Bovine papillomavirus type 2 (BPV-2) is an oncogenic virus infecting both epithelial and mesenchymal cells. Its life cycle, similar to other papillomaviruses (PVs), appears to be linked to epithelial differentiation. Human and bovine PVs have been known to reside in a latent, episomal form in PBMCs; therefore, it is believed that blood cells, like all mesenchymal cells, function as non-permissive carriers. Here, for the first time in veterinary and comparative medicine, the BPV-2 E5 oncoprotein and the major structural L1 capsid protein, known to be expressed only in productive infections, were shown to occur in defined subsets of PBMCs. E5 oncoprotein was detected in sorted T-and B-cells as well as in monocytes by flow cytometry and Western blot analysis. However, CD4 + and CD8 + lymphocytes appeared to be the main circulating targets of the virus, thus possibly representing the most important reservoir of active BPV-2 in blood. L1 protein was identified by flow cytometry in a population of blood cells recognized as lymphocytes by morphological scatter properties. Western blot analysis was performed on lysates obtained from the sorted subpopulations of PBMCs and detected L1 protein in CD4 + and CD8 + cells only. Thus, this study showed that CD4 + and CD8 + lymphocytes are permissive for BPV-2 and are new, hitherto unknown sites of productive PV infection. In light of these observations, the life cycle of PVs needs to be revisited to gain novel insights into the epidemiology of BPV infection and the pathogenesis of related diseases.
INTRODUCTIONBovine papillomaviruses (BPVs) are a heterogeneous group of viruses responsible for tumours of the skin, genital and paragenital area, eye, upper gastrointestinal tract and urinary bladder (IARC, 2007). BPVs, like all other papillomaviruses (PVs), are usually strictly species specific. However, cases of cross-species infection are known to occur. BPV type 1 (BPV-1) and BPV-2, belonging to the genus Deltapapillomavirus (de Villiers et al., 2004), are responsible for infections in equids resulting in sarcoids (Chambers et al., 2003;Trenfield et al., 1985), as well as in bison and water buffaloes leading to warts (Literák et al., 2006;Silvestre et al., 2009). In addition, a variant of BPV-8, classified in the genus Epsilonpapillomavirus, also causes papillomas of the skin in bison (Tomita et al., 2007). More recently, it has been suggested that BPVs could be responsible for cutaneous sarcoids in cats and captive African lions (Munday & Knight, 2010;Orbell et al., 2010).BPV-1 and -2 are closely related serotypes (Shafti-Keramat et al., 2009) and can infect both epithelial and mesenchymal cells. Similar to other PVs, BPV-1/-2 replication and virion production are confined to the epithelial region of the lesions, whilst infection of mesenchymal cells appears to be non-productive (Campo, 2006;Shafti-Keramat et al., 2009).BPV-2 is known to play a central role in bladder carcinogenesis of adult cattle reared on pasturelands rich in bracken fern. In these animals, tumours of the u...