Mucosal Human Papillomaviruses Encode Four Different E5 Proteins Whose Chemistry and Phylogeny Correlate with Malignant or Benign Growth

Abstract

We performed a phylogenetic study of the E2-L2 region of human mucosal papillomaviruses (PVs) and of the proteins therein encoded. Hitherto, proteins codified in this region were known as E5 proteins. We show that many of these proteins could be spurious translations, according to phylogenetic and chemical coherence criteria between similar protein sequences. We show that there are four separate families of E5 proteins, with different characteristics of phylogeny, chemistry, and rate of evolution. For the sake of clarity, we propose a change in the present nomenclature. E5␣ is present in groups A5, A6, A7, A9, and A11, PVs highly associated with malignant carcinomas of the cervix and penis. E5␤ is present in groups A2, A3, A4, and A12, i.e., viruses associated with certain warts. E5␥ is present in group A10, and E5␦ is encoded in groups A1, A8, and A10, which are associated with benign transformations. The phylogenetic relationships between mucosal human PVs are the same when considering the oncoproteins E6 and E7 and the E5 proteins and differ from the phylogeny estimated for the structural proteins L1 and L2. Besides, the protein divergence rate is higher in early proteins than in late proteins, increasing in the order L1 < L2 < E6 Ϸ E7 < E5. Moreover, the same proteins have diverged more rapidly in viruses associated with malignant transformations than in viruses associated with benign transformations. The E5 proteins display, therefore, evolutionary characteristics similar to those of the E6 and E7 oncoproteins. This could reflect a differential involvement of the E5 types in the transformation processes.Papillomaviruses (PV) are a group of small DNA viruses that infect vertebrates. They are related to virtually all clinical cases of cervical cancer and are also involved in other benign and malignant proliferative disorders, such as skin warts, genital warts, laryngeal papillomas, and possibly non-melanoma skin cancer (21,25,26,32,43,56). Cladistic relationships between PVs have been described on the basis of their phylogeny (9, 22). Briefly, the major categories are the supergroup, the group, the type, the subtype, and the variant. Supergroups are identified as clades with well-recognized differences in biology, whereas the rest of the categories are customarily described on the basis of decreasing phylogenetic distance (9,22

Comparative Analysis of 19 Genital Human Papillomavirus Types with Regard to p53 Degradation, Immortalization, Phylogeny, and Epidemiologic Risk Classification

“…A recently published phylogenetic analysis based on the nucleotide sequence of the E6 proteins (37) revealed that distinct phylogenetic branches of E6 proteins can be recognized. One clade consisted out of known high-risk HPV types and included HPV70 (37).…”

Les papillomavirus humains cutanés oncogènes sont-ils des commensaux défectifs ?

“…Ainsi, selon le type de papillomavirus, deux protéines virales (E5 et E8) pourraient interférer avec la régulation du zinc et favoriser l'activation de voies de signalisation impliquées dans la synthèse de facteurs de transcription essentiels pour l'expression et la répli-cation du génome viral (Figure 2). Parmi les PVH cutanés ou muqueux, les PVH du genre β se distinguent par l'absence des gènes E5 et E8 [9]. Ainsi, nos résultats viennent corroborer l'hypothèse récem-ment formulée [2] selon laquelle les PVH β, en particulier le PVH5 oncogène, sont des commensaux défectifs très répandus et asymptomatiques dans la population générale.…”

Molecular Bases of Human Papillomavirus Pathogenesis in the Development of Cervical Cancer

“…They showed that there is a clear pattern of divergence from late to early genes at the protein level, which increased in the progression L1 < L2 < E6 ≈ E7 < E5. Among the E5 proteins from the alpha genus it was clear that there was not an evident sequence similarity and that the evolutionary divergence between present proteins rises to 80% (Bravo & Alonso, 2004). The few common characteristics for the alpha genus E5 proteins are the high hydrophobicity, the high Ile+Leu+Val content and the presence of transmembranal regions.…”

“…The less conserved viral sequences from the alpha genus are those from the E5 gene, since the homology in this genus is only of 25% and 40% when only the HR-HPV types are considered. Few years ago, Bravo and Alonso (2004) described the evolutionary characteristics of the E5 proteins and compared them with the E6 and E7 oncogenic proteins and with the structural proteins L1 and L2. They showed that there is a clear pattern of divergence from late to early genes at the protein level, which increased in the progression L1 < L2 < E6 ≈ E7 < E5.…”

“…The few common characteristics for the alpha genus E5 proteins are the high hydrophobicity, the high Ile+Leu+Val content and the presence of transmembranal regions. Taking into consideration these characteristics of the E5 protein, Bravo and Alonso (2004) identified 4 groups of E5 proteins in the alpha genus (E5 , E5 , E5 and E5 ) and proposed that besides of the phylogenetic characteristics, the chemical part of the proteins have to be www.intechopen.com Human Papillomavirus and Related Diseases -From Bench to Bedside -Research Aspects 252 taken into consideration to have a more specific classification, as it has been suggested that the protein chemistry is an important restriction for protein evolution (Babbit & Gerlt, 1997).…”