytopathogenic effects in the infected oral mucosae is of increasing interest.

We surveyed a variety of papillomatous lesions, trichilemmoma, and bowenoid papulosis for the presence of papillomavirus common antigen using an unlabeled antibody peroxidase-antiperoxidase technique and an antibody against papillomavirus common antigen. Papillomavirus common antigen was detected in four of six verruca vulgaris lesions overlying the nuclei of koilocytotic cells. The antigen was observed much less often in the granular zone of verrucous lesions that did not contain koilocytotic cells. Thirteen of 18 lesions of bowenoid papulosis had positive immunostaining overlying occasional nuclei in the granular zone but the antigen was not detected in the granular zone of squamous cell carcinoma in situ or of trichilemmoma. These data support the hypothesis that some lesions of bowenoid papulosis represent a form of cutaneous infection by papillomavirus.

Wart associated antigens were observed by the indirect immunoperoxidase technique in light and electron microscopy. Positive reaction products could be found in the nuclei of wart cells, in which virus particles were labeled with a specific immune rabbit serum and with human sera from patients with warts. Tissue antigens, differing from the viral labeled inclusions, were detected within the cytoplasm of some infected cells, by means of IgM and IgG antibodies from patients with warts. In these particular cells the positive reaction occurred in irregular patterns giving microgranular precipitates, which suggests that the antigen was not uniform. No staining was observed on the cell surface. This study has shown direct immunomorphological evidence in vivo of a specific immune reaction in man directed against whole virus and wart specific cellular antigens.

The malignant transformation of cutaneous lesions in epidermodysplasia verruciformis (E.V.), which lesions are caused by a human papilloma virus (HPV), can be compared to that experimentally induced by the polyoma virus. Thus, HPV would undergo a lytic, transformant and/or abortive cycle in epidermal cells. In this latter case, it would increase cell DNA synthesis and there would be production of cellular antigens coded by the virus. This production of cellular antigens would be the result of the incorporation of part of HPV-DNA into the genome of the cell. The presence of part of HPV-DNA in the cell genome would also increase the susceptibility of infected cells to malignant transformation with other Papova viruses. On practical grounds it is not advisable to use potentially mutagenic treatments such as X or U. V. irradiations in the management of HPV induced lesions in man, especially those of E.V.

In order to clarify the relationship between human papillomavirus (HPV) and a variety of surface epithelial lesions, the presence of papillomavirus genus-specific common structural antigen (pgs-antigen) was immunohistochemically investigated in 256 cases of various tumors and tumorous lesions. The pgs-antigen was demonstrated in cases of verruca vulgaris (11/23 cases), condyloma acuminatum (13/26), adult laryngeal papilloma (3/12) and bowenoid papulosis (2/2). No pgs-antigen was observed in ordinary Bowen's disease and other hyperkeratotic skin lesions, such as keratoacanthoma and seborrheic keratosis. In uterine cervical lesions, about 15% of cervical dysplasia, most of which later developed into carcinoma in situ, contained pgs-antigen-positive koilocytotic cells. These results suggest that HPV infection is frequently present in human hyperplastic and atypical surface epithelial lesions of Japanese patients and might indicate possible association with neoplastic transformation, especially in the cervix and skin.

The papillary lesions of oral verruca vulgaris, condyloma acuminatum, and verrucous carcinoma were examined for the presence of papovavirus antigens by the peroxidase-antiperoxidase immunohistochemical methods. The antigens could be detected in the nuclei of cells only in the stratum granulosum and stratum corneum in some cases of verruca vulgaris and condyloma acuminatum but in no case of verrucous carcinoma.

The characterization of different types of human papilloma viruses made it possible to study the specific immune responses to purified viral antigens in patients with warts. The specific cell-mediated immunity was investigated by means of a leukocyte migration inhibition factor test in 9 patients with epidermodysplasia verruciformis and 4 patients with regressing plane warts. The results show a significant increase in specific cell-mediated reactivity concomitant with the regression of the warts.

HPVs are associated with a variety of proliferative squamous lesions. 27 different types of HPV have been identified by DNA molecular hybridization studies. Genus- and type-specific HPV structural antigens can be detected in approximately half of benign warts and condylomata by immunocytochemistry; positive lesions are considered infectious. Genus- and type-specific putative HPV DNA sequences replicating as episomes can be recovered from the majority of benign (exophytic and flat condylomata) and malignant squamous lesions of the cervix and anogenital area. The type of HPV determines, in part, the anatomic site, clinical appearance, and natural history (including potential malignant conversion) of the lesion.