A study of genotyping for management of human papillomavirus-positive, cytology-negative cervical screening results.

The effective management of women with human papillomavirus (HPV)-positive, cytology-negative results is critical to the introduction of HPV testing into cervical screening. HPV typing has been recommended for colposcopy triage, but it is not clear which combinations of high-risk HPV types provide clinically useful information. This study included 18,810 women with Hybrid Capture 2 (HC2)-positive, cytology-negative results and who were age ≥30 years from Kaiser Permanente Northern California. The median follow-up was 475 days (interquartile range [IQR], 0 to 1,077 days; maximum, 2,217 days). The baseline specimens from 482 cases of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) and 3,517 random HC2-positive noncases were genotyped using 2 PCR-based methods. Using the case-control sampling fractions, the 3-year cumulative risks of CIN3+ were calculated for each individual high-risk HPV type. The 3-year cumulative risk of CIN3+ among all women with HC2-positive, cytology-negative results was 4.6%. HPV16 status conferred the greatest type-specific risk stratification; women with HC2-positive/HPV16-positive results had a 10.6% risk of CIN3+, while women with HC-2 positive/HPV16-negative results had a much lower risk of 2.4%. The next most informative HPV types and their risks in HPV-positive women were HPV33 (5.9%) and HPV18 (5.9%). With regard to the etiologic fraction, 20 of 71 cases of cervical adenocarcinoma in situ (AIS) and adenocarcinoma in the cohort were positive for HPV18. HPV16 genotyping provides risk stratification useful for guiding clinical management; the risk among HPV16-positive women clearly exceeds the U.S. consensus risk threshold for immediate colposcopy referral. HPV18 is of particular interest because of its association with difficult-to-detect glandular lesions. There is a less clear clinical value of distinguishing the other high-risk HPV types.

Plasma cytokine levels and human papillomavirus infection at the cervix in rural Nigerian women.

INTRODUCTION: We conducted a study to test the hypothesis that systemic dysregulation of Th1/Th2 cytokine levels was associated with detection of carcinogenic or overall human papillomavirus (HPV) at the cervix among 964 women residing in a rural village in Nigeria. METHODS: Levels in plasma were measured for 19 cytokines, including Th1-like cytokines IL-2, IL-12 (p40), TNF-a, IFN-g; Th2-like cytokines IL-4, IL-5, IL-6, IL-10, IL-13; innate/inflammation cytokines IL-1a, IL-1b, IL-8, eotaxin, MCP-1, MIP-1a, and IL-7; and cell development cytokines G-CSF, VEGF, and IL-17. Analysis was restricted to 5 cytokines, TNF-α (Th1), IL-8 (Th2), eotaxin and MCP-1 (innate/inflammation), and G-CSF (cell development), whose levels were detected in 80% or more of the samples measured as well as had a coefficient of variation of <30%. RESULTS: Strong correlations were noted between levels of eotaxin and TNF-α (r=0.75), IL-8 and MCP-1 (r=0.60), eotaxin and G-CSF (r=0.44), and G-CSF and IFN-γ (r=0.43). Detection of carcinogenic or non-carcinogenic HPV DNA was unrelated to cytokine levels, except for levels of eotaxin and TNF-α, which were inversely correlated, albeit weakly, with detection of any carcinogenic HPV (P=0.048 and P=0.067, respectively). In analyses stratified by age group, levels of eotaxin were inversely correlated with detection of any HPV DNA (P=0.026) and carcinogenic HPV (P=0.042) in older, but not younger, women. CONCLUSIONS: Our results do not support the hypothesis of association between systemic cytokine dysregulation and detection of HPV at the cervix in Nigerian women, but subgroup analyses raise questions about inverse associations between eotaxin and TNF-α in older women.

Novel genital alphapapillomaviruses in baboons (Papio hamadryas anubis) with cervical dysplasia.

