I am interested in the arms-race between viruses and hosts, from an evolutionary perspective. The antiviral mechanisms that animals have evolved and the anti-antiviral strategies that have been selected in viruses. Amazing interplay. I am also interested in the connection between infection and cancer, exemplified by papillomaviruses: how merely seven ORFs can drive crazy the clockwork of a human cell genetic program.
Co-infections by multiple Human Papillomaviruses (HPVs) are observed in approximately 6-8% of inv... more Co-infections by multiple Human Papillomaviruses (HPVs) are observed in approximately 6-8% of invasive cervical cancer (ICC) cases worldwide. But neither the presence of persistent HPVs co-infections nor their etiological role in the development of ICC is well understood. Cervical HPVs co-infections have been observed randomly, mostly in women with pre-neoplastic lesions, and only few studies have globally analyzed ICC cases. Here we explored the HPVs multiple infection patterns in a large worldwide sample of cross-sectional ICC cases. Paraffin-embedded ICC biopsy samples were tested using stringent HPV genotyping. Logistic regression models were used to identify the most likely pairwise HPV types in multiple infections. Multivariate analysis was applied to detect significant HPV co-infection patterns beyond pairwise HPVs comparison. Among 8,780 HPV DNA-positive ICC cases worldwide, 6.7% (N = 587) contained multiple HPVs. Pairwise analysis revealed that HPV16|74, HPV31|33, HPV31|44, HPV33|44 and HPV45|70 pairs were significantly more frequently found together in multiple infections compared to any other HPV type combination, which supports the occasional role of Alpha-10 LR-HPVs in cervical cancers. In contrast, HPV16|31, HPV16|45, HPV16|51 and HPV18|HPV45 pairs were significantly less frequently found together than with any other HPV pair combination. Multivariate analysis sustained the results and revealed for the first time a distinct co-infection pattern in African ICCs stemming from the clustering of oncogenic HPV51/35/18/52 co-infections in African women. We suggest that the differential geographic HPVs co-infections clustering observed might be compatible with a specific modulation of the natural history/oncogenic potential of particular HPVs multiple infections and warrant monitoring for post-vaccinated.
Plasmids are nucleic acid molecules that can drive their own replication in a living cell. They c... more Plasmids are nucleic acid molecules that can drive their own replication in a living cell. They can be transmitted horizontally and can thrive in the host cell to high copy numbers. Plasmid replication and gene expression consume cellular resources and cells carrying plasmids incur fitness costs. But many plasmids carry genes that can be beneficial under certain conditions, allowing the cell to endure in the presence of antibiotics, toxins, competitors or parasites. Horizontal transfer of plasmid-encoded genes can thus instantaneously confer differential adaptation to local or transient selection conditions. This conflict between cellular fitness and plasmid spread sets the scene for multilevel selection processes. We have engineered a system to study the short term evolutionary impact of different synonymous versions of a plasmid-encoded antibiotic resistance gene. Applying experimental evolution under different selection conditions and deep sequencing allowed us to show rapid local adaptation to the presence of antibiotic and to the specific version of the resistance gene transferred. We describe the presence of clonal interference at two different levels: at the within-cell level, because a single cell can carry several plasmids, and at the between-cell level, because a bacterial population may contain several clones carrying different plasmids and displaying different fitness in the presence|absence of antibiotic. Understanding the within-cell and between-cell dynamics of plasmids after horizontal gene transfer is essential to unravel the dense network of mobile elements underlying the worldwide threat to public health of antibiotic resistance.
Human Papillomavirus 16 (HPV16) causes 70% of invasive cervical cancers (ICC) worldwide. Interact... more Human Papillomavirus 16 (HPV16) causes 70% of invasive cervical cancers (ICC) worldwide. Interaction between HPV16 genetic diversity, host genetics and target tissue largely determine the chances to trigger carcinogenesis. We have analyzed the differential prevalence of viral variants in 233 HPV16-monoinfected squamous (SCC), glandular (ADC) and mixed (ADSC) ICCs from four continents, assessing the contribution of geographical origin and cancer histology. We have further quantified the contribution of viral variants and cancer histology to differences in age at tumor diagnosis. The model fitted to the data explained 97% of the total variance: the largest explanatory factors were differential abundance among HPV16 variants (78%) and their interaction with cancer histology (9.2%) and geography (10.1%). HPV16_A1-3 variants were more prevalent in SCC while HPV16_D variants were increased in glandular ICCs. We confirm further a non-random geographical structure of the viral variants distribution. ADCs were diagnosed at younger ages than SCCs, independently of the viral variant triggering carcinogenesis. HPV16 variants are differentially associated with histological ICCs types, and ADCs are systematically diagnosed in younger women. Our results have implications for the implementation of cervical cancer screening algorithms, to ensure proper early detection of elusive ADCs.
Invasive penile cancer is a rare disease with an approximately 22 000 cases per year. The inciden... more Invasive penile cancer is a rare disease with an approximately 22 000 cases per year. The incidence is higher in less developed countries, where penile cancer can account for up to 10% of cancers among men in some parts of Africa, South America, and Asia. To describe the human papillomavirus (HPV) DNA prevalence, HPV type distribution, and detection of markers of viral activity (ie, E6*I mRNA and p16(INK4a)) in a series of invasive penile cancers and penile high-grade squamous intraepithelial lesions (HGSILs) from 25 countries. A total of 85 penile HGSILs and 1010 penile invasive cancers diagnosed from 1983 to 2011 were included. After histopathologic evaluation of formalin-fixed paraffin-embedded samples, HPV DNA detection and genotyping were performed using the SPF-10/DEIA/LiPA25 system, v.1 (Laboratory Biomedical Products, Rijswijk, The Netherlands). HPV DNA-positive cases were additionally tested for oncogene E6*I mRNA and all cases for p16(INK4a) expression, a surrogate marker of oncogenic HPV activity. HPV DNA prevalence and type distributions were estimated. HPV DNA was detected in 33.1% of penile cancers (95% confidence interval [CI], 30.2-36.1) and in 87.1% of HGSILs (95% CI, 78.0-93.4). The warty-basaloid histologic subtype showed the highest HPV DNA prevalence. Among cancers, statistically significant differences in prevalence were observed only by geographic region and not by period or by age at diagnosis. HPV16 was the most frequent HPV type detected in both HPV-positive cancers (68.7%) and HGSILs (79.6%). HPV6 was the second most common type in invasive cancers (3.7%). The p16(INK4a) upregulation and mRNA detection in addition to HPV DNA positivity were observed in 69.3% of HGSILs, and at least one of these HPV activity markers was detected in 85.3% of cases. In penile cancers, these figures were 22.0% and 27.1%, respectively. About a third to a fourth of penile cancers were related to HPV when considering HPV DNA detection alone or adding an HPV activity marker, respectively. The observed HPV type distribution reinforces the potential benefit of current and new HPV vaccines in the reduction of HPV-related penile neoplastic lesions. About one-third to one-quarter of penile cancers were related to human papillomavirus (HPV). The observed HPV type distribution reinforces the potential benefit of current and new HPV vaccines to prevent HPV-related penile neoplastic lesions.
Every human suffers through life a number of papillomaviruses (PVs) infections, most of them asym... more Every human suffers through life a number of papillomaviruses (PVs) infections, most of them asymptomatic. A notable exception are persistent infections by Human Papillomavirus 16 (HPV16), the most oncogenic infectious agent for humans and responsible for most infection-driven anogenital cancers. Oncogenic potential is not homogeneous among HPV16 lineages, and genetic variation within HPV16 exhibits some geographic structure. However, an in-depth analysis of the HPV16 evolutionary history is still wanting. We have analysed extant HPV16 diversity and compared the evolutionary and phylogeographical patterns of humans and of HPV16. We show that codivergence with modern humans explains at most 30% of the present viral geographical distribution. The most explanatory scenario suggests that ancestral HPV16 already infected ancestral human populations, and that viral lineages co-diverged with the hosts in parallel with the split between archaic Neanderthal-Denisovans and ancestral modern human populations, generating the ancestral HPV16A and HPV16BCD viral lineages, respectively. We propose that after out-of-Africa migration of modern human ancestors, sexual transmission between human populations introduced HPV16A into modern human ancestor populations. We hypothesise that differential coevolution of HPV16 lineages with different but closely related ancestral human populations and subsequent host-switch events in parallel with introgression of archaic alleles into the genomes of modern human ancestors may be largely responsible for the present-day differential prevalence and association with cancers for HPV16 variants.
Human papillomavirus (HPV)16 is the most oncogenic human papillomavirus, responsible for most pap... more Human papillomavirus (HPV)16 is the most oncogenic human papillomavirus, responsible for most papillomavirus-induced anogenital cancers. We have explored by sequencing and phylogenetic analysis the viral variant lineages present in 692 HPV16-monoinfected invasive anogenital cancers from Europe, Asia, and Central/South America. We have assessed the contribution of geography and anatomy to the differential prevalence of HPV16 variants and to the nonsynonymous E6 T350G polymorphism. Most (68%) of the variance in the distribution of HPV16 variants was accounted for by the differential abundance of the different viral lineages. The most prevalent variant (above 70% prevalence) in all regions and in all locations was HPV16_A1-3, except in Asia, where HPV16_A4 predominated in anal cancers. The differential prevalence of variants as a function of geographical origin explained 9% of the variance, and the differential prevalence of variants as a function of anatomical location accounted for less than 3% of the variance. Despite containing similar repertoires of HPV16 variants, we confirm the worldwide trend of cervical cancers being diagnosed significantly earlier than other anogenital cancers (early fifties vs. early sixties). Frequencies for alleles in the HPV16 E6 T350G polymorphism were similar across anogenital cancers from the same geographical origin. Interestingly, anogenital cancers from Central/South America displayed higher 350G allele frequencies also within HPV16_A1-3 lineage compared with Europe. Our results demonstrate ample variation in HPV16 variants prevalence in anogenital cancers, which is partly explained by the geographical origin of the sample and only marginally explained by the anatomical location of the lesion, suggesting that tissue specialization is not essential evolutionary forces shaping HPV16 diversity in anogenital cancers.
