Human Oncoviruses and p53 Tumor Suppressor Pathway Deregulation at the Origin of Human Cancers

Viral oncogenesis is a multistep process largely depending on the complex interplay between viruses and host factors. The oncoviruses are capable of subverting the cell signaling machinery and metabolic pathways and exploit them for infection, replication, and persistence. Several viral oncoproteins are able to functionally inactivate the tumor suppressor p53, causing deregulated expression of many genes orchestrated by p53, such as those involved in apoptosis, DNA stability, and cell proliferation. The Epstein–Barr virus (EBV) BZLF1, the high-risk human papillomavirus (HPV) E6, and the hepatitis C virus (HCV) NS5 proteins have shown to directly bind to and degrade p53. The hepatitis B virus (HBV) HBx and the human T cell lymphotropic virus-1 (HTLV-1) Tax proteins inhibit p53 activity through the modulation of p300/CBP nuclear factors, while the Kaposi’s sarcoma herpesvirus (HHV8) LANA, vIRF-1 and vIRF-3 proteins have been shown to destabilize the oncosuppressor, causing a decrease in its levels in the infected cells. The large T antigen of the Merkel cell polyomavirus (MCPyV) does not bind to p53 but significantly reduces p53-dependent transcription. This review describes the main molecular mechanisms involved in the interaction between viral oncoproteins and p53-related pathways as well as in the development of therapeutic strategies targeting such interactions

Identification of Human Herpesvirus 8 Sequences in Conjunctiva Intraepithelial Neoplasia and Squamous Cell Carcinoma of Ugandan Patients

The incidence of squamous cell carcinoma of the conjunctiva is particularly high in sub-Saharan Africa with temporal trends similar to those of Kaposi sarcoma (KS). Human herpesvirus type 8 (HHV8), has not yet been investigated in conjunctiva tumors. In this study biopsies and PBMCs of conjunctiva neoplasia patients along with nonneoplastic conjunctiva tissues have been analyzed for HHV8 sequences by PCR targeting ORF26. All amplimers were subjected to nucleotide sequencing followed by phylogenetic analysis. HHV8 DNA has been identified in 12 out of 48 (25%) HIV-positive, and in 2 out of 24 (8.3%) HIV-negative conjunctiva neoplastic tissues and in 4 out of 33 (12.1%) PBMC samples from conjunctiva neoplasia diseased patients as well as in 4 out of 60 (6.7%) nontumor conjunctiva tissues. The viral load ranged from 1 to 400 copies/105 cells. Phylogenetic analysis showed that the majority of HHV8 ORF26 amplimers clustered with subtypes R (n=11) and B2 (n=6). This variant distribution is in agreement with that of HHV8 variants previously identified in Ugandan KS cases. The presence of HHV8 in conjunctiva tumors from HIV-positive patients warrants further studies to test whether HHV8 products released by infected cells may have paracrine effects on the growth of conjunctiva lesions

Candidate Soluble Immune Mediators in Young Women with High-Risk Human Papillomavirus Infection: High Expression of Chemokines Promoting Angiogenesis and Cell Proliferation.

BACKGROUND:The causal interpretation of cervical immune response to Human Papillomavirus (HPV) infection is complex and poorly characterized mainly due to the delicate balance that exists between viral infection, increase of inflammatory cytokines and host risk factors. This study aims to explore the significance of cervical immune mediators associated to cell survival, angiogenesis and interaction with immune response, in predicting the risk to develop HPV-related intraepithelial lesions. METHODS:A panel of 48 cytokines and growth factors were explored in a selected cohort of 168 immunocompetent women including 88 diagnosed with low (LSIL) or high (HSIL) squamous intraepithelial lesions of the cervix and 80 with normal cervical cytology (NIL). HPV genotyping was performed by Linear Array HPV test and the soluble concentration of 48 immune molecules was analyzed using the Bio-Plex platform. RESULTS:The prevalence of single HR-HPV infection was 30% in NIL and 100% in LSIL and HSIL women. The expression of 13 cytokines, including interleukins IL-6, IL-3, IL-12p40, IL-12p70, IL-16, IL-18, LIF, of chemokines CCL7 (MCP-3), CXCL9 (MIG), CXCL12 (SDF-1α) and of the tropic factors VEGF, G-CSF, M-CSF were significantly associated with the presence of infection, with levels being higher in women with precancerous lesions compared to NIL HPV negative women. Only the growth factor GM-CSF was positively associated with the cytological abnormalities. CONCLUSIONS:The ability of HR-HPV to escape from innate immune recognition and to orchestrate the production of specific inflammatory and growth factors, involved in early inflammatory response and in the cell-proliferating phase of intraepithelial damage, was documented in women before the development of cervical lesions

Detection of Human Papillomaviruses in the Nasopharynx of Breastfed Infants: New Findings and Meta-Analysis

Vertical transmission of human papillomaviruses (HPVs) from mother to infant is known to occur during labor, delivery or breastfeeding. Infection with mucosal HPV 6 and 11 may cause recurrent respiratory papillomatosis in children, which is a rare and severe respiratory disease. The cutaneous HPV genotypes have also been described to be transmitted from mother to newborn through skin-to-skin contacts and during breastfeeding. To investigate the perinatal transmission of alpha and beta HPVs we collected nasopharyngeal specimens from 0–12-months-old infants born by vaginal delivery and breastfed at the time of sample collection. The mucosal and cutaneous HPVs were searched by nested PCR using the MY09/11-MGPs and CP65/70-CP66/69 primer sets, respectively, and genotypes identified by direct sequencing analysis. Fourteen out of 113 (12.4%) samples tested positive for HPV and sequence analysis allowed us to identify eight beta genotypes (HPV 5b, 20, 25, 100, 107, 124, 152 and RTRX7). Moreover, we performed a comprehensive review of published studies on the prevalence of mucosal and cutaneous HPVs among 5126 newborns and observed that 10% and 53% were positive for alpha and beta HPVs, respectively. In all studies there was an inverse correlation between the rate of alpha HPV positivity and age, while a significant positive trend was observed in beta HPV detection and age with the highest rate among children older than 12 months (Χ2 test for trend of 10.6, p < 0.001). Further studies are needed to confirm the hypothesis that beta HPVs are transmitted to breastfeeding infants through shedding of viruses in the breast milk or on the external breast epithelium

The median values of significant immune mediators between HPV+CYT- <i>vs</i> LSIL <i>vs</i> HSIL groups.

<p>The median values of significant immune mediators between HPV+CYT- <i>vs</i> LSIL <i>vs</i> HSIL groups.</p

The median values of significant immune mediators in cervical fluid of HR-HPV positive women.

<p>The median values of significant immune mediators in cervical fluid of HR-HPV positive women.</p

The median values of significant immune mediators between HPV+CYT- <i>vs</i> LSIL <i>vs</i> HSIL groups.

<p>The median values of significant immune mediators between HPV+CYT- <i>vs</i> LSIL <i>vs</i> HSIL groups.</p

Concentrations of immune mediators with deregulated expression in cervical-vaginal fluid of HPV positive and HPV negative women.

<p>Concentrations of immune mediators with deregulated expression in cervical-vaginal fluid of HPV positive and HPV negative women.</p

Cytokines, chemokines and trophic factors detected by Luminex multiplex panel technology.

<p>Cytokines, chemokines and trophic factors detected by Luminex multiplex panel technology.</p