The 4th of March is HPV awareness day. HPV stands for Human Papillomavirus which is a double-stranded DNA virus. Over 220 genotypes of HPV have been identified to date and these can broadly be classified into high- and low-risk viruses based on their ability to cause cancer during a prolonged and abortive infection. The two strains that cause the vast majority of cancer cases are HPV16 and HPV18.

It’s worth pointing out that normal infection even with a high-risk HPV strain doesn’t always proceed to cancer. Normally a transient and productive infection occurs which results in the formation of new virions of HPV. These are recognised by the immune response and infection is then cleared by the body's immune system. A problem can arise when we get persistence of infection. Here, the viral life cycle can become disrupted and this can drive increased cell cycling. This is driven by two of HPV’s proteins which are classed as oncoproteins: E6 and E7. Oncoproteins are classed as proteins that can drive a cell towards cancer. E6 and E7 act to inhibit the normal role of the cell cycle checkpoint proteins p53 and Retinoblastoma protein. These cell cycle checkpoint proteins normally act to prevent unhealthy cells from committing to the continuation of the cell cycle. However, with E6 and E7 inhibition of their normal roles, even unhealthy cells can proceed through the cell cycle which can allow for the accumulation of genetic mutations and tumorigenesis. HPV is responsible for 5% of cancers worldwide, including cancers in the anogenital region, including cervical cancer and oropharyngeal cancers. Some HPVs are sexually transmitted.

There are now many health measures that exist which can allow us to prevent infection with HPV or to detect it early enough to allow for treatment before progression of the disease can occur. Whilst no antiviral exists to HPV, there is a prophylactic vaccine which is administered before puberty (commonly around the time of infection). This vaccine is composed of virus-like particles (VLP’s) of the viral capsid protein, L1. L1 can be thought of as almost Lego building blocks that form the structure of the virion. Conveniently for researchers working on the vaccine, these L1 proteins spontaneously self-assemble to form structures that resemble the virus – these virus-like particles. When administered via the vaccine, these VLPs are recognised by the immune response and the body can mount a strong, protective immune response which can protect against subsequent infection. Different vaccines exist against HPV, with up to 9 strains of the virus covered, but importantly all of them protect against HPV16 and HPV18 which cause the majority of disease.

The other really important preventative health measure against HPV is a smear test. It used to be that a cervical smear was taken and used for cytology to detect any abnormal and potentially tumorigenic cells. Now a test is used to detect HPV first and if positive, is followed up with cytology to look for any cellular changes. HPV primary screening was adopted as common practice as it was determined to be more accurate than cytology alone. It’s important to note that just because you are HPV positive, this doesn’t mean you will have cellular changes. I recently attended the Betty Macgregor memorial lecture and I think her story is important to include in the narrative of screening. She was the cytologist who made NE Scotland the UK’s first centre for systematic cervical screening and due to her results, screening was taken up throughout the UK.

There are also many great public engagement groups which are helping to spread the word about HPV and cervical cancer. Just a few of these include Jo’s Cervical Cancer Trust – the UK's leading cervical cancer charity which offers a helpline, stories and information, I am Cervivor – a cervical cancer patient advocacy group dedicated to eradicating cervical cancer and Ask About HPV- an initiative developed by IPVS to spread information about HPV. Disseminating information about HPV and its role in testing and cervical cancer is especially important as a recent study by CRUK revealed that only 12% of individuals surveyed knew the role HPV testing played in cervical screening.

My PhD is in HPV and one of the most interesting parts to me about the virus is how it has two parts to its life cycle – an early and late stage and it intricately coordinates these with the differentiation status of the cells of the epithelium that it infects. If we imagine the epithelium as a wall, the cells or bricks at the bottom are actively proliferating, undifferentiated cells. Here the virus is in the early stages of its life cycle. As we then move up the wall of our epithelium the bricks towards the upper half represent cells that are beginning to differentiate and those at the top represent terminally differentiated cells. In these differentiated cells, the virus switches to the late stage of its life cycle.

My supervisor, Professor Sheila Graham, and I recently published a review article in the Journal of Medical Virology that reviews the current understanding of the late events of the viral life cycle and how this coincides with epithelial cell differentiation. The virus needs to undergo this switch as the linkage of the late viral events to epithelial differentiation ensures immune evasion – the viral late proteins are highly immunogenic, as mentioned previously, and the upper epithelial layers are an immune-privileged site. Moreover, as some of these late proteins are capsid proteins, the expression of these in the upper epithelial layers ensures spatial coupling of virion formation to the site of virion egress.

We considered how late viral expression is inhibited in undifferentiated cells as whilst there are early and late promoters within the HPV genome, it is not quite as simple as an on/off switch between these in undifferentiated and differentiated cells. In fact, the RNA Pol II is already loaded onto the late promoter in undifferentiated cells but it is transcription elongation which is inhibited. Other layers of regulation include early and late polyadenylation sites and these are reinforced by the binding of polyadenylation enhancing factors and splicing factors which encourage the formation and or activity of the cleavage/polyA complex on the early 3’UTR. Moreover, even if late viral transcripts are produced in undifferentiated cells multiple mechanisms make them unstable and improperly processed which would target them for degradation

We then considered the activation of viral late gene expression in differentiated cells. Multiple mechanisms control this including viral genome amplification, epigenetic changes, chromatin remodelling, and transcription controlled by differentiation stage-specific transcription complexes alongside inhibition of repressive transcription factors that previously kept the expression of these late transcripts inhibited. Again, splicing and polyadenylation play a large role and the use of the late polyadenylation site is upregulated in these differentiated tissues. HPVs also contain a late regulatory element in their genome which whilst playing a role in inhibiting late mRNA polyadenylation in undifferentiated cells, may in turn activate the splicing of late transcripts in differentiated cells. These are just a few examples from this review and if interested, it is published in the Journal of Medical Virology

Finally, I would recommend everyone to go to your smear test. The latest cervical screening figures from NHS England (2021-2022) revealed that almost a third (30%) of eligible people didn’t attend their appointment when last invited. This is a really important preventative health measure against cervical disease. Also, get vaccinated if you are eligible!