Human papillomavirus (HPV)16 is the most oncogenic human papillomavirus, responsible for most pap... more Human papillomavirus (HPV)16 is the most oncogenic human papillomavirus, responsible for most papillomavirus-induced anogenital cancers. We have explored by sequencing and phylogenetic analysis the viral variant lineages present in 692 HPV16-monoinfected invasive anogenital cancers from Europe, Asia, and Central/South America. We have assessed the contribution of geography and anatomy to the differential prevalence of HPV16 variants and to the nonsynonymous E6 T350G polymorphism. Most (68%) of the variance in the distribution of HPV16 variants was accounted for by the differential abundance of the different viral lineages. The most prevalent variant (above 70% prevalence) in all regions and in all locations was HPV16_A1-3, except in Asia, where HPV16_A4 predominated in anal cancers. The differential prevalence of variants as a function of geographical origin explained 9% of the variance, and the differential prevalence of variants as a function of anatomical location accounted for less than 3% of the variance. Despite containing similar repertoires of HPV16 variants, we confirm the worldwide trend of cervical cancers being diagnosed significantly earlier than other anogenital cancers (early fifties vs. early sixties). Frequencies for alleles in the HPV16 E6 T350G polymorphism were similar across anogenital cancers from the same geographical origin. Interestingly, anogenital cancers from Central/South America displayed higher 350G allele frequencies also within HPV16_A1-3 lineage compared with Europe. Our results demonstrate ample variation in HPV16 variants prevalence in anogenital cancers, which is partly explained by the geographical origin of the sample and only marginally explained by the anatomical location of the lesion, suggesting that tissue specialization is not essential evolutionary forces shaping HPV16 diversity in anogenital cancers.
Human Papillomaviruses (HPVs) are involved in the etiology of anogenital and head and neck cancer... more Human Papillomaviruses (HPVs) are involved in the etiology of anogenital and head and neck cancers. The HPV DNA prevalence greatly differs by anatomical site. Indeed, the high rates of viral DNA prevalence in anal and cer-vical carcinomas contrast with the lower fraction of cancer cases attributable to HPVs in other anatomical sites, chiefly the vulva, the penis and head and neck. Here we analyzed 2635 Formalin Fixed Paraffin Embedded surgical samples that had previously tested negative for the presence of HPVs DNA using the SPF10/DEIA procedure, in order to identify the presence of other PVs not explicitly targeted by standard molecular epidemiologic approaches. All samples were reanalyzed using five broad-PV PCR primer sets (CP1/2, FAP6064/FAP64, SKF/SKR, MY9/MY11, MFI/MFII) targeting the main PV main clades. In head and neck carcinoma samples (n = 1141), we recovered DNA from two BetaHPVs, namely HPV20 and HPV21, and from three cutaneous AlphaPVs, namely HPV2, HPV57 and HPV61. In vulvar squamous cell carcinoma samples (n = 902), we found one of the samples containing DNA of one cutaneous HPV, namely HPV2, and 29 samples contained DNA from essentially mucosal HPVs. In penile squamous cell carcinoma samples (n = 592), we retrieved the DNA of HPV16 in 16 samples. Our results show first that the SPF10/DEIA is very sensitive, as we recovered only 2.1% (55/2635) false negative results; second, that although the DNA of cutaneous HPVs can be detected in cancer samples, their relative contribution remains anyway minor (0.23%; 6/2635) and may be neglected for screening and vaccination purposes; and third, their contribution to malignancy is not necessarily warranted and needs to be elucidated.
Background: Feline immunodeficiency virus (FIV) is a global pathogen of Felidae species and a mod... more Background: Feline immunodeficiency virus (FIV) is a global pathogen of Felidae species and a model system for Human immunodeficiency virus (HIV)‑induced AIDS. In felids such as the domestic cat (Felis catus), APOBEC3 (A3) genes encode for single‑domain A3Z2s, A3Z3 and double‑domain A3Z2Z3 anti‑viral cytidine deaminases. The feline A3Z2Z3 is expressed following read‑through transcription and alternative splicing, introducing a previously untrans‑ lated exon in frame, encoding a domain insertion called linker. Only A3Z3 and A3Z2Z3 inhibit Vif‑deficient FIV. Feline A3s also are restriction factors for HIV and Simian immunodeficiency viruses (SIV). Surprisingly, HIV‑2/SIV Vifs can counteract feline A3Z2Z3. Results: To identify residues in feline A3s that Vifs need for interaction and degradation, chimeric human–feline A3s were tested. Here we describe the molecular direct interaction of feline A3s with Vif proteins from cat FIV and present the first structural A3 model locating these interaction regions. In the Z3 domain we have identified residues involved in binding of FIV Vif, and their mutation blocked Vif‑induced A3Z3 degradation. We further identified additional essen‑ tial residues for FIV Vif interaction in the A3Z2 domain, allowing the generation of FIV Vif resistant A3Z2Z3. Mutated feline A3s also showed resistance to the Vif of a lion‑specific FIV, indicating an evolutionary conserved Vif–A3 binding. Comparative modelling of feline A3Z2Z3 suggests that the residues interacting with FIV Vif have, unlike Vif‑interacting residues in human A3s, a unique location at the domain interface of Z2 and Z3 and that the linker forms a homeobox‑ like domain protruding of the Z2Z3 core. HIV‑2/SIV Vifs efficiently degrade feline A3Z2Z3 by possible targeting the linker stretch connecting both Z‑domains. Conclusions: Here we identified in feline A3s residues important for binding of FIV Vif and a unique protein domain insertion (linker). To understand Vif evolution, a structural model of the feline A3 was developed. Our results show that HIV Vif binds human A3s differently than FIV Vif feline A3s. The linker insertion is suggested to form a homeo‑box domain, which is unique to A3s of cats and related species, and not found in human and mouse A3s. Together, these findings indicate a specific and different A3 evolution in cats and human.
Background: No reports exist on genotype-specific human papillomavirus (HPV) acquisition in girls... more Background: No reports exist on genotype-specific human papillomavirus (HPV) acquisition in girls after first sex in sub-Saharan Africa, despite high HPV prevalence and cer-vical cancer incidence. Methods: We followed 503 HP-unvaccinated girls aged 15-16 years in Mwanza, Tanzania, 3-monthly for 18 months with interviews and self-administered vaginal swabs. Swabs were tested for 13 higHRisk and 24 low-risk HPV genotypes. Incidence, clearance and duration of overall HPV and genotype-specific infections were calculated and associated factors evaluated. Results: A total of 106 participants reported first sex prior to enrolment (N ¼ 29) or during follow-up (N ¼ 77). One was HIV-positive at the final visit. The remaining 105 girls contributed 323 adequate specimens. Incidence of any new HPV genotype was 225/100 person-years (pys), and incidence of vaccine types HPV-6,-11,-16 and-18 were 12, 2, 2 and 7/100 pys, respectively. Reporting sex in the past 3 months and knowing the most recent sexual partner for a longer period before sex were associated with HPV acquisition. Median time from reported sexual debut to first HPVinfection was 5 months, and infection duration was 6 months. Conclusion: This is the first description of HPV acquisition after first sex in sub-Saharan Africa where the incidence of cervical cancer is amongst the highest in the world. HPV incidence was very high after first sex, including some vaccine genotypes, and infection duration was short. This very high HPV incidence may help explain high cervical cancer rates, and supports recommendations that the HPV vaccine should be given to girls before first sex.
Background: The increasing abundance of sequence data has exacerbated a long known problem: gene ... more Background: The increasing abundance of sequence data has exacerbated a long known problem: gene trees and species trees for the same terminal taxa are often incongruent. Indeed, genes within a genome have not all followed the same evolutionary path due to events such as incomplete lineage sorting, horizontal gene transfer, gene duplication and deletion, or recombination. Considering conflicts between gene trees as an obstacle, numerous methods have been developed to deal with these incongruences and to reconstruct consensus evolutionary histories of species despite the heterogeneity in the history of their genes. However, inconsistencies can also be seen as a source of information about the specific evolutionary processes that have shaped genomes. Results: The goal of the approach here proposed is to exploit this conflicting information: we have compiled eleven variables describing phylogenetic relationships and evolutionary pressures and submitted them to dimensionality reduction techniques to identify genes with similar evolutionary histories. To illustrate the applicability of the method, we have chosen two viral datasets, namely papillomaviruses and Turnip mosaic virus (TuMV) isolates, largely dissimilar in genome, evolutionary distance and biology. Our method pinpoints viral genes with common evolutionary patterns. In the case of papillomaviruses, gene clusters match well our knowledge on viral biology and life cycle, illustrating the potential of our approach. For the less known TuMV, our results trigger new hypotheses about viral evolution and gene interaction. Conclusions: The approach here presented allows turning phylogenetic inconsistencies into evolutionary information, detecting gene assemblies with similar histories, and could be a powerful tool for comparative pathogenomics.
Background: We conducted a large international study to estimate fractions of head and neck cance... more Background: We conducted a large international study to estimate fractions of head and neck cancers (HNCs) attributable to human papillomavirus (HPV-AFs) using six HPV-related biomarkers of viral detection, transcription, and cellular transformation.
