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1 Ist. Naz. Tumori ‘Fond. G. Pascale’, Cappella Cangiani, I-80131 Naples, Italy
2 Agency for Public Health, Lazio Region, Rome, Italy
3 Gynaecology Department, University of Medicine, Naples, Italy
Correspondence
Franco Maria Buonaguro
irccsvir{at}unina.it
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Bosch et al., 1995; IARC, 1995; Walboomers et al., 1999). To date, more than 40 HPV genotypes have been identified in the female genital tract and have been grouped as (i) ‘high-risk’ viruses (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59), associated with a high relative risk of cervical cancer; (ii) ‘low-risk’ viruses (HPV types 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81 and 89), associated with benign epithelial proliferations; (iii) ‘probable carcinogenic’ viruses (HPV types 26, 53, 66, 68, 73 and 82), associated with cervical cancer in a few case–control studies; and (iv) ‘undetermined risk’ viruses (HPV types 2a, 3, 7, 10, 27, 28, 29, 30, 32, 34, 55, 57, 62, 67, 69, 71, 74, 77, 83, 84, 85, 86, 87, 90 and 91), whose oncogenicity has not yet been determined (Muñoz et al., 2003, 2006; Smith et al., 2007).
Epidemiological studies, performed mainly on human immunodeficiency virus (HIV)-negative women, have shown that, despite the high prevalence and strong association with cervical neoplasia, the majority of HPV infections with high- and low-risk types are transient and only a fraction of persistent infections progress on to high-grade SIL and invasive cancer, underscoring the interplay of a number of environmental, viral and host factors in HPV-related tumour progression (Massad et al., 1999; Castellsagué & Muñoz, 2003; Wang & Hildesheim, 2003).
HIV-infected women are at higher risk of persistent HPV infection and cervical neoplasia (Sun et al., 1997; Ahdieh et al., 2001; Rowhani-Rahbar et al., 2007), probably due to an inability to control the expression and replication of HPV by an HIV-compromised immune system. HIV-positive women with or without cytological abnormalities are infected with a broader range of HPV types than HIV-negative women. In a recent meta-analysis including 5578 HIV-positive women worldwide, HPV16 accounted for a smaller proportion of HPV infections in HIV-positive women than in the general female population. This was also the case in women with high-grade SIL. Conversely, other types (high-risk types 18, 51, 52, 58 and low-risk types 11, 53, 61) were more frequently detected in HIV-positive women with high-grade SIL (Clifford et al., 2006). It has also been speculated that HIV infection may increase the oncogenicity of high-risk HPV types and possibly the activity of low-risk HPV types (Tweddel et al., 1994). However, it remains unclear to what extent HPV types that rarely progress to severe lesions in immunocompetent women can cause high-grade SIL and invasive cancer among HIV-positive women. This question is particularly relevant with regard to cervical cancer prevention among this high-risk population, given that methods for detecting HPV DNA currently in clinical use may not detect all known and unknown HPV types (Poljak et al., 2002).
Moreover, for any given HPV type, viral isolates that differ by less than 2 % of the L1 gene DNA sequence are designated variants, and they appear to segregate according to ethnic groups (Bernard et al., 2006). Thus, genomic variants can be considered markers of specific HPV genomes and accordingly can be used in epidemiological and aetiological studies to investigate transmission of HPV within and among populations (Xi et al., 2006; Tornesello et al., 2007). The most studied HPV16 isolates, classified as European and non-European (Asian, Asian–American, African 1 and 2) variants, differ in their biological properties and in their oncogenic potential (Tornesello et al., 2000, 2004; Xi et al., 1997, 2002, 2007; Hiller et al., 2006). Only a few studies, all performed in the USA, have evaluated the prevalence and natural history of HPV16 variants in HIV-positive women and compared them with HIV-negative women (Chaturvedi et al., 2004; Schlecht et al., 2005).
