Prevalence and Risk Factors of Infection with High Risk Human Papilloma Viruses among HIV-Positive Women with Clinical Manifestations of Tuberculosis in a Middle-Income Country

Women living with HIV-1 are at high risk of infection with human papillomavirus of high carcinogenic risk (HR HPVs). M. tuberculosis (TB) promotes HPV infection and increases the risk to develop HPV-associated cancer. Our knowledge of persisting HR HPVs genotypes, and of the factors promoting HR HPV infection in people living with HIV-1 with clinical TB manifestations is sparse. Here, we analyzed 58 women living with HIV-1 with clinical TB manifestations (WLWH with TB) followed up in specialized centers in Russia, a middle income country endemic for HIV-1 and TB, for the presence in cervical smears of DNA of twelve HR HPV genotypes. DNA encoding HPV16 E5, E6/E7 was sequenced. Sociodemographic data of patients was collected by questionnaire. All women were at C2-C3 stages of HIV-infection (by CDC). The majority were over 30 years old, had secondary education, were unemployed, had sexual partners, experienced 2–3 pregnancies and at least one abortion, and were smokers. The most prevalent was HPV16 detected in the cervical smears of 38% of study participants. Altogether 34.5% of study participants were positive for HR HPV types other than HPV16; however, but none of these types was seen in more than 7% of tested samples. Altogether, 20.7% of study participants were positive for several HR HPV types. Infections with HPVs other than HPV16 were common among WLWH with generalized TB receiving combined ART/TB-therapy, and associated with their ability to work, indirectly reflecting both their health and lifestyle. The overall prevalence of HR HPVs was associated with sexual activity of women reflected by the number of pregnancies, and of HPV 16, with young age; none was associated to CD4+-counts, route of HIV-infection, duration of life with HIV, forms of TB-infection, or duration of ART, characterizing the immune status. Thus, WLWH with TB—especially young—were predisposed to infection with HPV16, advancing it as a basis for a therapeutic HPV vaccine. Phylogenetic analysis of HPV16 E5, E6/E7 DNA revealed no common ancestry; sequences were similar to those of the European and American HPV16 strains, indicating that HPV vaccine for WLWH could be the same as HPV16 vaccines developed for the general population. Sociodemographic and health correlates of HR HPV prevalence in WLWH deserve further analysis to develop criteria/recommendations for prophylactic catch-up and therapeutic HPV vaccination of this highly susceptible and vulnerable population group.

Human Papillomavirus 16 E5 Inhibits Interferon Signaling and Supports Episomal Viral Maintenance

ABSTRACT Human papillomaviruses (HPVs) infect keratinocytes of stratified epithelia. Long-term persistence of infection is a critical risk factor for the development of HPV-induced malignancies. Through the actions of its oncogenes, HPV evades host immune responses to facilitate its productive life cycle. In this work, we discovered a previously unknown function of the HPV16 E5 oncoprotein in the suppression of interferon (IFN) responses. This suppression is focused on keratinocyte-specific IFN-κ and is mediated through E5-induced changes in growth factor signaling pathways, as identified through phosphoproteomics analysis. The loss of E5 in keratinocytes maintaining the complete HPV16 genome results in the derepression of IFNK transcription and subsequent JAK/STAT-dependent upregulation of several IFN-stimulated genes (ISGs) at both the mRNA and protein levels. We also established a link between the loss of E5 and the subsequent loss of genome maintenance and stability, resulting in increased genome integration. IMPORTANCE Persistent human papillomavirus infections can cause a variety of significant cancers. The ability of HPV to persist depends on evasion of the host immune system. In this study, we show that the HPV16 E5 protein can suppress an important aspect of the host immune response. In addition, we find that the E5 protein is important for helping the virus avoid integration into the host genome, which is a frequent step along the pathway to cancer development.