Background: Invasive penile cancer is a rare disease with an approximately 22 000 cases per year... more Background: Invasive penile cancer is a rare disease with an approximately 22 000 cases per year. The incidence is higher in less developed countries, where penile cancer can account for up to 10% of cancers among men in some parts of Africa, South America, and Asia. Objective: To describe the human papillomavirus (HPV) DNA prevalence, HPV type distribution, and detection of markers of viral activity (ie, E6*I mRNA and p16 INK4a) in a series of invasive penile cancers and penile high-grade squamous intraepithelial lesions (HGSILs) from 25 countries. A total of 85 penile HGSILs and 1010 penile invasive cancers diagnosed from 1983 to 2011 were included. Design, setting, and participants: After histopathologic evaluation of formalin-fixed paraffin-embedded samples, HPV DNA detection and genotyping were performed using
Purpose: Acquisition of human papillomavirus (HPV) in women occurs predominantly through
vaginal ... more Purpose: Acquisition of human papillomavirus (HPV) in women occurs predominantly through vaginal sex. However, HPV has been detected in girls reporting no previous sex. We aimed to determine incidence and risk factors for HPV acquisition in girls who report no previous sex in Tanzania, a country with high HPV prevalence and cervical cancer incidence. Methods: We followed 503 adolescent girls aged 15e16 years in Mwanza, Tanzania, with face-toface interviews and self-administered vaginal swabs every 3 months for 18 months; 397 girls reported no sex before enrollment or during follow-up; of whom, 120 were randomly selected. Samples from enrollment, 6-, 12-, and 18-month visits were tested for 37 HPV genotypes. Incidence, clearance, point prevalence, and duration of any HPV and genotype-specific infections were calculated and associated factors were evaluated. Results: Of 120 girls who reported no previous sex, 119 were included, contributing 438 samples. HPV was detected in 51 (11.6%) samples. The overall incidence of new HPV infections was 29.4/100 person-years (95% confidence interval: 15.9e54.2). The point prevalence of vaccine types HPV-6,- 11,-16, and -18 was .9%, .9%, 2.0%, and 0%, respectively. Spending a night away from home and using the Internet were associated with incident HPV, and reporting having seen a pornographic movie was inversely associated with HPV incidence. Conclusions: Incident HPV infections were detected frequently in adolescent girls who reported no previous sex over 18 months. This is likely to reflect under-reporting of sex. A low-point prevalence of HPV genotypes in licensed vaccines was seen, indicating that vaccination of these girls might still be effective.
Viruses rely completely on the hosts' machinery for translation of viral transcripts. However, fo... more Viruses rely completely on the hosts' machinery for translation of viral transcripts. However, for most viruses infecting humans, codon usage preferences (CUPrefs) do not match those of the host. Human papillomaviruses (HPVs) are a showcase to tackle this paradox: they present a large genotypic diversity and a broad range of phenotypic presentations, from asymptomatic infections to productive lesions and cancer. By applying phylogenetic inference and dimensionality reduction methods, we demonstrate first that genes in HPVs are poorly adapted to the average human CUPrefs, the only exception being capsid genes in viruses causing productive lesions. Phylogenetic relationships between HPVs explained only a small proportion of CUPrefs variation. Instead, the most important explanatory factor for viral CUPrefs was infection phenotype, as orthologous genes in viruses with similar clinical presentation displayed similar CUPrefs. Moreover, viral genes with similar spatio-temporal expression patterns showed also similar CUPrefs. Our results suggest that CUPrefs in HPVs reflect either variations in the mutation bias or differential selection pressures depending on the clinical presentation and expression timing. We propose that poor viral CUPrefs may be central to a trade-off between strong viral gene expression and the potential for eliciting protective immune response.
Anal condylomata are common in HIV-positive individuals and among men who have sex with men (MSM)... more Anal condylomata are common in HIV-positive individuals and among men who have sex with men (MSM). Generally attributable to infection by low-risk human papillomaviruses (HPVs), condylomata are considered benign low-grade squamous intraepithelial lesions (SILs). However, anal condylomata have occasionally been linked to high-grade SIL and to oncogenic, high-risk HPVs. Here we describe the range of intraepithelial lesions and of the associated HPVs in heterosexual men and women and MSM. Perianal and anal condylomata were collected from 243 patients (56 heterosexual women, 61 heterosexual men and 126 MSM, including 41 HIV-positive MSM). We assessed lesion histology and HPV genotype. Prevalence estimates and Poisson models were used. Irrespective of HIV infection status, MSM showed a higher proportion of condylomata as high-grade SILs compared to heterosexual men/women. High-grade SILs were also more prevalent in anal than in perianal lesions in all patient groups. HIV-positive MSM exhibited increased prevalence ratio (4.6; 95% con!dence interval 2.1–10.0) of perianal low-grade SILs containing only high-risk HPVs compared to HIV-negative MSM. In addition, more than 64% of anal SILs with a high-grade component, regardless of HIV infection, were exclusively associated with low-risk HPVs. In anal condylomata, both high-grade and low-grade SILs can be associated with high-risk and/or low-risk HPVs. Particularly, low-grade perianal SILs associated with high-risk HPVs were common in HIV-positive MSM, while presence of only low-risk HPVs in high-grade SILs were common in both MSM groups. Our !ndings sound a note of caution for the common clinical practice for the treatment of anal condylomata as benign lesions in MSM and HIV-positive patients.
The Vulpes vulpes papillomavirus type 1, VvulPV1, genome is
7,519-bp in length and shows classica... more The Vulpes vulpes papillomavirus type 1, VvulPV1, genome is 7,519-bp in length and shows classical PV structure: an upstream regulatory region, the early genes E6, E7, E1, and E2, and the late ones, L2 and L1, and misses any E5 gene (3). Maximum likelihood phylogenetic analyses, all using the E1E2, L2L1, or E1E2L2L1 gene concatenates, place VvulPV1 as a basal, sister taxon to Gammapapillomavirus (GammaPV) genus, both at nucleotide and amino acid levels. GammaPV is the largest, and still expanding, PV genus (1). This genus includes PVs found exclusively in humans, retrieved from hair follicles, healthy skin and mucosa, and lesions in skin and mucosa. The closest relative to VvulPV1 is HPV180, a member of GammaPV species 10, based on the L1 nucleotide sequence sharing 63% identity. The average identity on the L1 gene of VvulPV1 with all members of the GammaPV genus is 59.2%. Regarding the rest of the genome, the less conserved gene is E6 and the more conserved gene is E1, respectively, sharing on average 47.2% and 60.4% identity at the nucleotide level with other members of the GammaPV genus. Sticking to the present rules for PV classification (4, 5) VvulPV1 should belong to the GammaPV genus, as nucleotide identity to its closest relative based on L1 is marginally above the 60% threshold.
Papillomaviruses (PVs) are a numerous family of small dsDNA viruses infecting virtually all mamma... more Papillomaviruses (PVs) are a numerous family of small dsDNA viruses infecting virtually all mammals. PVs cause infections without triggering a strong immune response, and natural infection provides only limited protection against reinfection. Most PVs are part and parcel of the skin microbiota. In some cases, infections by certain PVs take diverse clinical presentations from highly productive self-limited warts to invasive cancers. We propose PVs as an excellent model system to study the evolutionary interactions between the immune system and pathogens causing chronic infections: genotypically, PVs are very diverse, with hundreds of different genotypes infecting skin and mucosa; phenotypically, they display extremely broad gradients and trade-offs between key phenotypic traits, namely productivity, immunogenicity, prevalence, oncogenicity and clinical presentation. Public health interventions have been launched to decrease the burden of PV-associated cancers, including massive vaccination against the most oncogenic human PVs, as well as systematic screening for PV chronic anogenital infections. Anti-PVs vaccines elicit protection against infection, induce cross-protection against closely related viruses and result in herd immunity. However, our knowledge on the ecological and intrapatient dynamics of PV infections remains fragmentary. We still need to understand how the novel anthropogenic selection pressures posed by vaccination and screening will affect viral circulation and epidemiology. We present here an overview of PV evolution and the connection between PV genotypes and the phenotypic, clinical manifestations of the diseases they cause. This differential link between viral evolution and the gradient cancer-warts-asymptomatic infections makes PVs a privileged playground for evolutionary medicine research.
Background/Aim: Great controversy exists about
the association between Human Papillomavirus (HPV)... more Background/Aim: Great controversy exists about the association between Human Papillomavirus (HPV) and breast tumors. The aim of this study was to explore the presence of HPV DNA in a large set of breast cancer cases. Materials and Methods: Techniques used followed the standards for an international retrospective survey of HPVDNA genotyping, coordinated by our own group and the DDL Laboratories in Rijswijk, the Netherlands. Paraffinembedded samples were used. SPF-10 broad-spectrum primers were applied, followed by deoxyribonucleic acid enzyme immunoassay and genotyping by reverse-line probe assay. Results: A total of 78 samples were included in the study, 2 of benign conditions and 76 carcinomas, including different histological subtypes. HPV was not present in any of the specimens studied irrespective of histology, hormonal status and stage of disease. Conclusion: Our data do not support the involvement of HPV in breast carcinogenesis as no evidence of its presence was found.
AIM:
This work describes the human papillomavirus (HPV) prevalence and the HPV type distributi... more AIM:
This work describes the human papillomavirus (HPV) prevalence and the HPV type distribution in a large series of vaginal intraepithelial neoplasia (VAIN) grades 2/3 and vaginal cancer worldwide.
METHODS:
We analysed 189 VAIN 2/3 and 408 invasive vaginal cancer cases collected from 31 countries from 1986 to 2011. After histopathological evaluation of sectioned formalin-fixed paraffin-embedded samples, HPV DNA detection and typing was performed using the SPF-10/DNA enzyme immunoassay (DEIA)/LiPA25 system (version 1). A subset of 146 vaginal cancers was tested for p16INK4a expression, a cellular surrogate marker for HPV transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance.
RESULTS:
HPV DNA was detected in 74% (95% confidence interval (CI): 70-78%) of invasive cancers and in 96% (95% CI: 92-98%) of VAIN 2/3. Among cancers, the highest detection rates were observed in warty-basaloid subtype of squamous cell carcinomas, and in younger ages. Concerning the type-specific distribution, HPV16 was the most frequently type detected in both precancerous and cancerous lesions (59%). p16INK4a overexpression was found in 87% of HPV DNA positive vaginal cancer cases.