The purpose of our study was to determine the prevalence and persistence of specific mucosal HPV genotypes and HPV16 variants in HIV-positive Italian women with normal or abnormal cytology and to determine the risk profile of uncommon viral types, which may contribute to the increased incidence of SIL observed in HIV-infected women. Furthermore, we considered the joint effects of immunosuppression (CD4+ counts) and HIV viral load on the prevalence of HPV infection.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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) and (ii) to assess the relationship between HPV genotypes and cytological results. During each visit, cervical cell scrapings were collected with a cytobrush from the ecto- and endocervix of each woman and after spreading of cells on slides (Pap smears), the remaining cells were suspended in 1 ml lysis buffer [10 mM Tris/HCl (pH 7.6), 5 mM EDTA, 150 mM NaCl, 1 % SDS] and stored at –20 °C until analysis. Genomic DNA was extracted from cervical-scraping cell lysates by digestion with proteinase K (150 µg ml–1 at 60 °C for 30 min), followed by DNA purification by phenol and phenol : chloroform : isoamyl alcohol (25 : 24 : 1) extraction and ethanol precipitation in 0.3 M sodium acetate (pH 4.6). The time since diagnosis of HIV infection, HIV RNA plasma viral loads, CD4+ T-cell counts and antiretroviral therapy regimens were obtained from the patients' records available from the Department of Infectious Disease, Medical School of ‘Federico II’ University. For HIV-positive patients, peripheral blood CD4+ and CD8+ cell counts were determined by flow cytometry and plasma HIV RNA loads were determined using an Amplicor HIV-1 Monitor assay (Roche Diagnostic Systems).
Detection of HPV sequences by PCR.
A DNA quality test, performed by amplification with specific oligonucleotide primers targeting a fragment of exon 7 within the TP53 gene, and DNA quantity analysis, evaluated by spectrophotometric measurements, were used to determine that all 227 samples were suitable for viral DNA analysis.
HPV detection was carried out by nested PCR using MY09/MY11 primers as the outer pair and GP5+/GP6+ primers as the inner pair to amplify the L1 conserved region, as described previously (Tornesello et al., 2006). All samples were further amplified using a set of oligonucleotides specifically designed to amplify the HPV16 region containing the E6 and E7 genes (nt 34–879) and long control region (LCR) (nt 7289–115) as described previously (Tornesello et al., 1997). DNA was amplified in a Perkin-Elmer GeneAmp PCR System 9600 thermal cycler with the following steps for both amplification reactions: an initial cycle of 1 min denaturation at 94 °C, followed by 32 cycles of 1 min annealing at 55 °C, 2 min extension at 72 °C and 30 s denaturation at 94 °C, with a final cycle of 1 min annealing at 55 °C and 5 min elongation at 72 °C. A reaction mixture without template DNA, as a negative control, was included in every set of five clinical specimens for each PCR run. Six plasmid clones containing HPV6, -11, -16, -18, -31 and -33 were used as positive controls.
HPV DNA sequence analysis.
HPV genotypes were identified by direct sequence analysis of GP5+/GP6+ nested PCR-amplified products obtained from each HPV-positive sample. PCR products were extracted with phenol and chloroform : isoamyl alcohol and purified by precipitation at 37 °C for 15 min in 1.25 M NaCl and 20 % polyethylene glycol 6000. Purified DNA samples were subjected to direct nucleotide sequencing using a rapid method modified from Winship (1989). Briefly, DNA samples (30–100 ng) were denatured at 95 °C in the presence of 10 % DMSO, immediately cooled in liquid nitrogen and subsequently sequenced with a Sequenase 2.0 kit according to the manufacturer's instructions (GE Healthcare), but with modification to the labelling step (3 min on ice). All samples were amplified and analysed in duplicate to identify point mutations possibly originating from the PCR. Sequences were analysed on a 6 % polyacrylamide wedge sequencing gel. HPV type identification was performed by alignment of HPV sequences with those present in the GenBank database using the BLASTN software (http://www.ncbi.nlm.nih.gov/blast/html).
All DNA samples (n=40) showing sequence patterns compatible with multiple infections were subcloned in SmaI-digested pBS– vector (Stratagene) and subjected to sequence analysis following procedures described previously (Tornesello et al., 2007).
HPV16 classes were identified by sequencing the E6/E7 genes and the LCR regions in both directions with several primers internal to the amplified products. Multiple sequence alignments of the full-length E6 and E7 genes and the 5' region of the L1 gene, as well as the LCR sequence, of 26 HPV16 samples were performed using MEGALIGN of the Lasergene software (DNASTAR). HPV16 sequences and base positions were numbered according to the 1997 sequence database (Los Alamos National Laboratory, Los Alamos, NM, USA) and variant designation was done according to Yamada et al. (1997).
Statistical analysis.