Genital Alphapapillomavirus (αPV) infections are one of the most common sexually transmitted human infections worldwide. Women infected with the highly oncogenic genital human papillomavirus (HPV) types 16 and 18 are at high risk for development of cervical cancer. Related oncogenic αPVs exist in rhesus and cynomolgus macaques. Here the authors identified 3 novel genital αPV types (PhPV1, PhPV2, PhPV3) by PCR in cervical samples from 6 of 15 (40%) wild-caught female Kenyan olive baboons (Papio hamadryas anubis). Eleven baboons had koilocytes in the cervix and vagina. Three baboons had dysplastic proliferative changes consistent with cervical squamous intraepithelial neoplasia (CIN). In 2 baboons with PCR-confirmed PhPV1, 1 had moderate (CIN2, n = 1) and 1 had low-grade (CIN1, n = 1) dysplasia. In 2 baboons with PCR-confirmed PhPV2, 1 had low-grade (CIN1, n = 1) dysplasia and the other had only koilocytes. Two baboons with PCR-confirmed PhPV3 had koilocytes only. PhPV1 and PhPV2 were closely related to oncogenic macaque and human αPVs. These findings suggest that αPV-infected baboons may be useful animal models for the pathogenesis, treatment, and prophylaxis of genital αPV neoplasia. Additionally, this discovery suggests that genital αPVs with oncogenic potential may infect a wider spectrum of non-human primate species than previously thought.

Novel betapapillomavirus associated with hand and foot papillomas in a cynomolgus macaque.

Betapapillomavirus is a genus of papillomaviruses (PVs) commonly found in human skin and associated with both benign and malignant skin lesions. Only 2 previous beta-PVs have been fully characterized in nonhuman species. This report describes a novel beta-PV, named Macaca fascicularis PV type 2 (MfPV2), isolated from exophytic skin papillomas on the hands and feet of a 2-year-old male cynomolgus monkey (M. fascicularis). On histology the papillomas were composed of diffusely thickened epidermis with superficial foci of cytomegaly, cytoplasmic pallor, marginalized chromatin, and rare eosinophilic intranuclear inclusion bodies. Positive immunostaining for p16 and the proliferation marker Ki67 was present multifocally within affected epidermis, most prominently within basal-type cells. Complete sequence identity (100%) was noted between PV genomes fully sequenced from hand and foot lesions. The MfPV2 genome was 7632 base pairs in length and included putative open reading frames (ORFs) for E1, E2, E4, E6, E7, L1, and L2 genes, similar to other PVs. The closest relatives to MfPV2 based on the L1 ORF sequence were all beta-PVs. These included human PV (HPV) 9, HPV115, HPV76, HPV75, and MfPV1 (60-70% pairwise identity for all), the latter of which was also isolated from hand and foot papillomas in a cynomolgus macaque. Phylogenetic analysis placed MfPV2 in a new species group (beta-6), distinct from HPVs (beta-1 to beta-5) and MfPV1 (beta-1). These findings characterize a new nonhuman beta-PV and provide additional support for the idea that tissue tropism among ancestral primate PVs developed prior to divergence of certain Old World primate lineages.

Gene expression profiles in HPV-infected head and neck cancer.

Epidemiological and laboratory evidence indicate that, in addition to tobacco and alcohol, human papillomaviruses (HPV) play an important aetiological role in a subset of head and neck squamous cell carcinoma (HNSCC). To evaluate the molecular pathogenesis of HPV-infected HNSCC, we compared gene expression patterns between HPV-positive and -negative HNSCC tumours using cDNA microarrays. Tumour tissue was collected from 42 histologically confirmed HNSCC patients from an inner-city area of New York. Total DNA and RNA were extracted and purified from frozen tumour samples and gene expression levels were compared to a universal human reference RNA standard using a 27 323 cDNA microarray chip. HPV detection and genotyping were performed using an MY09/11-PCR system and RT-PCR. HPV was detected in 29% of HNSCC tumours. Most harboured only HPV16 and expressed the HPV16-E6 oncogene. HPV prevalence was highest in pharyngeal tumours (45%). Gene expression patterns that differentiated HPV-positive from negative tumours were compared by supervised classification analysis, and a multiple-gene signature was found to predict HPV16 prevalence in primary HNSCC with a false discovery rate < 0.2. Focusing on never-smokers, we further identified a distinct subset of 123 genes that were specifically dysregulated in HPV16-positive HNSCC. Overexpressed genes in HPV-positive HNSCC tumours included the retinoblastoma-binding protein (p18), replication factor-C gene, and an E2F-dimerization partner transcription factor (TFDP2) that have also been found to be overexpressed in cervical cancer. An additional subset of genes involved in viral defence and immune response, including interleukins and interferon-induced proteins, was found to be down-regulated in HPV-positive tumours, supporting a characteristic and unique transcriptional profile in HPV-induced HNSCC.