CONCLUSIONS:
HPV was identified in a large proportion of invasive vaginal cancers and in almost all VAIN 2/3. HPV16 was the most common type detected. A large impact in the reduction of the burden of vaginal neoplastic lesions is expected among vaccinated cohorts.
Co-infections by multiple Human Papillomaviruses (HPVs) are observed in approximately 6-8% of inv... more Co-infections by multiple Human Papillomaviruses (HPVs) are observed in approximately 6-8% of invasive cervical cancer (ICC) cases worldwide. But neither the presence of persistent HPVs co-infections nor their etiological role in the development of ICC is well understood. Cervical HPVs co-infections have been observed randomly, mostly in women with pre-neoplastic lesions, and only few studies have globally analyzed ICC cases. Here we explored the HPVs multiple infection patterns in a large worldwide sample of cross-sectional ICC cases. Paraffin-embedded ICC biopsy samples were tested using stringent HPV genotyping. Logistic regression models were used to identify the most likely pairwise HPV types in multiple infections. Multivariate analysis was applied to detect significant HPV co-infection patterns beyond pairwise HPVs comparison. Among 8,780 HPV DNA-positive ICC cases worldwide, 6.7% (N = 587) contained multiple HPVs. Pairwise analysis revealed that HPV16|74, HPV31|33, HPV31|44, HPV33|44 and HPV45|70 pairs were significantly more frequently found together in multiple infections compared to any other HPV type combination, which supports the occasional role of Alpha-10 LR-HPVs in cervical cancers. In contrast, HPV16|31, HPV16|45, HPV16|51 and HPV18|HPV45 pairs were significantly less frequently found together than with any other HPV pair combination. Multivariate analysis sustained the results and revealed for the first time a distinct co-infection pattern in African ICCs stemming from the clustering of oncogenic HPV51/35/18/52 co-infections in African women. We suggest that the differential geographic HPVs co-infections clustering observed might be compatible with a specific modulation of the natural history/oncogenic potential of particular HPVs multiple infections and warrant monitoring for post-vaccinated.
Plasmids are nucleic acid molecules that can drive their own replication in a living cell. They c... more Plasmids are nucleic acid molecules that can drive their own replication in a living cell. They can be transmitted horizontally and can thrive in the host cell to high copy numbers. Plasmid replication and gene expression consume cellular resources and cells carrying plasmids incur fitness costs. But many plasmids carry genes that can be beneficial under certain conditions, allowing the cell to endure in the presence of antibiotics, toxins, competitors or parasites. Horizontal transfer of plasmid-encoded genes can thus instantaneously confer differential adaptation to local or transient selection conditions. This conflict between cellular fitness and plasmid spread sets the scene for multilevel selection processes. We have engineered a system to study the short term evolutionary impact of different synonymous versions of a plasmid-encoded antibiotic resistance gene. Applying experimental evolution under different selection conditions and deep sequencing allowed us to show rapid local adaptation to the presence of antibiotic and to the specific version of the resistance gene transferred. We describe the presence of clonal interference at two different levels: at the within-cell level, because a single cell can carry several plasmids, and at the between-cell level, because a bacterial population may contain several clones carrying different plasmids and displaying different fitness in the presence|absence of antibiotic. Understanding the within-cell and between-cell dynamics of plasmids after horizontal gene transfer is essential to unravel the dense network of mobile elements underlying the worldwide threat to public health of antibiotic resistance.
Human Papillomavirus 16 (HPV16) causes 70% of invasive cervical cancers (ICC) worldwide. Interact... more Human Papillomavirus 16 (HPV16) causes 70% of invasive cervical cancers (ICC) worldwide. Interaction between HPV16 genetic diversity, host genetics and target tissue largely determine the chances to trigger carcinogenesis. We have analyzed the differential prevalence of viral variants in 233 HPV16-monoinfected squamous (SCC), glandular (ADC) and mixed (ADSC) ICCs from four continents, assessing the contribution of geographical origin and cancer histology. We have further quantified the contribution of viral variants and cancer histology to differences in age at tumor diagnosis. The model fitted to the data explained 97% of the total variance: the largest explanatory factors were differential abundance among HPV16 variants (78%) and their interaction with cancer histology (9.2%) and geography (10.1%). HPV16_A1-3 variants were more prevalent in SCC while HPV16_D variants were increased in glandular ICCs. We confirm further a non-random geographical structure of the viral variants distribution. ADCs were diagnosed at younger ages than SCCs, independently of the viral variant triggering carcinogenesis. HPV16 variants are differentially associated with histological ICCs types, and ADCs are systematically diagnosed in younger women. Our results have implications for the implementation of cervical cancer screening algorithms, to ensure proper early detection of elusive ADCs.
Invasive penile cancer is a rare disease with an approximately 22 000 cases per year. The inciden... more Invasive penile cancer is a rare disease with an approximately 22 000 cases per year. The incidence is higher in less developed countries, where penile cancer can account for up to 10% of cancers among men in some parts of Africa, South America, and Asia. To describe the human papillomavirus (HPV) DNA prevalence, HPV type distribution, and detection of markers of viral activity (ie, E6*I mRNA and p16(INK4a)) in a series of invasive penile cancers and penile high-grade squamous intraepithelial lesions (HGSILs) from 25 countries. A total of 85 penile HGSILs and 1010 penile invasive cancers diagnosed from 1983 to 2011 were included. After histopathologic evaluation of formalin-fixed paraffin-embedded samples, HPV DNA detection and genotyping were performed using the SPF-10/DEIA/LiPA25 system, v.1 (Laboratory Biomedical Products, Rijswijk, The Netherlands). HPV DNA-positive cases were additionally tested for oncogene E6*I mRNA and all cases for p16(INK4a) expression, a surrogate marker of oncogenic HPV activity. HPV DNA prevalence and type distributions were estimated. HPV DNA was detected in 33.1% of penile cancers (95% confidence interval [CI], 30.2-36.1) and in 87.1% of HGSILs (95% CI, 78.0-93.4). The warty-basaloid histologic subtype showed the highest HPV DNA prevalence. Among cancers, statistically significant differences in prevalence were observed only by geographic region and not by period or by age at diagnosis. HPV16 was the most frequent HPV type detected in both HPV-positive cancers (68.7%) and HGSILs (79.6%). HPV6 was the second most common type in invasive cancers (3.7%). The p16(INK4a) upregulation and mRNA detection in addition to HPV DNA positivity were observed in 69.3% of HGSILs, and at least one of these HPV activity markers was detected in 85.3% of cases. In penile cancers, these figures were 22.0% and 27.1%, respectively. About a third to a fourth of penile cancers were related to HPV when considering HPV DNA detection alone or adding an HPV activity marker, respectively. The observed HPV type distribution reinforces the potential benefit of current and new HPV vaccines in the reduction of HPV-related penile neoplastic lesions. About one-third to one-quarter of penile cancers were related to human papillomavirus (HPV). The observed HPV type distribution reinforces the potential benefit of current and new HPV vaccines to prevent HPV-related penile neoplastic lesions.
Every human suffers through life a number of papillomaviruses (PVs) infections, most of them asym... more Every human suffers through life a number of papillomaviruses (PVs) infections, most of them asymptomatic. A notable exception are persistent infections by Human Papillomavirus 16 (HPV16), the most oncogenic infectious agent for humans and responsible for most infection-driven anogenital cancers. Oncogenic potential is not homogeneous among HPV16 lineages, and genetic variation within HPV16 exhibits some geographic structure. However, an in-depth analysis of the HPV16 evolutionary history is still wanting. We have analysed extant HPV16 diversity and compared the evolutionary and phylogeographical patterns of humans and of HPV16. We show that codivergence with modern humans explains at most 30% of the present viral geographical distribution. The most explanatory scenario suggests that ancestral HPV16 already infected ancestral human populations, and that viral lineages co-diverged with the hosts in parallel with the split between archaic Neanderthal-Denisovans and ancestral modern human populations, generating the ancestral HPV16A and HPV16BCD viral lineages, respectively. We propose that after out-of-Africa migration of modern human ancestors, sexual transmission between human populations introduced HPV16A into modern human ancestor populations. We hypothesise that differential coevolution of HPV16 lineages with different but closely related ancestral human populations and subsequent host-switch events in parallel with introgression of archaic alleles into the genomes of modern human ancestors may be largely responsible for the present-day differential prevalence and association with cancers for HPV16 variants.
Human papillomavirus (HPV)16 is the most oncogenic human papillomavirus, responsible for most pap... more Human papillomavirus (HPV)16 is the most oncogenic human papillomavirus, responsible for most papillomavirus-induced anogenital cancers. We have explored by sequencing and phylogenetic analysis the viral variant lineages present in 692 HPV16-monoinfected invasive anogenital cancers from Europe, Asia, and Central/South America. We have assessed the contribution of geography and anatomy to the differential prevalence of HPV16 variants and to the nonsynonymous E6 T350G polymorphism. Most (68%) of the variance in the distribution of HPV16 variants was accounted for by the differential abundance of the different viral lineages. The most prevalent variant (above 70% prevalence) in all regions and in all locations was HPV16_A1-3, except in Asia, where HPV16_A4 predominated in anal cancers. The differential prevalence of variants as a function of geographical origin explained 9% of the variance, and the differential prevalence of variants as a function of anatomical location accounted for less than 3% of the variance. Despite containing similar repertoires of HPV16 variants, we confirm the worldwide trend of cervical cancers being diagnosed significantly earlier than other anogenital cancers (early fifties vs. early sixties). Frequencies for alleles in the HPV16 E6 T350G polymorphism were similar across anogenital cancers from the same geographical origin. Interestingly, anogenital cancers from Central/South America displayed higher 350G allele frequencies also within HPV16_A1-3 lineage compared with Europe. Our results demonstrate ample variation in HPV16 variants prevalence in anogenital cancers, which is partly explained by the geographical origin of the sample and only marginally explained by the anatomical location of the lesion, suggesting that tissue specialization is not essential evolutionary forces shaping HPV16 diversity in anogenital cancers.