The data were analysed with Epi Info 6 Statistical Analysis System Software (version 6.04b, 1997, Centers for Disease Control and Prevention, USA), and GraphPad Prism (version 4.00 for Windows, GraphPad Software, CA, USA). An unpaired t-test was used for comparisons of continuous variables (i.e. age); a 
2 test, Yates-corrected 2 test and, where appropriate, two-sided Fisher's exact test were used for comparison of categorical data. Differences were considered to be statistically significant when P values were less than 0.05. A logistic multivariate model was built to calculate the prevalence of odds ratios and 95 % confidence intervals to analyse the possible relationship between HPV prevalence and HIV therapy, CD4+ cell counts and HIV viral load among HIV-positive women. The period prevalence was defined as the percentage of women with any HPV infection detected either at the baseline (point prevalence) or at least once during the follow-up visits of the enrolled women over the study period. A persistent infection was defined as a type-specific infection that was detected at least twice during follow-up visits. Multiple infection was defined as the detection of more than one HPV type in the same sample.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). At the time of enrolment, for 43 (38.4 %) HIV-positive women more than 5 years had elapsed since their seroconversion. The risk factor for the acquisition of HIV was known for all 112 HIV-positive study participants and was mainly due to heterosexual contacts (75 % of the women) and injection drug use (20.5 %). Among the 112 HIV-positive women, 33 (29.5 %) had abnormal Pap smears: 19 cases (17 %) were atypical squamous cells of uncertain significance (ASCUS) or low-grade SIL, and 14 cases (12.5 %) were high-grade SIL. In contrast, among the 115 HIV-negative women, eight (6.9 %) had abnormal Pap smears: six cases (5.2 %) were ASCUS or low-grade SIL, and two cases (1.7 %) were high-grade SIL.
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). Among the 15 HPV genotypes identified in HIV-negative women, eight (types 16, 18, 31, 33, 52, 53, 58 and 66) were of high-risk or probable high-risk type, one (HPV62) was of undetermined risk type and six (types 6, 54, 61, 70, 72 and 81) were low-risk HPVs. Moreover, multiple infections were detected in 9.8 and 1.7 % of HIV-positive and HIV-negative women, respectively. The period prevalence of high-risk and probable high-risk HPVs was 33.9 and 13.9 % among HIV-positive and HIV-negative women, respectively. However, undetermined-risk and low-risk HPVs were detected in 6.2 and 19.6 % of HIV-positive and in 0.9 and 5.2 % of HIV-negative women, respectively. The most common genotypes identified in HIV-infected subjects were HPV types 16 (16.1 %), 81 (7.1 %), 58 (4.5 %), 72 (4.5 %) and 33 (3.6 %).
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. In HIV-infected women, the HPV types 16, 58 and 81, as single or multiple infections, were the most prevalent in ASCUS/low-grade SIL (36.8, 10.5 and 15.8 %, respectively) and high-grade SIL (28.6, 14.3 and 14.3 %, respectively), whilst HPV62, -66, and -72 were mainly prevalent among ASCUS/low-grade SIL. Conversely, HPV type-specific prevalence among the 12 HIV-negative cytologically normal women, the six ASCUS/low-grade SIL and the two high-grade SIL showed only HPV16 as the most common (33.3, 50 and 100 %, respectively) among all groups, whilst other high-risk, undetermined and low-risk types were underrepresented.
Among the 33 HIV-positive women with cytological abnormalities, two out of 19 with low-grade SIL and one out of 14 with high-grade SIL were treated by laser ablation during the follow-up; furthermore, six out of 14 were treated by excision therapy (conization in one woman and loop electrosurgical excision in five women). Persistence of HPV infection and recurrence of SIL were observed in all treated HIV-positive women independent of the HPV category risk (Fig. 1). None of the eight HIV-negative women with SIL underwent ablative or excisional treatment during the follow-up, as the higher cytological/histological abnormality status was identified in the last visit.
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, HPV16 isolates obtained from 18 HIV-positive and eight HIV-negative women were classified into variant lineages based on sequencing analysis of whole E6 and E7 genes and the LCR region. Whilst the HPV16 G350 European variant was prevalent in both HIV-positive (66.7 % of HPV16 isolates) and HIV-negative women (50 % of HPV16 isolates), the HPV16 African 2 (Af2) variant was only detected in HIV-positive women (22.2 % of HPV16 isolates), suggesting different sexual mixing behaviours between HIV-positive and HIV-negative women. Among women who had more than one HPV16-positive visit (92.3 %), the initial HPV16 variant continued to be detected at the follow-up visits. Furthermore, no co-infections with different HPV16 variants were detected either at the baseline or during the follow-up.