Determinants of human papillomavirus 16 serological conversion and persistence in a population-based cohort of 10 000 women in Costa Rica.

Determinants of human papillomavirus (HPV)-16 serological conversion and persistence were assessed in a population-based cohort of 10 049 women in Guanacaste, Costa Rica. Serologic responses to HPV-16 were measured in 7986 women by VLP-based enzyme-linked immunosorbent assay at both study enrollment (1993/94) and at 5-7 years of follow-up. Seropositive women were defined as >/=5 standard deviations above the mean optical density obtained for studied virgins at enrollment (n=573). Seroconnversion (n=409), persistence (n=675), and clearance (n=541) were defined based on enrollment and follow-up serology measurements. Age-specific distributions revealed that HPV-16 seroconversion was highest among 18- to 24-year-old women, steadily declining with age; HPV-16 seropersistence was lowest in women 65+ years. In age-adjusted multivariate logistic regression models, a 10-fold risk increase for HPV-16 seroconversion was associated with HPV-16 DNA detection at enrollment and follow-up; two-fold risk of seroconversion to HPV-16 was associated with increased numbers of lifetime and recent sexual partners and smoking status. Determinants of HPV-16 seropersistence included a 1.5-fold risk increase associated with having one sexual partner during follow-up, former oral contraceptive use, and a 3-fold risk increase associated with HPV-16 DNA detection at both enrollment and follow-up. Higher HPV-16 viral load at enrollment was associated with seroconversion, and higher antibody titres at enrollment were associated with seropersistence.

A case-control study of endogenous hormones and cervical cancer.

Both parity and oral contraceptive use are associated with elevated circulating levels of sex hormones, at least transiently, and with increased risk of cervical cancer in human papillomavirus (HPV)-infected women. We directly evaluated whether elevations in the physiologic levels of these hormones predispose to the development of cervical neoplasia. We identified 67 premenopausal and 43 postmenopausal women with cervical intraepithelial neoplasia 2, 3, or cervical cancer (>/=CIN2) diagnosed during enrollment of a population-based cohort of 10 077 women. Four controls, two chosen randomly and two chosen from women testing positive for cancer-associated HPV, were matched to each case on menopausal status, age, days since last menses (pre), or years since menopause (post). Sex hormone-binding globulin, oestradiol, oestrone, oestrone-sulphate, dehydroepiandrosterone sulphate, and progesterone were measured in enrollment plasma. There was no consistent association between the sex hormones and risk of >/=CIN2. Excluding cases with invasive disease had a minimal impact on results. Though this case-control study was based on a well-defined population, it was limited by reliance on a single measure of hormone levels taken at the time of diagnosis. Nonetheless, our results do not support the hypothesis that plasma levels of sex hormones have an important bearing on the risk of cervical neoplasia in HPV-infected women.

A population based study of herpes simplex virus 2 seroprevalence in rural Costa Rica.

OBJECTIVES: To determine seroprevalence and determinants of herpes simplex virus 2 (HSV-2) seropositivity, in a random sample of a population based cohort of 10 049 women of Guanacaste, Costa Rica, using a highly sensitive and specific serological assay. METHODS: Seroprevalence was determined by a type specific HSV-2 ELISA assay in an age stratified random sample of 1100 women. Univariate and multivariate logistic regression was used to calculate odds ratios and 95% confidence intervals for risk factors of seropositivity. RESULTS: Overall age adjusted HSV-2 seroprevalence was 38.5% (95% CI, 37.5 to 39.5), and it was strongly associated with increasing age (p(Trend<0.0001)), both among monogamous women and women with multiple sexual partners. A greater number of lifetime sexual partners increased the risk of seropositivity, with a 28.2% (95% CI, 24.4 to 32.2) seroprevalence among monogamous women and 75% (95% CI, 65.6 to 83.0) seroprevalence for those with four or more partners (OR = 7.6 95% CI, 4.7 to 12.4 p(Trend<0.0001)). Barrier contraceptive use was negatively associated with HSV-2 seropositivity (OR 0.54, 95% CI, 0.31 to 0.94). Women with antibodies against HPV 16, 18, or 31 were 1.6 times more likely to be HSV-2 seropositive (OR 1.6, 95% CI, 1.2 to 2.1). CONCLUSIONS: HSV-2 infection is highly endemic in Guanacaste, even among lifetime monogamous women, suggesting a role of male behaviour in the transmission of the infection. Until vaccination against HSV-2 is available, education to prevent high risk sexual behaviour and the use of condoms appear as preventive measures against HSV-2.

