Cottontail rabbit papillomavirus (CRPV)-induced papillomas can progress into malignant carcinomas, remain persistent or regress. Both host immunity and virus genetic background play critical roles in these events. To test how host immunity influences CRPV-induced papilloma evolution, both EIII/JC (inbred) and New Zealand White (outbred) rabbits were treated with an immunosuppressive drug, cyclosporin A (CsA), for 80 days and the regression of three regressive constructs, H.CRPVr (a CRPV regressive strain), H.CRPVp-E6r (a progressive strain with regressive E6) and H.CRPVp-CE6rm (H.CRPVp with the carboxyl terminal of regressive E6, containing mutations at amino acid residues E252G, G258D and S259P) was checked. Papillomas induced by H.CRPVr and H.CRPVp-E6r on control inbred and outbred rabbits regressed totally around week 8, whereas papillomas on all CsA-treated rabbits grew progressively. After cessation of CsA treatment, papillomas began to regress in six outbred rabbits: 14 of 18 papillomas induced by CRPVr, 11 of 18 papillomas induced by H.CRPVp-E6r and eight of 10 papillomas induced by H.CRPVp-CE6rm regressed around week 21. In four CsA-treated inbred rabbits, two of 17 papillomas induced by H.CRPVr and one of 17 papillomas induced by H.CRPVp-E6r regressed. These data indicate that papillomas induced by a regressive CRPV strain can become persistent in the transiently immunosuppressed host. However, returning immunity can lead to regression and clearance of large papillomas (with increased antigenicity) in an outbred population, whilst these same antigenic papillomas persist in inbred rabbits.
BavinckJ. N.,
GissmanL.,
ClaasF. H.7 other authors1993; Relation between skin cancer, humoral responses to human papillomaviruses, and HLA class II molecules in renal transplant recipients. J Immunol 151:1579–1586
ChristensenN. D.,
HanR.,
KreiderJ. W.1999; Cottontail rabbit papillomavirus. In Persistent Viral Infections pp 485–502 Edited by
AhmedR.,
ChenI. S. Y.
Chichester, UK: Wiley;
DavidsonE. J.,
DavidsonJ. A.,
SterlingJ. C.,
BaldwinP. J. W.,
KitchenerH. C.,
SternP. L.2003; Association between human leukocyte antigen polymorphism and human papillomavirus 16-positive vulval intraepithelial neoplasia in British women. Cancer Res 63:400–403
DupontE.,
HuygenK.,
SchandeneL.,
VandercruysM.,
PalflietK.,
WybranJ.1985; Influence of in vivo immunosuppressive drugs on production of lymphokines. Transplantation 39:143–147[CrossRef]
HanR.,
BreitburdF.,
MarcheP. N.,
OrthG.1992; Linkage of regression and malignant conversion of rabbit viral papillomas to MHC class II genes. Nature 356:66–68[CrossRef]
HanR.,
CladelN. M.,
ReedC. A.,
PengX.,
ChristensenN. D.1999; Protection of rabbits from viral challenge by gene gun-based intracutaneous vaccination with a combination of cottontail rabbit papillomavirus E1, E2, E6, and E7 genes. J Virol 73:7039–7043
HuJ.,
CladelN. M.,
PickelM. D.,
ChristensenN. D.2002a; Amino acid residues in the carboxy-terminal region of cottontail rabbit papillomavirus E6 influence spontaneous regression of cutaneous papillomas. J Virol 76:11801–11808[CrossRef]
HuJ.,
HanR.,
CladelN. M.,
PickelM. D.,
ChristensenN. D.2002b; Intracutaneous DNA vaccination with the E8 gene of cottontail rabbit papillomavirus induces protective immunity against virus challenge in rabbits. J Virol 76:6453–6459[CrossRef]
OrthG.,
FavreM.,
BreitburdF.,
CroissantO.,
JablonskaS.,
ObalekS.,
Jarzabek-ChorzelskaM.,
RzesaG.1980; Epidermodysplasia verruciformis: a model for the role of papillomaviruses in human cancer. In Viruses in Naturally Occurring Cancers vol 7 pp 259–282 Edited by
EssexM.,
TodaroG,
zur HausenH.
Cold Spring Harbor, NY: Cold Spring Harbor Laboratory;
SalmonJ.,
RamozN.,
CassonnetP.,
OrthG.,
BreitburdF.1997; A cottontail rabbit papillomavirus strain (CRPVb) with strikingly divergent E6 and E7 oncoproteins: an insight in the evolution of papillomaviruses. Virology 235:228–234[CrossRef]
SalmonJ.,
NonnenmacherM.,
CazéS.,
FlamantP.,
CroissantO.,
OrthG.,
BreitburdF.2000; Variation in the nucleotide sequence of cottontail rabbit papillomavirus a and b subtypes affects wart regression and malignant transformation and level of viral replication in domestic rabbits. J Virol 74:10766–10777[CrossRef]
ShahA. K.,
BrundageR. C.,
GratwohlA.,
SawchukR. J.1992; Pharmacokinetic model for subcutaneous absorption of cyclosporine in the rabbit during chronic treatment. J Pharm Sci 81:491–495[CrossRef]
SundaramP.,
TigelaarR. E.,
XiaoW.,
BrandsmaJ. L.1998; Intracutaneous vaccination of rabbits with the E6 gene of cottontail rabbit papillomavirus provides partial protection against virus challenge. Vaccine 16:613–623[CrossRef]
TiebenL. M.,
BerkhoutR. J. M.,
SmitsH. L.,
Bouwes BavinckJ. N.,
VermeerB. J.,
BruijnJ. A.,
Van der WoudeF. J.,
ter ScheggetJ.1994; Detection of epidermodysplasia verruciformis-like human papillomavirus types in malignant and premalignant skin lesions of renal transplant recipients. Br J Dermatol 131:226–230
WalboomersJ. M. M.,
JacobsM. V.,
ManosM. M.7 other authors1999; Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189:12–19[CrossRef]