Adenoassociated Virus Type 2-Induced Inhibition of the Human Papillomavirus Type 18 Promoter in Transgenic Mice

Abstract

The epithelium of the cervix uteri has been reported to be frequently coinfected with both human papillomaviruses (HPV) and helper virus-dependent adenoassociated viruses (AAV). Seroepidemiological data suggest that AAV infection could inhibit cervical cancer that is caused by specific ("high-risk") types of papillomaviruses. In vitro, infection with AAV type 2 (AAV-2) or transfection of AAV-2 early (rep) genes has been shown to inhibit transformation by papillomaviruses. To analyze the effects of AAV on HPV in vivo, we studied the influence of AAV-2 infection on the promoter activity of high-risk HPV type 18 (HPV-18) in mice, transgenic for sequences of the upstream regulatory region (URR) of HPV-18 controlling transcription of the reporter gene, lacZ. Transgenic animals (or tongue cells thereof, explanted and grown in culture) were treated with dexamethasone to induce the HPV-18 promoter. Simultaneously they were (i) infected with AAV, (ii) inoculated with AAV virus-like particles (VLPs; empty capsids), or (iii) mock infected. Inoculation with AAV-2 or VLPs inhibited activation of the HPV-18 promoter. In vitro, in baby hamster kidney cells transfected with the HPV-18-lacZ construct, tissue extracts from AAV-infected animals suppressed the HPV-18 URR to a similar extent as AAV infection did. Down-regulation of the HPV-18 promoter was less efficient with extracts from animals inoculated with VLPs and was not observed with extracts from uninfected or dexamethasone-treated animals. This indicates that AAV induces cellular factor(s) in vivo capable of mediating down-regulation of the HPV-18 promoter also in cells in vitro. In contrast, promoters of the low-risk HPV types (HPV-6, HPV-11) were not influenced by AAV infection as opposed to promoters of the high-risk types (HPV-18 and HPV-16).

The Interplay between Adeno-Associated Virus and Its Helper Viruses

“…This notion has driven the investigation of a number of studies that have particularly addressed the question of whether or not AAV may inhibit HPV-16 and, if it does, what the molecular mechanisms behind this phenomenon are. In fact, it has been found that AAV Rep proteins can suppress the papillomavirus promoter and hence inhibit the transformation of papillomavirus-infected cells in cellulo and in vivo [ 244 , 245 , 246 ]. Unfortunately, the hype around HPV-16 and AAV eased when new studies on the incidents of cervical cancer in the context of AAV seroprevalence showed that there is no correlation between AAV seroprevalence and the occurrence of HPV-16-induced carcinomas [ 247 ].…”

HPV E1 up-regulates replication-related biochemistries of AAV Rep78

“…The Ad and herpes virus helper genes have been studied extensively, however the specific biochemical functions of the HPV helper genes are yet to be determined. HPV-AAV interaction is also of interest as HPV is the main risk factor for the development of cervical cancer and AAV has been shown to inhibit papillomavirus-associated oncogenicity in epidemiologic, animal, and laboratory settings (Mayor et al, 1976; Georg-Fries et al, 1984; Hermonat, 1989; 1991; Su and Wu, 1996; Hermonat et al, 1997; Horer et al, 1995; Coker et al, 2001; Walz et al, 2002). The replication protein of HPV, E1, has a degree of homology with the Rep78 protein (Castella et al, 2006).…”

Adeno-associated virus may play a protective role against human papillomavirus-induced cervical lesions independent of HIV serostatus

“…AAV, a sexually-transmitted parvovirus without a definitive association to any human disease thus far, exerts a suppressive role on transformation induced by oncogenic viruses, such as HPV. 22,29,30 As a satellite virus, AAV requires co-infection with a helper virus to cause productive infection and HPV is reported to be the most prevalent such virus in the AAV-infected genital tract. 9,10,18…”

“…9,10,18 A possible bidirectional action was also observed, with AAV acting as a suppressor agent on HPV replication. 19–22 It becomes more meaningful if one takes into account the fact that HIV favours HPV infection and increases the persistence of HPV and consequently the progression of cervical lesions to cervical carcinoma. 23–25 AAVs, on the other hand, may play a protective role in HIV-positive women intervening in the course of HPV infection.…”