Seroprevalence of human papillomavirus-16, -18, -31, and -45 in a population-based cohort of 10000 women in Costa Rica.

Human papillomavirus (HPV) seroprevalence and determinants of seropositivity were assessed in a 10049-woman population-based cohort in Guanacaste, Costa Rica. Serologic responses based on VLP-based ELISA were obtained from the plasma collected at study enrollment in 1993/1994 for HPV-16 (n=9949), HPV-18 (n=9928), HPV-31 (n=9932), and HPV-45 (n=3019). Seropositivity was defined as five standard deviations above the mean optical density obtained for studied virgins (n=573). HPV-16, -18, -31, and -45 seroprevalence was 15, 15, 16, and 11%, respectively. Of women DNA-positive for HPV-16, -18, -31, or -45, seropositivity was 45, 34, 51, and 28%, respectively. Peak HPV seroprevalence occurred a decade after DNA prevalence; lifetime number of sexual partners was the key determinant of seropositivity independent of DNA status and age. DNA- and sero-positive women showed the highest risk for concurrent CIN3/cancer, followed by DNA-positive, sero-negative women.

Polymorphism of the insulin gene is associated with increased prostate cancer risk.

High insulin levels are linked with increased cancer risk, including prostate cancer. We examined the associations between prostate cancer with polymorphisms of the insulin gene (INS) and its neighbouring genes, tyrosine-hydroxylase and IGF-II (TH and IGF2). In this study, 126 case-control pairs matched on age, race, and countries of origin were genotyped for +1127 INS-PstI in INS, -4217 TH-PstI in TH, and +3580 IGF2-MspI in IGF2. The homozygous CC genotype of +1127 INS-PstI occurred in over 60% of the population. It was associated with an increased risk of prostate cancer in nondiabetic Blacks and Caucasians (OR=3.14, P=0.008). The CC genotype was also associated with a low Gleason score <7 (OR=2.60, P=0.022) and a late age of diagnosis (OR=2.10, P=0.046). Markers in the neighbouring genes of INS showed only null to modest associations with prostate cancer. The polymorphism of INS may play a role in the aetiology of prostate cancer. Given the high prevalence of the CC genotype and its association with late age of onset of low-grade tumours, this polymorphism may contribute to the unique characteristics of prostate cancer, namely a high prevalence of indolent cancers and the dramatic increase in incidence with age.

Human leukocyte antigen class I and II alleles and risk of cervical neoplasia: results from a population-based study in Costa Rica.

To examine human leukocyte antigen (HLA) involvement in the development of all grades of cervical neoplasia, a nested case-control study of 10,077 women in Guanacaste, Costa Rica, was conducted. Participants had invasive cervical cancer, high-grade squamous intraepithelial lesions (HSILs; n=166), or low-grade squamous intraepithelial lesions (LSILs); were positive for human papillomavirus (HPV) with no evidence of cervical neoplasia (n=320); or were HPV negative with no evidence of cervical neoplasia but with a history of high-risk sexual behavior (n=173). Compared with women who were HPV negative, women with HLA-DRB1*1301 were associated with decreased risk for cancer/HSILs (odds ratio [OR], 0.4; 95% confidence interval [CI], 0.2-0.7) and for LSILs/HPV (OR, 0.6; 95% CI, 0.3-0.9). Women with both HLA-B*07 and HLA-DQB1*0302 had an 8.2-fold increased risk for cancer/HSILs (95% CI, 1.8-37.2) and a 5.3-fold increased risk for LSILs/HPV (95% CI, 1.2-23.7). These results support the hypothesis that multiple risk alleles are needed in order to increase risk for cervical neoplasia, but a single protective allele may be sufficient for protection.

An association of cervical inflammation with high-grade cervical neoplasia in women infected with oncogenic human papillomavirus (HPV).