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, HPV DNA was detected in 30.6 % of HIV-positive women with CD4+ counts of >500 copies µl–1, in 42.8 % of women with CD4+ counts of 200–500 copies µl–1 and in 26.5 % of women with CD4+ counts of <200 copies µl–1; none of these differences reached statistical significance (P>0.05), although a trend was observed with levels of immune suppression (P trend=0.208). Furthermore, no significant difference in HPV prevalence was observed between HIV-positive women treated by mono/combination therapy (P=0.386), whilst a borderline difference was observed between women treated by highly active antiretroviral therapy (HAART) and those left untreated (P=0.068).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). The HPV prevalence at baseline of 39.3 % in HIV-positive women was consistent with previous studies performed among HIV-infected Italian women participating in the multi-institutional DIANAIDS study (Cappiello et al., 1997; Rezza et al., 1998). Overall, 20 HPV genotypes were identified, including 10 high-risk or probable high-risk viral types (types 16, 18, 31, 33, 35, 45, 52, 53, 58 and 66), four of undetermined risk (types 55, 62, 83 and 84) and six low-risk viruses (types 6, 54, 61, 70, 72 and 81). Fifteen of the 20 HPV genotypes were common to both groups of women. Of the remaining five genotypes, identified only in the HIV-infected women, HPV55 and -84 have never been detected in HIV-negative Italian women, whilst HPV35, -45 and -83 were identified previously in a different study among HIV-negative women with normal and low-grade SIL cytology from the same geographical region (Tornesello et al., 2006). Thus, the spectrum of HPV types detected was similar among HIV-positive and HIV-negative women, and no single HPV type, apart from HPV16, was detected in more than 20 % of the HPV-positive women in either group. Among the HIV-positive women, however, the relative distribution of HPV81 (16.3 %), -58 (10.2 %), -72 (10.2 %), -33 (8.2 %) and -62 (8.2 %) was 1.5–3-fold higher than in HIV-negative women. HPV55, -62 and -81 are not included in the most used commonly detection systems and have not been searched for in the majority of studies performed on HIV-positive women; thus, the real prevalence within different populations and the related cancer risk remains unknown (Clifford et al., 2006). In a recent study, Cerqueira et al. (2007) also reported a high prevalence of HPV81 and -62 (14 and 7.2 %, respectively) in HIV-positive Brazilian women (Cerqueira et al., 2007). Thus, the frequency of these viral types may be wider than reported to date. On the other hand, a study conducted in Rochester (New York) reported as the most common (in decreasing order of frequency) the HPV types 56, 53, 16, 58, 52, 83, 84 and 33 (Luque et al., 2006). Geographical differences in the prevalence of different HPV types may explain, in part, some of the disparities among these studies conducted in widely separated geographical areas. In this study, most women had only one HPV type detected at the time of sample collection, and only 22.5 % of HPV positivity in HPV-infected women and 10 % HPV positivity in HIV-negative women was due to infection with multiple viral types. These results probably represent an underestimate of the true number of multiple HPV infections. The advantage of direct sequence analysis is to detect all known and probably most unknown HPV types, with the possible inconvenience, in mixed HPV infections, of identifying only the dominant HPV type over others with lower viral load.
Several studies have reported that women with HIV are more likely to have abnormal Pap smear results than HIV-negative women. The DIANAIDS study group in Italy reported abnormal Pap smear results in 24 % of HIV-infected women compared with 8.9 % of HIV-negative controls (Rezza et al., 1997). In this study, among the HIV-infected group, 33 out of 112 women (29.5 %) were diagnosed with cervical cytological abnormalities: 19 (16.9 %) had ASCUS/low-grade SIL, 12.5 % had high-grade SIL and none had cancer. In contrast, 7.1 % of controls had abnormal results and only 1.8 % had high-grade SIL. HPV16 was the most represented in normal cytology (8.8 %), ASCUS/low-grade SIL (36.8 %) and high-grade SIL (28.6 %). Furthermore, in HIV-positive women, 18 % of low-grade SIL and 8 % of high-grade SIL samples were positive for undetermined-risk (HPV62) and low-risk (HPV6, -54, -72 and -81) HPV viruses. In HIV-negative women, on the other hand, only the undetermined-risk HPV62 and low-risk HPV54 were found in low-grade SIL samples, but no HPV types other than the high-risk viruses HPV16, -18 and -58 were identified in high-grade SIL samples. In contrast, Luque et al. (2006) reported that, in HIV-positive women from the New York area, the most common genotypes were HPV56, -53, -16 and -58, in descending order of prevalence, with HPV56 and -53 most commonly associated with low-grade SIL and HPV52 and -58 most commonly associated with high-grade SIL.
