Progress in eliminating HPV-associated disease

This special collection (Editors Peter L. Stern & Karen Canfell) consists of a series of reviews summarizing some of the key insights presented and discussed at the 32nd International Papillomavirus Conference (IPVC) and Asia-Oceania Research Organization in Genital Infection and Neoplasia (AOGIN) 2018, which was held in October 2018, in Sydney Australia. The conference was held at a pivotal moment for the International Papillomavirus Society, AOGIN and for HPV research: it came hard on the heels of the announcement by the Director-General of the World Health Organization (WHO) that cervical cancer elimination was within reach and that WHO would focus on the development of a draft strategic plan for elimination. Accordingly, the excitement was palpable as those involved in cutting-edge research in the basic sciences, clinical research and public health in this field came together to discuss the latest findings and insights in the genetics, cellular and molecular biology of HPV infection and carcinogenesis as well as the impact of current primary and secondary prevention strategies and the means for their further optimization. The first seven articles focus on more basic considerations of the natural history of HPV infection and disease. Importantly, all have important implications for the development and implementation of optimal screening or preventative or therapeutic regimes for HPV associated cancers. To begin, Brown & Leo [1] discuss the appropriate methodologies to identify relevant genetic factors in HPV infection and cervical neoplasia. Rare high and more common low penetrance host factors have been identified as influencing HPV persistence. The strongest associations are with Major Histocompatibility Complex (MHC) (Human leucocyte antigen, HLA) polymorphisms (implicating the immune response) and could potentially identify individuals at particular risk. Disease associated single nucleotide polymorphisms (SNPs) can also be used to identify populations with an increased risk for cervical cancer but more studies are required to identify the non-MHC factors. The next article by Doorbar [2] considers the cells in the epithelial tissue structures of the cervix (and other vulnerable tissues) that provide the targets for productive HPV infection and but also the potential for latency. This is important in considering the issues of HPV persistence, the critical factor in risk for developing cervical neoplasia. The next two articles examine the details of uptake and internalization of HPV during the infection process. The extracellular events are discussed in the context of wound healing whereby HPV hijacks normal cellular processes to facilitate virus entry, as discussed by Ozbun [3]. The HPV capsids interact with heparin sulphate proteoglycans (HSPG) and other molecules for cell binding and subsequently trigger post-entry trafficking to the nucleus. Mikuličić & Florin [4] describe the virus associated entry complex and clathrin independent endocytosis process. Tetraspanins and annexin provide spatial organization of the HPV associated molecules through recruitment of trafficking factors and L2 membrane penetration for virus entry. These events are critical to the understanding of how prophylactic vaccines may work or be further optimized. For a productive infection, HPV genome replication is linked to differentiation of the epithelial tissue and the latter involves remodelling of genome. Clearly such epigenetic differential methylation events significantly influence the HPV cell cycle. Doebertz and Prigge [5] present the case for initiation of transformation as linked to methylation of the HPV E2 binding sites in the upstream regulatory region (URR). The potential for such events may also relate to the target cell status in the tissue hierarchy. Smola [6] describes the consequences of a persistent HPV infection leading to chronic inflammatory responses which reinforce the infection and undermine otherwise potentially curative immune responses. In time, inadequate DNA repair provides for genetic mutations that can allow for further escape from natural tissue or immune control mechanisms driving neoplasia. This article emphasizes the importance of a functional immune system to enable the clearance of natural HPV infections. Given the emerging impact of some cancer immunotherapies these observations highlight the need to consider multifactorial approaches in treatment development. The biology of the beta PVs associated with cutaneous infections are somewhat different from the mucosal high risk PVs. As reviewed by Tomassino [7], the development of cutaneous squamous cell carcinoma appears to require UV exposure with the beta HPV infection necessary but thereafter dispensable. Thus therapeutic approaches targeting viral oncogenes where expression is obligatory for cancer driven by mucosal types is not a viable approach in skin cancers. The latter half of the special edition focuses on some of the successes, as well as the upcoming clinical and public health challenges and opportunities, in HPV prevention. The major burden of disease for HPV-related cancer is in lowand middle-income countries (LMIC), and for many of these, particularly in the sub-Saharan African region, human immunodeficiency virus (HIV) infection is endemic. Lacey [8] discusses the increase in risk of progression of HPV-related cancer in HIV-positive individuals. It is well established that immune responses to vaccination are not optimal in those with HIV infection, although anti-viral therapy (ART) plays a modulating role. However, there is currently limited and inconsistent direct evidence on the effectiveness of HPV vaccination in HIV-positive individuals. If standard HPV vaccination regimes prove to be less effective in HIV-positive individuals, possible public health responses might include the delivery of alternate vaccine regimes and/or dosing schedules in HPV-endemic populations or in individuals known to be HIV-positive. However, Lacey notes that the clinical evidence is