Previous reports of genital conditions, such as nonspecific genital infection/sore or vaginal discharge associated with cervical cancer (L. A. Brinton et al., J. Natl. Cancer Inst. (Bethesda), 79: 23-30, 1987; C. J. Jones et al., Cancer Res., 50: 3657-3662, 1990), suggest a possible link between either genital tract inflammation or changes in bacteria flora consistent with bacterial vaginosis (BV) and cervical cancer. To test whether changes in vaginal bacterial flora or the degree of cervical inflammation are associated with women having a human papillomavirus (HPV) infection or with women infected with oncogenic HPV having high-grade cervical lesions (high-grade squamous intraepithelial lesions or cancer), we conducted a case-control study of women <50 years old enrolled in the Costa Rican natural history study of HPV and cervical neoplasia. To test whether BV and inflammation were associated with HPV DNA positivity, Analysis 1 was restricted to women with no or mild (low-grade or equivocal) cytological abnormalities, and the degree of inflammation and Nugent score (a measure of BV) were compared between women infected (n = 220) and not infected (n = 130) with HPV. To test whether BV and inflammation were associated with high-grade lesions, Analysis 2 was restricted to women infected with oncogenic HPV, and the degree of inflammation and Nugent score were compared between women with (n = 95) and without (n = 158) high-grade cervical lesions. In Analysis 1, BV and cervical inflammation were not associated with HPV infection. In Analysis 2, BV was not associated with high-grade lesions. However, we found a marginally significant positive trend of increasing cervical inflammation associated with high-grade lesions in oncogenic HPV-infected women, (P(trend) = 0.05). Overt cervicitis was associated with a 1.9-fold increase in risk of high-grade lesions (95% confidence interval, 0.90-4.1). The results of this study suggest that cervical inflammation may be associated with high-grade lesions and may be a cofactor for high-grade cervical lesions in women infected with oncogenic HPV.

The von Hippel-Lindau gene product inhibits renal cell apoptosis via Bcl-2-dependent pathways.

Previous studies have reported a protective role for the von Hippel-Lindau (VHL) gene products against pro-apoptotic cellular stresses, but the mechanisms remain unclear. In this study, we examined the role of VHL in renal cells subjected to chemical hypoxia, using four VHL-negative and two VHL-positive cell lines. VHL-negative renal carcinoma cells underwent apoptosis following chemical hypoxia (short-term glucose deprivation and antimycin treatment), as evidenced by morphologic changes and internucleosomal DNA cleavage. Reintroduction of VHL expression prevented this apoptosis. VHL-negative cells displayed a significant (greater than 5-fold) activation of caspase 9 and release of cytochrome c into the cytosol following chemical hypoxia. In contrast, VHL-positive cells showed minimal caspase 9 activation, and absence of cytochrome c release under the same conditions. Caspase 8 was only minimally activated in both VHL-negative and -positive cells. In addition, VHL-positive cells displayed a striking up-regulation of Bcl-2 expression (5-fold) following chemical hypoxia. Antisense oligonucleotides to Bcl-2 significantly down-regulated Bcl-2 protein expression in VHL-positive cells and rendered them sensitive to apoptosis. Overexpression of Bcl-2 in VHL-negative cells conferred resistance to apoptosis. Our results suggest that VHL protects renal cells from apoptosis via Bcl-2-dependent pathways.

The relation of type 2 diabetes and cancer.

Increasing evidence indicates that individuals with type 2 diabetes (diabetes) are at elevated risk for several common human malignancies, including cancers of the colon, breast, endometrium, pancreas, and liver. In particular, the consistent positive results reported by prospective investigations make it unlikely that methodologic issues, occult tumors, or chance results could explain the findings. Since diabetes and impaired fasting glucose together affect >25% of Americans above age 50, even a moderate etiologic association (e.g., relative risk = 1.5) would explain >10% of involved malignancies. Laboratory studies have suggested biologically plausible mechanisms. Insulin, for example, is typically at high levels during the development and early stages of diabetes. Activation of the insulin receptor by its ligand, or cross-activation of the insulin-like growth factor-I receptor, has been shown to be mitogenic and promote tumorigenesis in various model systems. A "unifying concept," in fact, holds that hyperinsulinemia may underlie the cancer associations of several additional risk factors, including high waist circumference, visceral fat, waist-to-hip ratio, body mass index, sedentary lifestyle, and energy intake. In this review, we assess current evidence regarding the relation of type 2 diabetes with cancer, and evaluate the findings in terms of well-accepted criteria for establishing causality.