Human papillomavirus (HPV)16 is the most oncogenic human papillomavirus, responsible for most pap... more Human papillomavirus (HPV)16 is the most oncogenic human papillomavirus, responsible for most papillomavirus-induced anogenital cancers. We have explored by sequencing and phylogenetic analysis the viral variant lineages present in 692 HPV16-monoinfected invasive anogenital cancers from Europe, Asia, and Central/South America. We have assessed the contribution of geography and anatomy to the differential prevalence of HPV16 variants and to the nonsynonymous E6 T350G polymorphism. Most (68%) of the variance in the distribution of HPV16 variants was accounted for by the differential abundance of the different viral lineages. The most prevalent variant (above 70% prevalence) in all regions and in all locations was HPV16_A1-3, except in Asia, where HPV16_A4 predominated in anal cancers. The differential prevalence of variants as a function of geographical origin explained 9% of the variance, and the differential prevalence of variants as a function of anatomical location accounted for less than 3% of the variance. Despite containing similar repertoires of HPV16 variants, we confirm the worldwide trend of cervical cancers being diagnosed significantly earlier than other anogenital cancers (early fifties vs. early sixties). Frequencies for alleles in the HPV16 E6 T350G polymorphism were similar across anogenital cancers from the same geographical origin. Interestingly, anogenital cancers from Central/South America displayed higher 350G allele frequencies also within HPV16_A1-3 lineage compared with Europe. Our results demonstrate ample variation in HPV16 variants prevalence in anogenital cancers, which is partly explained by the geographical origin of the sample and only marginally explained by the anatomical location of the lesion, suggesting that tissue specialization is not essential evolutionary forces shaping HPV16 diversity in anogenital cancers.
Human Papillomaviruses (HPVs) are involved in the etiology of anogenital and head and neck cancer... more Human Papillomaviruses (HPVs) are involved in the etiology of anogenital and head and neck cancers. The HPV DNA prevalence greatly differs by anatomical site. Indeed, the high rates of viral DNA prevalence in anal and cer-vical carcinomas contrast with the lower fraction of cancer cases attributable to HPVs in other anatomical sites, chiefly the vulva, the penis and head and neck. Here we analyzed 2635 Formalin Fixed Paraffin Embedded surgical samples that had previously tested negative for the presence of HPVs DNA using the SPF10/DEIA procedure, in order to identify the presence of other PVs not explicitly targeted by standard molecular epidemiologic approaches. All samples were reanalyzed using five broad-PV PCR primer sets (CP1/2, FAP6064/FAP64, SKF/SKR, MY9/MY11, MFI/MFII) targeting the main PV main clades. In head and neck carcinoma samples (n = 1141), we recovered DNA from two BetaHPVs, namely HPV20 and HPV21, and from three cutaneous AlphaPVs, namely HPV2, HPV57 and HPV61. In vulvar squamous cell carcinoma samples (n = 902), we found one of the samples containing DNA of one cutaneous HPV, namely HPV2, and 29 samples contained DNA from essentially mucosal HPVs. In penile squamous cell carcinoma samples (n = 592), we retrieved the DNA of HPV16 in 16 samples. Our results show first that the SPF10/DEIA is very sensitive, as we recovered only 2.1% (55/2635) false negative results; second, that although the DNA of cutaneous HPVs can be detected in cancer samples, their relative contribution remains anyway minor (0.23%; 6/2635) and may be neglected for screening and vaccination purposes; and third, their contribution to malignancy is not necessarily warranted and needs to be elucidated.
Background: Feline immunodeficiency virus (FIV) is a global pathogen of Felidae species and a mod... more Background: Feline immunodeficiency virus (FIV) is a global pathogen of Felidae species and a model system for Human immunodeficiency virus (HIV)‑induced AIDS. In felids such as the domestic cat (Felis catus), APOBEC3 (A3) genes encode for single‑domain A3Z2s, A3Z3 and double‑domain A3Z2Z3 anti‑viral cytidine deaminases. The feline A3Z2Z3 is expressed following read‑through transcription and alternative splicing, introducing a previously untrans‑ lated exon in frame, encoding a domain insertion called linker. Only A3Z3 and A3Z2Z3 inhibit Vif‑deficient FIV. Feline A3s also are restriction factors for HIV and Simian immunodeficiency viruses (SIV). Surprisingly, HIV‑2/SIV Vifs can counteract feline A3Z2Z3. Results: To identify residues in feline A3s that Vifs need for interaction and degradation, chimeric human–feline A3s were tested. Here we describe the molecular direct interaction of feline A3s with Vif proteins from cat FIV and present the first structural A3 model locating these interaction regions. In the Z3 domain we have identified residues involved in binding of FIV Vif, and their mutation blocked Vif‑induced A3Z3 degradation. We further identified additional essen‑ tial residues for FIV Vif interaction in the A3Z2 domain, allowing the generation of FIV Vif resistant A3Z2Z3. Mutated feline A3s also showed resistance to the Vif of a lion‑specific FIV, indicating an evolutionary conserved Vif–A3 binding. Comparative modelling of feline A3Z2Z3 suggests that the residues interacting with FIV Vif have, unlike Vif‑interacting residues in human A3s, a unique location at the domain interface of Z2 and Z3 and that the linker forms a homeobox‑ like domain protruding of the Z2Z3 core. HIV‑2/SIV Vifs efficiently degrade feline A3Z2Z3 by possible targeting the linker stretch connecting both Z‑domains. Conclusions: Here we identified in feline A3s residues important for binding of FIV Vif and a unique protein domain insertion (linker). To understand Vif evolution, a structural model of the feline A3 was developed. Our results show that HIV Vif binds human A3s differently than FIV Vif feline A3s. The linker insertion is suggested to form a homeo‑box domain, which is unique to A3s of cats and related species, and not found in human and mouse A3s. Together, these findings indicate a specific and different A3 evolution in cats and human.
Background: No reports exist on genotype-specific human papillomavirus (HPV) acquisition in girls... more Background: No reports exist on genotype-specific human papillomavirus (HPV) acquisition in girls after first sex in sub-Saharan Africa, despite high HPV prevalence and cer-vical cancer incidence. Methods: We followed 503 HP-unvaccinated girls aged 15-16 years in Mwanza, Tanzania, 3-monthly for 18 months with interviews and self-administered vaginal swabs. Swabs were tested for 13 higHRisk and 24 low-risk HPV genotypes. Incidence, clearance and duration of overall HPV and genotype-specific infections were calculated and associated factors evaluated. Results: A total of 106 participants reported first sex prior to enrolment (N ¼ 29) or during follow-up (N ¼ 77). One was HIV-positive at the final visit. The remaining 105 girls contributed 323 adequate specimens. Incidence of any new HPV genotype was 225/100 person-years (pys), and incidence of vaccine types HPV-6,-11,-16 and-18 were 12, 2, 2 and 7/100 pys, respectively. Reporting sex in the past 3 months and knowing the most recent sexual partner for a longer period before sex were associated with HPV acquisition. Median time from reported sexual debut to first HPVinfection was 5 months, and infection duration was 6 months. Conclusion: This is the first description of HPV acquisition after first sex in sub-Saharan Africa where the incidence of cervical cancer is amongst the highest in the world. HPV incidence was very high after first sex, including some vaccine genotypes, and infection duration was short. This very high HPV incidence may help explain high cervical cancer rates, and supports recommendations that the HPV vaccine should be given to girls before first sex.
Background: The increasing abundance of sequence data has exacerbated a long known problem: gene ... more Background: The increasing abundance of sequence data has exacerbated a long known problem: gene trees and species trees for the same terminal taxa are often incongruent. Indeed, genes within a genome have not all followed the same evolutionary path due to events such as incomplete lineage sorting, horizontal gene transfer, gene duplication and deletion, or recombination. Considering conflicts between gene trees as an obstacle, numerous methods have been developed to deal with these incongruences and to reconstruct consensus evolutionary histories of species despite the heterogeneity in the history of their genes. However, inconsistencies can also be seen as a source of information about the specific evolutionary processes that have shaped genomes. Results: The goal of the approach here proposed is to exploit this conflicting information: we have compiled eleven variables describing phylogenetic relationships and evolutionary pressures and submitted them to dimensionality reduction techniques to identify genes with similar evolutionary histories. To illustrate the applicability of the method, we have chosen two viral datasets, namely papillomaviruses and Turnip mosaic virus (TuMV) isolates, largely dissimilar in genome, evolutionary distance and biology. Our method pinpoints viral genes with common evolutionary patterns. In the case of papillomaviruses, gene clusters match well our knowledge on viral biology and life cycle, illustrating the potential of our approach. For the less known TuMV, our results trigger new hypotheses about viral evolution and gene interaction. Conclusions: The approach here presented allows turning phylogenetic inconsistencies into evolutionary information, detecting gene assemblies with similar histories, and could be a powerful tool for comparative pathogenomics.
Background: We conducted a large international study to estimate fractions of head and neck cance... more Background: We conducted a large international study to estimate fractions of head and neck cancers (HNCs) attributable to human papillomavirus (HPV-AFs) using six HPV-related biomarkers of viral detection, transcription, and cellular transformation.
