The Reservoir of Persistent Human Papillomavirus Infection; Strategies for Elimination Using Anti-Viral Therapies

Abstract

Human Papillomaviruses have co-evolved with their human host, with each of the over 200 known HPV types infecting distinct epithelial niches to cause diverse disease pathologies. Despite the success of prophylactic vaccines in preventing high-risk HPV infection, the development of HPV anti-viral therapies has been hampered by the lack of enzymatic viral functions, and by difficulties in translating the results of in vitro experiments into clinically useful treatment regimes. In this review, we discuss recent advances in anti-HPV drug development, and highlight the importance of understanding persistent HPV infections for future anti-viral design. In the infected epithelial basal layer, HPV genomes are maintained at a very low copy number, with only limited viral gene expression; factors which allow them to hide from the host immune system. However, HPV gene expression confers an elevated proliferative potential, a delayed commitment to differentiation, and preferential persistence of the infected cell in the epithelial basal layer, when compared to their uninfected neighbours. To a large extent, this is driven by the viral E6 protein, which functions in the HPV life cycle as a modulator of epithelial homeostasis. By targeting HPV gene products involved in the maintenance of the viral reservoir, there appears to be new opportunities for the control or elimination of chronic HPV infections.

Modeling and Mathematical Analysis of the Dynamics of HPV in Cervical Epithelial Cells: Transient, Acute, Latency, and Chronic Infections

“…The results of the local sensitivity analysis ( Figure 11 ) should be considered together with simulated outputs of virus dynamics models and the possible interventions to be carried out. In our model of the dynamics of HPV infection, the viral transmission rate ( β ) and viral production rate ( σ ) could be reduced by developing antiviral therapies targeting inhibition of new infections and viral replication, respectively, which is still under investigation [ 36 , 37 ]. The viral clearance rate ( γ ) is traditionally increased by the antibody immune response induced by vaccines.…”

“…Note that quantities A > 0 and C > 0, since γ and μ * C are positive parameters, and E is also positive. By the inequalities (37) and (38), we have that B is positive and D is nonnegative. Thus, in terms of this new notation, the quantities (40)-(43) can be rewritten as…”

E6AP is important for HPV E6’s role in regulating epithelial homeostasis and its loss impairs keratinocyte commitment to differentiation

“…In this study, our results clearly show that high or low-risk E6 expression increased the proportion of cycling cells at both pre-confluence and post-confluence (figure 1). Because E6 has a prominent role in overcoming normal keratinocyte contact inhibition (Kranjec et al, 2017; Luna et al, 2021; Zheng et al, 2022), cells expressing E6 typically reached a higher saturation density than the control cells. Nevertheless, 16E6-expressing cells always reach higher saturation density whereas 11E6-expressing cells reach lower density.…”

It Takes Two to Tango: A Review of Oncogenic Virus and Host Microbiome Associated Inflammation in Head and Neck Cancer

“…Infection of the basal layer establishes a reservoir of infected cells. The viral lifecycle has adapted to produce the majority viral proteins once in the apical layers of epithelium, which do not have as many active immune cells [79]. In the intermediate layer, the non-lytic replicative cycle produces fewer free viral markers that would otherwise alert the innate immune system [80].…”