In agreement with previous reports, we observed that treatment failed to eradicate high-grade SIL in several HIV-infected women. Different factors may be associated with higher rates of surgical treatment failure, including high-grade cervical intraepithelial neoplasia, large lesion size, satellite HPV-related lesions, persistent HPV infection and immune depression. Thus, recurrent SIL is common among HIV-positive women, even in the HAART era, and further emphasizes the need for follow-up after surgery. Although excisional therapy is highly effective in immunocompetent patients, such treatment seems to be effective only in preventing progression to cancer, at least in the short term, in HIV-infected women (Heard et al., 2005).
A significant association between HPV infection and HIV viral load of >10 000 copies ml–1 was observed in HIV-positive women (P<0.05). The reason for this finding is unclear, but it suggests some in vivo interaction between HPV and HIV viruses, which has been shown previously in vitro (Tornesello et al., 1993; Vernon et al., 1993; Buonaguro et al., 1994). Furthermore, HPV prevalence was higher among women with higher levels of immunosuppression (CD4+ counts of 200–500 and <200), but this trend was not statistically significant (P=0.208). Several other studies have reported no significant difference in median CD4+ cell counts at enrolment between women infected with HPV16 and/or -18 and women infected with other high-risk HPV types (Luque et al., 2006). Similarly, Levi et al. (2002) reported that the mean number of HPV types did not vary according to immune status, as measured by CD4+ cell counts among HIV-positive Brazilian women. Nevertheless, in two large studies performed in the USA on the prevalence of each HPV type in HIV-positive women with different grades of immune suppression, it was observed that the prevalence and the incidence of HPV16 was more weakly associated with CD4+ cell counts than those of other HPV types (Strickler et al., 2003). This could imply that, if differences exist in the distribution of specific HPV types at different levels of immune suppression, they are not significantly evident in this and in other studies due to the relatively small sample size. On the other hand, it cannot be excluded that an impaired local immunity, not related to the number of circulating CD4+ cells, could be implicated in HPV persistence among HIV-positive women (Cardillo et al., 2001). Furthermore, HAART treatment was associated with higher prevalence of HPV infection, but this result could be due to the fact that HIV-positive women enter HAART treatment in advanced HIV disease status (i.e. CD4+ cell counts <350 cells µl–1 or HIV viral load >100 000 RNA copies ml–1).
Phylogenetic analysis based on the E6, E7 and LCR sequences of 18 HPV16 isolates from HIV-positive and eight isolates from HIV-negative women allowed the identification of Af2 variants only in four isolates obtained from HIV-positive subjects. The identification in a few HIV-positive women of certain viral genotypes (i.e. HPV55 and -84) and HPV16 Af2 variants, previously identified in high-risk West Africa women immigrants in South Italy but not in the Italian general population (Tornesello et al., 2007), suggests a different sexual mixing behaviour and mandates the need for monitoring a wider range of HPV genotypes potentially involved in cervical cytological abnormalities, particularly in HIV-positive women.
A major limitation of the present study is represented by the modest sample size and short follow-up period, hampering full evaluation of the relevance of several parameters of viral persistence or clearance, and the risk of neoplasias associated with specific HPV genotypes uncommonly detected among HIV-negative women.
In summary, several high-, low- and undetermined-risk HPV types other than HPV16 and -18 are frequently detected among women with coincident HIV infection and are often associated with abnormalities in cervical cytological results. These findings have important implications for the design of HPV vaccines and diagnostics in general, and in particular in this patient population. The consistent detection of the same HPV types and HPV16 variants in follow-up examinations also supports the hypothesis that the higher prevalence of HPV infection among HIV-positive women reflects persistence or reactivation of previously acquired HPV genotypes.
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ACKNOWLEDGEMENTS |
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Received 30 October 2007;
accepted 24 February 2008.
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