Background: Invasive penile cancer is a rare disease with an approximately 22 000 cases per year... more Background: Invasive penile cancer is a rare disease with an approximately 22 000 cases per year. The incidence is higher in less developed countries, where penile cancer can account for up to 10% of cancers among men in some parts of Africa, South America, and Asia. Objective: To describe the human papillomavirus (HPV) DNA prevalence, HPV type distribution, and detection of markers of viral activity (ie, E6*I mRNA and p16 INK4a) in a series of invasive penile cancers and penile high-grade squamous intraepithelial lesions (HGSILs) from 25 countries. A total of 85 penile HGSILs and 1010 penile invasive cancers diagnosed from 1983 to 2011 were included. Design, setting, and participants: After histopathologic evaluation of formalin-fixed paraffin-embedded samples, HPV DNA detection and genotyping were performed using
Purpose: Acquisition of human papillomavirus (HPV) in women occurs predominantly through
vaginal ... more Purpose: Acquisition of human papillomavirus (HPV) in women occurs predominantly through vaginal sex. However, HPV has been detected in girls reporting no previous sex. We aimed to determine incidence and risk factors for HPV acquisition in girls who report no previous sex in Tanzania, a country with high HPV prevalence and cervical cancer incidence. Methods: We followed 503 adolescent girls aged 15e16 years in Mwanza, Tanzania, with face-toface interviews and self-administered vaginal swabs every 3 months for 18 months; 397 girls reported no sex before enrollment or during follow-up; of whom, 120 were randomly selected. Samples from enrollment, 6-, 12-, and 18-month visits were tested for 37 HPV genotypes. Incidence, clearance, point prevalence, and duration of any HPV and genotype-specific infections were calculated and associated factors were evaluated. Results: Of 120 girls who reported no previous sex, 119 were included, contributing 438 samples. HPV was detected in 51 (11.6%) samples. The overall incidence of new HPV infections was 29.4/100 person-years (95% confidence interval: 15.9e54.2). The point prevalence of vaccine types HPV-6,- 11,-16, and -18 was .9%, .9%, 2.0%, and 0%, respectively. Spending a night away from home and using the Internet were associated with incident HPV, and reporting having seen a pornographic movie was inversely associated with HPV incidence. Conclusions: Incident HPV infections were detected frequently in adolescent girls who reported no previous sex over 18 months. This is likely to reflect under-reporting of sex. A low-point prevalence of HPV genotypes in licensed vaccines was seen, indicating that vaccination of these girls might still be effective.
Viruses rely completely on the hosts' machinery for translation of viral transcripts. However, fo... more Viruses rely completely on the hosts' machinery for translation of viral transcripts. However, for most viruses infecting humans, codon usage preferences (CUPrefs) do not match those of the host. Human papillomaviruses (HPVs) are a showcase to tackle this paradox: they present a large genotypic diversity and a broad range of phenotypic presentations, from asymptomatic infections to productive lesions and cancer. By applying phylogenetic inference and dimensionality reduction methods, we demonstrate first that genes in HPVs are poorly adapted to the average human CUPrefs, the only exception being capsid genes in viruses causing productive lesions. Phylogenetic relationships between HPVs explained only a small proportion of CUPrefs variation. Instead, the most important explanatory factor for viral CUPrefs was infection phenotype, as orthologous genes in viruses with similar clinical presentation displayed similar CUPrefs. Moreover, viral genes with similar spatio-temporal expression patterns showed also similar CUPrefs. Our results suggest that CUPrefs in HPVs reflect either variations in the mutation bias or differential selection pressures depending on the clinical presentation and expression timing. We propose that poor viral CUPrefs may be central to a trade-off between strong viral gene expression and the potential for eliciting protective immune response.
Anal condylomata are common in HIV-positive individuals and among men who have sex with men (MSM)... more Anal condylomata are common in HIV-positive individuals and among men who have sex with men (MSM). Generally attributable to infection by low-risk human papillomaviruses (HPVs), condylomata are considered benign low-grade squamous intraepithelial lesions (SILs). However, anal condylomata have occasionally been linked to high-grade SIL and to oncogenic, high-risk HPVs. Here we describe the range of intraepithelial lesions and of the associated HPVs in heterosexual men and women and MSM. Perianal and anal condylomata were collected from 243 patients (56 heterosexual women, 61 heterosexual men and 126 MSM, including 41 HIV-positive MSM). We assessed lesion histology and HPV genotype. Prevalence estimates and Poisson models were used. Irrespective of HIV infection status, MSM showed a higher proportion of condylomata as high-grade SILs compared to heterosexual men/women. High-grade SILs were also more prevalent in anal than in perianal lesions in all patient groups. HIV-positive MSM exhibited increased prevalence ratio (4.6; 95% con!dence interval 2.1–10.0) of perianal low-grade SILs containing only high-risk HPVs compared to HIV-negative MSM. In addition, more than 64% of anal SILs with a high-grade component, regardless of HIV infection, were exclusively associated with low-risk HPVs. In anal condylomata, both high-grade and low-grade SILs can be associated with high-risk and/or low-risk HPVs. Particularly, low-grade perianal SILs associated with high-risk HPVs were common in HIV-positive MSM, while presence of only low-risk HPVs in high-grade SILs were common in both MSM groups. Our !ndings sound a note of caution for the common clinical practice for the treatment of anal condylomata as benign lesions in MSM and HIV-positive patients.
The Vulpes vulpes papillomavirus type 1, VvulPV1, genome is
7,519-bp in length and shows classica... more The Vulpes vulpes papillomavirus type 1, VvulPV1, genome is 7,519-bp in length and shows classical PV structure: an upstream regulatory region, the early genes E6, E7, E1, and E2, and the late ones, L2 and L1, and misses any E5 gene (3). Maximum likelihood phylogenetic analyses, all using the E1E2, L2L1, or E1E2L2L1 gene concatenates, place VvulPV1 as a basal, sister taxon to Gammapapillomavirus (GammaPV) genus, both at nucleotide and amino acid levels. GammaPV is the largest, and still expanding, PV genus (1). This genus includes PVs found exclusively in humans, retrieved from hair follicles, healthy skin and mucosa, and lesions in skin and mucosa. The closest relative to VvulPV1 is HPV180, a member of GammaPV species 10, based on the L1 nucleotide sequence sharing 63% identity. The average identity on the L1 gene of VvulPV1 with all members of the GammaPV genus is 59.2%. Regarding the rest of the genome, the less conserved gene is E6 and the more conserved gene is E1, respectively, sharing on average 47.2% and 60.4% identity at the nucleotide level with other members of the GammaPV genus. Sticking to the present rules for PV classification (4, 5) VvulPV1 should belong to the GammaPV genus, as nucleotide identity to its closest relative based on L1 is marginally above the 60% threshold.
Papillomaviruses (PVs) are a numerous family of small dsDNA viruses infecting virtually all mamma... more Papillomaviruses (PVs) are a numerous family of small dsDNA viruses infecting virtually all mammals. PVs cause infections without triggering a strong immune response, and natural infection provides only limited protection against reinfection. Most PVs are part and parcel of the skin microbiota. In some cases, infections by certain PVs take diverse clinical presentations from highly productive self-limited warts to invasive cancers. We propose PVs as an excellent model system to study the evolutionary interactions between the immune system and pathogens causing chronic infections: genotypically, PVs are very diverse, with hundreds of different genotypes infecting skin and mucosa; phenotypically, they display extremely broad gradients and trade-offs between key phenotypic traits, namely productivity, immunogenicity, prevalence, oncogenicity and clinical presentation. Public health interventions have been launched to decrease the burden of PV-associated cancers, including massive vaccination against the most oncogenic human PVs, as well as systematic screening for PV chronic anogenital infections. Anti-PVs vaccines elicit protection against infection, induce cross-protection against closely related viruses and result in herd immunity. However, our knowledge on the ecological and intrapatient dynamics of PV infections remains fragmentary. We still need to understand how the novel anthropogenic selection pressures posed by vaccination and screening will affect viral circulation and epidemiology. We present here an overview of PV evolution and the connection between PV genotypes and the phenotypic, clinical manifestations of the diseases they cause. This differential link between viral evolution and the gradient cancer-warts-asymptomatic infections makes PVs a privileged playground for evolutionary medicine research.
Background/Aim: Great controversy exists about
the association between Human Papillomavirus (HPV)... more Background/Aim: Great controversy exists about the association between Human Papillomavirus (HPV) and breast tumors. The aim of this study was to explore the presence of HPV DNA in a large set of breast cancer cases. Materials and Methods: Techniques used followed the standards for an international retrospective survey of HPVDNA genotyping, coordinated by our own group and the DDL Laboratories in Rijswijk, the Netherlands. Paraffinembedded samples were used. SPF-10 broad-spectrum primers were applied, followed by deoxyribonucleic acid enzyme immunoassay and genotyping by reverse-line probe assay. Results: A total of 78 samples were included in the study, 2 of benign conditions and 76 carcinomas, including different histological subtypes. HPV was not present in any of the specimens studied irrespective of histology, hormonal status and stage of disease. Conclusion: Our data do not support the involvement of HPV in breast carcinogenesis as no evidence of its presence was found.
AIM:
This work describes the human papillomavirus (HPV) prevalence and the HPV type distributi... more AIM:
This work describes the human papillomavirus (HPV) prevalence and the HPV type distribution in a large series of vaginal intraepithelial neoplasia (VAIN) grades 2/3 and vaginal cancer worldwide.
METHODS:
We analysed 189 VAIN 2/3 and 408 invasive vaginal cancer cases collected from 31 countries from 1986 to 2011. After histopathological evaluation of sectioned formalin-fixed paraffin-embedded samples, HPV DNA detection and typing was performed using the SPF-10/DNA enzyme immunoassay (DEIA)/LiPA25 system (version 1). A subset of 146 vaginal cancers was tested for p16INK4a expression, a cellular surrogate marker for HPV transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance.
