Abstract

Infection by oncogenic human papillomavirus (HPV) is the principle cause of cervical cancer and other anogenital cancers. The majority of cervical cancer cases occur in low- and middle-income countries (LMIC). Prophylactic vaccines exist to combat HPV infection but accessibility to these in LMIC is limited. Alternative preventative measures against HPV infection are therefore also needed to control cervical cancer risk. HPV employs multiple mechanisms to evade the host immune response. Therefore, an approach to promote HPV recognition by the immune system can reduce infection. Surfactant proteins A and D (SP-A and SP-D) are highly effective innate opsonins of pathogens. Their function is primarily understood in the lung, but they are also expressed at other sites of the body, including the female reproductive tract (FRT). We hypothesized that raised levels of SP-A and/or SP-D may enhance immune recognition of HPV and reduce infection. Co-immunoprecipitation and flow cytometry experiments showed that purified human SP-A protein directly bound HPV16 pseudovirions (HPV16-PsVs), and the resulting HPV16-PsVs/SP-A complex enhanced uptake of HPV16-PsVs by RAW264.7 murine macrophages. In contrast, a recombinant fragment of human SP-D bound HPV16-PsVs weakly and had no effect on viral uptake. To assess if SP-A modulates HPV16-PsVs infection in vivo, a murine cervicovaginal challenge model was applied. Surprisingly, neither naïve nor C57BL/6 mice challenged with HPV16-PsVs expressed SP-A in the FRT. However, pre-incubation of HPV16-PsVs with purified human SP-A at a 1:10 (w/w) ratio significantly reduced the level of HPV16-PsV infection. When isolated cells from FRTs of naïve C57BL/6 mice were incubated with HPV16-PsVs and stained for selected innate immune cell populations by flow cytometry, significant increases in HPV16-PsVs uptake by eosinophils, neutrophils, monocytes, and macrophages were observed over time using SP-A-pre-adsorbed virions compared to control particles. This study is the first to describe a biochemical and functional association of HPV16 virions with the innate immune molecule SP-A. We show that SP-A impairs HPV16-PsVs infection and propose that SP-A is a potential candidate for use in topical microbicides which provide protection against new HPV infections.

Highlights

  • Human papillomavirus (HPV) is the most common viral infection of the reproductive tract.According to their association with malignancy, human papillomavirus (HPV) are broadly divided into high-risk and low-risk types

  • L1 (CamVir) revealed a direct biochemical association between the virions and SP-A and to a much lesser degree with recombinant SP-D: while HPV16-PsVs could be detected in the eluate when the HPV/SP-A input was immunoprecipitated with an SP-A antibody (Figure 1A), the majority of the virions derived from the HPV/SP-D input were detected in the flow through (FT) fraction and very little in the eluate when immunoprecipitated with an SP-D antibody (Figure 1B)

  • To test whether this physical interaction between SP-A and HPV16-PsVs had any functional consequences on immune cell recognition, virus internalization assays using the murine macrophage cell line RAW264.7 were performed

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Summary

Introduction

Human papillomavirus (HPV) is the most common viral infection of the reproductive tract.According to their association with malignancy, HPVs are broadly divided into high-risk and low-risk types. High-risk HPVs represent one of the seven groups of oncogenic viruses known to date which have been recognized to be consistently associated with various types of human cancer [1], with HPV types 16 and 18 being the most common oncogenic HPV types world-wide and the major cause of cervical cancer [2]. This disease is substantially more prevalent in low-and middle-income countries (LMIC), and is the leading cause of female cancer-associated deaths in Sub-Saharan Africa, not least due to the concomitant Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemic in this region [3,4,5]. This inhibitory effect was supported by clinical trials demonstrating a negative association of HPV infection with the vaginal microbicide Carraguard [9]

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