HPV co-factors related to the development of cervical cancer: results from a population-based study in Costa Rica.

We examined factors associated with high-grade squamous intraepithelial lesions (HSIL) and cervical cancer among human papillomavirus (HPV)-infected women in a prevalent case-control study conducted within a population-based cohort of 10 077 women in Costa Rica. We compared 146 women with HPV-positive HSIL or cancer (HSIL/CA) against 843 HPV-positive women without evidence of HSIL/CA. Subjects completed a risk factor questionnaire. We evaluated the associations between exposures and HSIL/CA among women positive for any HPV and restricted to those positive for high-risk HPV types. Risk of HSIL/CA increased with increasing number of live births (P(trend)= 0.04). Women who smoked 6+ cigarettes/day had a RR for HSIL/CA of 2.7 (95% CI = 1.1-6.7) compared to non-smokers. Current use of barrier contraceptives was associated with a reduction in risk of HSIL/CA (RR = 0.39; 95% CI = 0.16-0.96). Sexual behaviour and a self-reported history of sexually transmitted diseases (STDs) other than HPV were not associated with HSIL/CA. Oral contraceptive use was associated with HSIL/CA among women with <3 pregnancies. Effects were similar in analysis restricted to women positive for high-risk HPV types. Among women positive for high-risk HPV types, 44% of HSIL/CA could be attributed to multiparity (>/=3 pregnancies) and/or smoking. Among HPV-positive women, multiparity and smoking are risk factors for HSIL/CA. Oral contraceptive use may be associated with HSIL/CA in subgroups of women.

Endoplasmic reticulum/cytosolic localization of von Hippel-Lindau gene products is mediated by a 64-amino acid region.

Inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene causes both the familial cancer syndrome VHL disease and corresponding sporadic tumor types, including renal-cell carcinoma. Subcellular localization of VHL gene products was determined by indirect immunofluorescence. Both native and exogenously expressed VHL proteins displayed a cytoplasmic peri-nuclear immunostaining pattern, which co-localized with markers for the endoplasmic reticulum (ER). In addition, subcellular fractionation indicated that both native and exogenously expressed VHL products are found predominantly in the cytosolic compartment. Deletion analyses demonstrated that a 64-amino acid region of VHL (residues 114-177) is responsible for cytosolic as well as ER subcellular localization. Taken together, the immunostaining and biochemical fractionation studies suggest that VHL localizes to the cytosolic face of the ER. The relationship between VHL subcellular localization and VHL-associated ubiquitination was examined. Chimeric VHL-green fluorescent protein (GFP) products, which localized to the peri-nuclear region, were shown to undergo ubiquitination. VHL amino acids 114-177 were necessary and sufficient for this modification. Consistent with a role of VHL in ubiquitination, expression of VHL led to enhanced ubiquitination of cellular proteins, and amino acids 114-177 were also critical for this effect. Therefore, amino acids 114-177 were required for accurate VHL subcellular localization, ubiquitination of VHL-GFP products and VHL-dependent increases in cellular ubiquitination. Since mutations in this region of VHL are frequently detected in renal-cell carcinomas, these results suggest that proper VHL subcellular localization and associated ubiquitination functions may be necessary for VHL-mediated tumor suppression.

Complete nucleotide sequence and analysis of a novel human papillomavirus (HPV 84) genome cloned by an overlapping PCR method.

Molecular diagnosis of human papillomaviruses (HPVs) in cervicovaginal samples reveals a plethora of known and novel HPV genomes. We describe the use of an overlapping PCR method to clone and analyze the complete genome of HPV 84 from cervicovaginal cells obtained from a 21-year-old Caucasian female with a normal Pap smear. The 7948-bp complete nucleotide sequence of HPV 84 was determined from five overlapping PCR products by sequence walking. A BLAST homology search demonstrated that HPV 84 was most closely related to HPV 61 (89%), HPV 72 (86%), and HPV 83 (85%) by nucleotide sequence analysis of the L1 open reading frame, placing it in the HPV genome homology group A3. Previously, this virus had been identified as Pap155. Based on extensive epidemiological data, HPV 84 is a highly prevalent genital papillomavirus primarily detected in normal and HIV-infected women.