RESULTS:
HPV DNA was detected in 74% (95% confidence interval (CI): 70-78%) of invasive cancers and in 96% (95% CI: 92-98%) of VAIN 2/3. Among cancers, the highest detection rates were observed in warty-basaloid subtype of squamous cell carcinomas, and in younger ages. Concerning the type-specific distribution, HPV16 was the most frequently type detected in both precancerous and cancerous lesions (59%). p16INK4a overexpression was found in 87% of HPV DNA positive vaginal cancer cases.
CONCLUSIONS:
HPV was identified in a large proportion of invasive vaginal cancers and in almost all VAIN 2/3. HPV16 was the most common type detected. A large impact in the reduction of the burden of vaginal neoplastic lesions is expected among vaccinated cohorts.
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Papers by Ignacio G Bravo
We have analysed extant HPV16 diversity and compared the evolutionary and phylogeographical patterns of humans and of HPV16. We show that codivergence with modern humans explains at most 30% of the present viral geographical distribution. The most explanatory scenario suggests that ancestral HPV16 already infected ancestral human populations, and that viral lineages co-diverged with the hosts in parallel with the split between archaic Neanderthal-Denisovans and ancestral modern human populations, generating the ancestral HPV16A and HPV16BCD viral lineages, respectively.
We propose that after out-of-Africa migration of modern human ancestors, sexual transmission between human populations introduced HPV16A into modern human ancestor populations. We hypothesise that differential coevolution of HPV16 lineages with different but closely related ancestral human populations and subsequent host-switch events in parallel with introgression of archaic alleles into the genomes of modern human ancestors may be largely responsible for the present-day differential prevalence and association with cancers for HPV16 variants.
Results: The goal of the approach here proposed is to exploit this conflicting information: we have compiled eleven variables describing phylogenetic relationships and evolutionary pressures and submitted them to dimensionality reduction techniques to identify genes with similar evolutionary histories. To illustrate the applicability of the method, we have chosen two viral datasets, namely papillomaviruses and Turnip mosaic virus (TuMV) isolates, largely dissimilar in genome, evolutionary distance and biology. Our method pinpoints viral genes with common evolutionary patterns. In the case of papillomaviruses, gene clusters match well our knowledge on viral biology and life cycle, illustrating the potential of our approach. For the less known TuMV, our results trigger new hypotheses about viral evolution and gene interaction.
Conclusions: The approach here presented allows turning phylogenetic inconsistencies into evolutionary information, detecting gene assemblies with similar histories, and could be a powerful tool for comparative pathogenomics.
vaginal sex. However, HPV has been detected in girls reporting no previous sex. We aimed to
determine incidence and risk factors for HPV acquisition in girls who report no previous sex in
Tanzania, a country with high HPV prevalence and cervical cancer incidence.
Methods: We followed 503 adolescent girls aged 15e16 years in Mwanza, Tanzania, with face-toface
interviews and self-administered vaginal swabs every 3 months for 18 months; 397 girls
reported no sex before enrollment or during follow-up; of whom, 120 were randomly selected.
Samples from enrollment, 6-, 12-, and 18-month visits were tested for 37 HPV genotypes. Incidence,
clearance, point prevalence, and duration of any HPV and genotype-specific infections were
calculated and associated factors were evaluated.
Results: Of 120 girls who reported no previous sex, 119 were included, contributing 438 samples.
HPV was detected in 51 (11.6%) samples. The overall incidence of new HPV infections was 29.4/100
person-years (95% confidence interval: 15.9e54.2). The point prevalence of vaccine types HPV-6,-
11,-16, and -18 was .9%, .9%, 2.0%, and 0%, respectively. Spending a night away from home and using
the Internet were associated with incident HPV, and reporting having seen a pornographic movie
was inversely associated with HPV incidence.
Conclusions: Incident HPV infections were detected frequently in adolescent girls who reported
no previous sex over 18 months. This is likely to reflect under-reporting of sex. A low-point
prevalence of HPV genotypes in licensed vaccines was seen, indicating that vaccination of these
girls might still be effective.
by low-risk human papillomaviruses (HPVs), condylomata are considered benign low-grade squamous intraepithelial lesions (SILs). However,
anal condylomata have occasionally been linked to high-grade SIL and to oncogenic, high-risk HPVs. Here we describe the range of
intraepithelial lesions and of the associated HPVs in heterosexual men and women and MSM. Perianal and anal condylomata were
collected from 243 patients (56 heterosexual women, 61 heterosexual men and 126 MSM, including 41 HIV-positive MSM). We assessed
lesion histology and HPV genotype. Prevalence estimates and Poisson models were used. Irrespective of HIV infection status, MSM
showed a higher proportion of condylomata as high-grade SILs compared to heterosexual men/women. High-grade SILs were also more
prevalent in anal than in perianal lesions in all patient groups. HIV-positive MSM exhibited increased prevalence ratio (4.6; 95%
con!dence interval 2.1–10.0) of perianal low-grade SILs containing only high-risk HPVs compared to HIV-negative MSM. In addition,
more than 64% of anal SILs with a high-grade component, regardless of HIV infection, were exclusively associated with low-risk HPVs. In
anal condylomata, both high-grade and low-grade SILs can be associated with high-risk and/or low-risk HPVs. Particularly, low-grade
perianal SILs associated with high-risk HPVs were common in HIV-positive MSM, while presence of only low-risk HPVs in high-grade SILs
were common in both MSM groups. Our !ndings sound a note of caution for the common clinical practice for the treatment of anal
condylomata as benign lesions in MSM and HIV-positive patients.
7,519-bp in length and shows classical PV structure: an upstream
regulatory region, the early genes E6, E7, E1, and E2, and the late
ones, L2 and L1, and misses any E5 gene (3). Maximum likelihood
phylogenetic analyses, all using the E1E2, L2L1, or E1E2L2L1 gene
concatenates, place VvulPV1 as a basal, sister taxon to Gammapapillomavirus
(GammaPV) genus, both at nucleotide and amino
acid levels. GammaPV is the largest, and still expanding, PV genus
(1). This genus includes PVs found exclusively in humans, retrieved
from hair follicles, healthy skin and mucosa, and lesions in
skin and mucosa. The closest relative to VvulPV1 is HPV180, a
member of GammaPV species 10, based on the L1 nucleotide
sequence sharing 63% identity. The average identity on the L1
gene of VvulPV1 with all members of the GammaPV genus is
59.2%. Regarding the rest of the genome, the less conserved gene is
E6 and the more conserved gene is E1, respectively, sharing on
average 47.2% and 60.4% identity at the nucleotide level with
other members of the GammaPV genus. Sticking to the present
rules for PV classification (4, 5) VvulPV1 should belong to the
GammaPV genus, as nucleotide identity to its closest relative
based on L1 is marginally above the 60% threshold.
PVs cause infections without triggering a strong immune response, and natural infection provides only
limited protection against reinfection. Most PVs are part and parcel of the skin microbiota. In some
cases, infections by certain PVs take diverse clinical presentations from highly productive self-limited
warts to invasive cancers. We propose PVs as an excellent model system to study the evolutionary
interactions between the immune system and pathogens causing chronic infections: genotypically,
PVs are very diverse, with hundreds of different genotypes infecting skin and mucosa; phenotypically,
they display extremely broad gradients and trade-offs between key phenotypic traits, namely productivity,
immunogenicity, prevalence, oncogenicity and clinical presentation. Public health interventions have
been launched to decrease the burden of PV-associated cancers, including massive vaccination against
the most oncogenic human PVs, as well as systematic screening for PV chronic anogenital infections.
Anti-PVs vaccines elicit protection against infection, induce cross-protection against closely related
viruses and result in herd immunity. However, our knowledge on the ecological and intrapatient
dynamics of PV infections remains fragmentary. We still need to understand how the novel anthropogenic
selection pressures posed by vaccination and screening will affect viral circulation and epidemiology.
We present here an overview of PV evolution and the connection between PV genotypes and
the phenotypic, clinical manifestations of the diseases they cause. This differential link between viral
evolution and the gradient cancer-warts-asymptomatic infections makes PVs a privileged playground
for evolutionary medicine research.
the association between Human Papillomavirus (HPV) and
breast tumors. The aim of this study was to explore the
presence of HPV DNA in a large set of breast cancer cases.
Materials and Methods: Techniques used followed the
standards for an international retrospective survey of HPVDNA
genotyping, coordinated by our own group and the
DDL Laboratories in Rijswijk, the Netherlands. Paraffinembedded
samples were used. SPF-10 broad-spectrum
primers were applied, followed by deoxyribonucleic acid
enzyme immunoassay and genotyping by reverse-line probe
assay. Results: A total of 78 samples were included in the
study, 2 of benign conditions and 76 carcinomas, including
different histological subtypes. HPV was not present in any
of the specimens studied irrespective of histology, hormonal
status and stage of disease. Conclusion: Our data do not
support the involvement of HPV in breast carcinogenesis as
no evidence of its presence was found.
This work describes the human papillomavirus (HPV) prevalence and the HPV type distribution in a large series of vaginal intraepithelial neoplasia (VAIN) grades 2/3 and vaginal cancer worldwide.
METHODS:
We analysed 189 VAIN 2/3 and 408 invasive vaginal cancer cases collected from 31 countries from 1986 to 2011. After histopathological evaluation of sectioned formalin-fixed paraffin-embedded samples, HPV DNA detection and typing was performed using the SPF-10/DNA enzyme immunoassay (DEIA)/LiPA25 system (version 1). A subset of 146 vaginal cancers was tested for p16INK4a expression, a cellular surrogate marker for HPV transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance.
RESULTS:
HPV DNA was detected in 74% (95% confidence interval (CI): 70-78%) of invasive cancers and in 96% (95% CI: 92-98%) of VAIN 2/3. Among cancers, the highest detection rates were observed in warty-basaloid subtype of squamous cell carcinomas, and in younger ages. Concerning the type-specific distribution, HPV16 was the most frequently type detected in both precancerous and cancerous lesions (59%). p16INK4a overexpression was found in 87% of HPV DNA positive vaginal cancer cases.
