Human papillomaviruses: Knowns, mysteries, and unchartered territories

Abstract

There has been an explosion in the number of papillomaviruses that have been identified and fully sequenced. Yet only a minute fraction of these has been studied in any detail. Most of our molecular research efforts have focused on the E6 and E7 proteins of "high-risk," cancer-associated human papillomaviruses (HPVs). Interactions of the high-risk HPV E6 and E7 proteins with their respective cellular targets, the p53 and the retinoblastoma tumor suppressors, have been investigated in minute detail. Some have thus questioned if research on papillomaviruses remains an exciting and worthwhile area of investigation. However, fundamentally new insights on the biological activities and cellular targets of the high-risk HPV E6 and E7 proteins have been discovered and previously unstudied HPVs have been newly associated with human diseases. HPV infections continue to be an important cause of human morbidity and mortality and since there are no antivirals to combat HPV infections, research on HPVs should remain attractive to new investigators and biomedical funding agencies, alike.

Keywords: human papillomavirus; persistent infection; signaling pathways; viral oncogenesis; viral oncoproteins; viral replication.

Figure 1:. Examples of Papillomavirus E5 proteins.

The bovine papillomavirus 1 (BPV1) E5 protein has been studied in the greatest detail and encodes a single-pass transmembrane protein. The beta, delta, zeta, and some epsilon E5s are also predicted to encode single-pass membrane proteins but there is limited sequence similarity between the E5 proteins encoded by the different groups. Some epsilon E5 proteins do not have recognizable transmembrane domains. In contrast, the alpha and gamma E5s encode multi-pass transmembrane proteins. Potential transmembrane sequences as predicted by the CCTOP server (https://cctop.ttk.hu/) are highlighted in crimson. See Table 1 for a full listing of papillomaviruses that encode E5 proteins.

Figure 2:. E10 proteins encoded by HPVs and animal PVs.

HPV101, HPV103 HPV108 are classified as gamma 6 PVs, whereas HPV214, HPV226, and HPV-mw02c24anr are currently unclassified gamma HPVs. Identical residues are highlighted by black boxes and chemically similar residues by gray boxes. Potential transmembrane sequences as predicted by the CCTOP server (https://cctop.ttk.hu/) are indicated by crimson bars. (A). Many bovine papillomaviruses (BPVs) as well as a PV isolated from a domestic goat (Capra hircus Papillomavirus 2; ChPV2), raindeer (Rangifer tarandus Papillomavirus 2; RtPV2), cottontail rabbit (Sylvilagus floridanus Papillomavirus 1; SfPV1 aka CRPV), and New Zealand white rabbit (Oryctolagus cuniculus Papillomavirus 1; OcPV1) also encode E10 proteins. The E10s encoded by BPV20, BPV41, ChPV2, RtPV2, SfPV1 and OcPV1 are overprinted on the E6 ORF. Amino acid residues conserved amongst all the animal PV encoded E10s are highlighted by pale green boxes, overprinted E10 residues conserved amongst BPV20, BPV40, ChPV2, and RtPV2 are highlighted by olive-colored boxes, and residues conserved between SfPV1 and OcPV1 E10s by moss green boxes. Chemically similar amino acid residues are highlighted by gray boxes. Potential transmembrane sequences as predicted by the CCTOP server (https://cctop.ttk.hu/) are indicated by crimson bars. (B). A papillomavirus isolated from the Javan rusa (Rusa timorensis papillomavirus 2; RtiPV2) also encodes an E10 protein but it shares no extensive sequence similarity to other E10s and is not predicted to contain a transmembrane region (C).

Figure 3:. Small E6 proteins encoded by avian papillomaviruses.

The amino acid sequences of E6 proteins encoded by papillomaviruses isolated from the Atlantic canary (Serinus canaria papillomavirus 1; ScPV1), mallard (Anas platyrhynchos Papillomavirus 1 and 2; AplaPV1 and AplaPV2), yellow-necked francolin (Francolinus leucoscepus Papillomavirus 1; FlPV1), Atlantic puffin (Fratercula arctica Papillomavirus 1; FarcPV1), American herring gull (Larus smithsonianus Papillomavirus 1; LsmiPV1), black-legged kittiwake (Rissa tridactyla Papillomavirus 1, RtriPV1), and Adelie penguin (Pygoscelis adeliae papillomavirus 1 and 2; PaPV1 and PaPV2) are shown and compared to the amino (E6N)- and carboxyl-terminal (E6C) regions of HPV16 E6. Identical residues are highlighted by black boxes and chemically similar residues by gray boxes. The CXXC (C=cysteine, X=any amino acid) metal binding motifs are highlighted in red.

Figure 4.. Unique E9 proteins encoded by avian papillomaviruses.

The amino acid sequences of E9 proteins encoded by papillomavirus isolated from the gray parrot (Psittacus erithacus Papillomavirus 1; PePV1), yellow-necked francolin (Francolinus leucoscepus Papillomavirus 1; FlPV1), common chaffinch (Fringilla coelebs Papillomavirus 1; FcPV1), mallard (Anas platyrhynchos Papillomavirus 1; AplaPV1), black-legged kittiwake (Rissa tridactyla Papillomavirus 1, RtriPV1), Atlantic puffin (Fratercula arctica Papillomavirus 1; FarcPV1), American herring gull (Larus smithsonianus Papillomavirus 1; LsmiPV1), Atlantic canary (Serinus canaria papillomavirus 1; ScPV1), and Adelie penguin (Pygoscelis adeliae papillomavirus 1 and 2; PaPV1 and PaPV1), are shown. Identical residues are highlighted by black boxes and chemically similar residues by gray boxes. The E9 ORFs are overprinted on the E1 ORF. See Table 3 for a full list of papillomaviruses with E9 ORFs.