CONCLUSIONS:
HPV was identified in a large proportion of invasive vaginal cancers and in almost all VAIN 2/3. HPV16 was the most common type detected. A large impact in the reduction of the burden of vaginal neoplastic lesions is expected among vaccinated cohorts.
We have analysed extant HPV16 diversity and compared the evolutionary and phylogeographical patterns of humans and of HPV16. We show that codivergence with modern humans explains at most 30% of the present viral geographical distribution. The most explanatory scenario suggests that ancestral HPV16 already infected ancestral human populations, and that viral lineages co-diverged with the hosts in parallel with the split between archaic Neanderthal-Denisovans and ancestral modern human populations, generating the ancestral HPV16A and HPV16BCD viral lineages, respectively.
We propose that after out-of-Africa migration of modern human ancestors, sexual transmission between human populations introduced HPV16A into modern human ancestor populations. We hypothesise that differential coevolution of HPV16 lineages with different but closely related ancestral human populations and subsequent host-switch events in parallel with introgression of archaic alleles into the genomes of modern human ancestors may be largely responsible for the present-day differential prevalence and association with cancers for HPV16 variants.
Results: The goal of the approach here proposed is to exploit this conflicting information: we have compiled eleven variables describing phylogenetic relationships and evolutionary pressures and submitted them to dimensionality reduction techniques to identify genes with similar evolutionary histories. To illustrate the applicability of the method, we have chosen two viral datasets, namely papillomaviruses and Turnip mosaic virus (TuMV) isolates, largely dissimilar in genome, evolutionary distance and biology. Our method pinpoints viral genes with common evolutionary patterns. In the case of papillomaviruses, gene clusters match well our knowledge on viral biology and life cycle, illustrating the potential of our approach. For the less known TuMV, our results trigger new hypotheses about viral evolution and gene interaction.
Conclusions: The approach here presented allows turning phylogenetic inconsistencies into evolutionary information, detecting gene assemblies with similar histories, and could be a powerful tool for comparative pathogenomics.
vaginal sex. However, HPV has been detected in girls reporting no previous sex. We aimed to
determine incidence and risk factors for HPV acquisition in girls who report no previous sex in
Tanzania, a country with high HPV prevalence and cervical cancer incidence.
Methods: We followed 503 adolescent girls aged 15e16 years in Mwanza, Tanzania, with face-toface
interviews and self-administered vaginal swabs every 3 months for 18 months; 397 girls
reported no sex before enrollment or during follow-up; of whom, 120 were randomly selected.
Samples from enrollment, 6-, 12-, and 18-month visits were tested for 37 HPV genotypes. Incidence,
clearance, point prevalence, and duration of any HPV and genotype-specific infections were
calculated and associated factors were evaluated.
Results: Of 120 girls who reported no previous sex, 119 were included, contributing 438 samples.
HPV was detected in 51 (11.6%) samples. The overall incidence of new HPV infections was 29.4/100
person-years (95% confidence interval: 15.9e54.2). The point prevalence of vaccine types HPV-6,-
11,-16, and -18 was .9%, .9%, 2.0%, and 0%, respectively. Spending a night away from home and using
the Internet were associated with incident HPV, and reporting having seen a pornographic movie
was inversely associated with HPV incidence.
Conclusions: Incident HPV infections were detected frequently in adolescent girls who reported
no previous sex over 18 months. This is likely to reflect under-reporting of sex. A low-point
prevalence of HPV genotypes in licensed vaccines was seen, indicating that vaccination of these
girls might still be effective.
by low-risk human papillomaviruses (HPVs), condylomata are considered benign low-grade squamous intraepithelial lesions (SILs). However,
anal condylomata have occasionally been linked to high-grade SIL and to oncogenic, high-risk HPVs. Here we describe the range of
intraepithelial lesions and of the associated HPVs in heterosexual men and women and MSM. Perianal and anal condylomata were
collected from 243 patients (56 heterosexual women, 61 heterosexual men and 126 MSM, including 41 HIV-positive MSM). We assessed
lesion histology and HPV genotype. Prevalence estimates and Poisson models were used. Irrespective of HIV infection status, MSM
showed a higher proportion of condylomata as high-grade SILs compared to heterosexual men/women. High-grade SILs were also more
prevalent in anal than in perianal lesions in all patient groups. HIV-positive MSM exhibited increased prevalence ratio (4.6; 95%
con!dence interval 2.1–10.0) of perianal low-grade SILs containing only high-risk HPVs compared to HIV-negative MSM. In addition,
more than 64% of anal SILs with a high-grade component, regardless of HIV infection, were exclusively associated with low-risk HPVs. In
anal condylomata, both high-grade and low-grade SILs can be associated with high-risk and/or low-risk HPVs. Particularly, low-grade
perianal SILs associated with high-risk HPVs were common in HIV-positive MSM, while presence of only low-risk HPVs in high-grade SILs
were common in both MSM groups. Our !ndings sound a note of caution for the common clinical practice for the treatment of anal
condylomata as benign lesions in MSM and HIV-positive patients.
7,519-bp in length and shows classical PV structure: an upstream
regulatory region, the early genes E6, E7, E1, and E2, and the late
ones, L2 and L1, and misses any E5 gene (3). Maximum likelihood
phylogenetic analyses, all using the E1E2, L2L1, or E1E2L2L1 gene
concatenates, place VvulPV1 as a basal, sister taxon to Gammapapillomavirus
(GammaPV) genus, both at nucleotide and amino
acid levels. GammaPV is the largest, and still expanding, PV genus
(1). This genus includes PVs found exclusively in humans, retrieved
from hair follicles, healthy skin and mucosa, and lesions in
skin and mucosa. The closest relative to VvulPV1 is HPV180, a
member of GammaPV species 10, based on the L1 nucleotide
sequence sharing 63% identity. The average identity on the L1
gene of VvulPV1 with all members of the GammaPV genus is
59.2%. Regarding the rest of the genome, the less conserved gene is
E6 and the more conserved gene is E1, respectively, sharing on
average 47.2% and 60.4% identity at the nucleotide level with
other members of the GammaPV genus. Sticking to the present
rules for PV classification (4, 5) VvulPV1 should belong to the
GammaPV genus, as nucleotide identity to its closest relative
based on L1 is marginally above the 60% threshold.
PVs cause infections without triggering a strong immune response, and natural infection provides only
limited protection against reinfection. Most PVs are part and parcel of the skin microbiota. In some
cases, infections by certain PVs take diverse clinical presentations from highly productive self-limited
warts to invasive cancers. We propose PVs as an excellent model system to study the evolutionary
interactions between the immune system and pathogens causing chronic infections: genotypically,
PVs are very diverse, with hundreds of different genotypes infecting skin and mucosa; phenotypically,
they display extremely broad gradients and trade-offs between key phenotypic traits, namely productivity,
immunogenicity, prevalence, oncogenicity and clinical presentation. Public health interventions have
been launched to decrease the burden of PV-associated cancers, including massive vaccination against
the most oncogenic human PVs, as well as systematic screening for PV chronic anogenital infections.
Anti-PVs vaccines elicit protection against infection, induce cross-protection against closely related
viruses and result in herd immunity. However, our knowledge on the ecological and intrapatient
dynamics of PV infections remains fragmentary. We still need to understand how the novel anthropogenic
selection pressures posed by vaccination and screening will affect viral circulation and epidemiology.
We present here an overview of PV evolution and the connection between PV genotypes and
the phenotypic, clinical manifestations of the diseases they cause. This differential link between viral
evolution and the gradient cancer-warts-asymptomatic infections makes PVs a privileged playground
for evolutionary medicine research.
the association between Human Papillomavirus (HPV) and
breast tumors. The aim of this study was to explore the
presence of HPV DNA in a large set of breast cancer cases.
Materials and Methods: Techniques used followed the
standards for an international retrospective survey of HPVDNA
genotyping, coordinated by our own group and the
DDL Laboratories in Rijswijk, the Netherlands. Paraffinembedded
samples were used. SPF-10 broad-spectrum
primers were applied, followed by deoxyribonucleic acid
enzyme immunoassay and genotyping by reverse-line probe
assay. Results: A total of 78 samples were included in the
study, 2 of benign conditions and 76 carcinomas, including
different histological subtypes. HPV was not present in any
of the specimens studied irrespective of histology, hormonal
status and stage of disease. Conclusion: Our data do not
support the involvement of HPV in breast carcinogenesis as
no evidence of its presence was found.
This work describes the human papillomavirus (HPV) prevalence and the HPV type distribution in a large series of vaginal intraepithelial neoplasia (VAIN) grades 2/3 and vaginal cancer worldwide.
METHODS:
We analysed 189 VAIN 2/3 and 408 invasive vaginal cancer cases collected from 31 countries from 1986 to 2011. After histopathological evaluation of sectioned formalin-fixed paraffin-embedded samples, HPV DNA detection and typing was performed using the SPF-10/DNA enzyme immunoassay (DEIA)/LiPA25 system (version 1). A subset of 146 vaginal cancers was tested for p16INK4a expression, a cellular surrogate marker for HPV transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance.
RESULTS:
HPV DNA was detected in 74% (95% confidence interval (CI): 70-78%) of invasive cancers and in 96% (95% CI: 92-98%) of VAIN 2/3. Among cancers, the highest detection rates were observed in warty-basaloid subtype of squamous cell carcinomas, and in younger ages. Concerning the type-specific distribution, HPV16 was the most frequently type detected in both precancerous and cancerous lesions (59%). p16INK4a overexpression was found in 87% of HPV DNA positive vaginal cancer cases.
CONCLUSIONS:
HPV was identified in a large proportion of invasive vaginal cancers and in almost all VAIN 2/3. HPV16 was the most common type detected. A large impact in the reduction of the burden of vaginal neoplastic lesions is expected among vaccinated cohorts.