The global control and prevention of cervical cancer caused by HPV
Prof Thomas Broker - University of Alabama, Birmingham, USA
My specialty has been the basic scientific virology of human papilloma viruses on which we have worked since 1980. We have looked at various aspects of the HPV genome, the relations of the many genotypes to one another, the bioinformatic nature of those relationships, the mechanisms of gene expression, RNA processing and derivation of the various messenger RNAs and proteins, especially from the early regions of the virus. Our lab has also worked on the mechanisms of viral DNA replication and regulation of replication and together looking at the interactions between the viral proteins and the host proteins such that the virus has co-opted the host to enable viral replication and persistence. In the course of this work I played an instrumental role in the development of PCR technologies for diagnosis of HPV, both known types and also, to a larger extent, previously unknown types that could be found by the methods I invented. Those PCR strategies are very much in global implementation from many different companies at this point. So diagnosis has been a very important part of the work we’ve done.
In that respect we did a major study on HPV in the context of immunosuppression, whether it was due to kidney failure and blood dialysis which augments HPV activity or more, especially in the context of HIV/AIDS, finding that about 85% of patients are HPV positive and of them about 5 out of 8 are positive for multiple HPV types over time.
My wife, Dr Louise Chow, and I have also pioneered a lot of the efforts on organotypic epithelial raft cultures, a three dimensional tissue environment in which we can study the relation between HPV infection or specific gene products and the impact on the host tissues. In this environment we have been able to look at the expression of viral HPV E6 or E7 proteins alone or together and the consequences on the host tissue and specifically on moving the host into a cell cycle.
So in normal skin the only cycling cells are the basal or parabasal cell layers and every stratum above the cycling layers have withdrawn from cell cycle and are differentiating and no longer capable of supporting DNA synthesis. But the E7 protein in targeting members of the retinoblastoma susceptibility family, which includes RB itself, but a close family member called P130, this enables non-cycling cells to be pushed back into S phase and it’s at that time that the virus gains the ability and the access to host replication proteins. So we’ve been able to examine this in these three dimensional tissue culture environment, we’ve done a great deal of genetic analyses of the requirements of E7 protein or E6 or E5 in successfully interacting with the host to enable that transition from non-cycling into cycling cells.
One of the big surprises we found in this model was that the host DNA replicates first, as it normally would during S phase, the DNA synthesis phase of the cell cycle, but unexpectedly the HPV genome does not replicate and amplify at that time. Rather once the host DNA has completed replication and the cells transition to the G2 phase of the cell cycle, the so-called gap 2 pre-mitotic phase, at that point the host cells stall or pause in an extended G2 and it’s at that time that the viral DNA replicates and amplifies from a basal support number of about 20 to 50 copies per cell in the carrier state up to about 5,000 to 7,000 genome copies after this period of amplification. Once that occurs the cells pass out of this replicative mode, the viral early proteins, E6 and E7 and E1 and E2, stop getting made and the cells then are capable of making the late capsid proteins L1 and L2 which then package the newly amplified viral DNA. At that point the particles begin a maturation process after having encapsidated the viral DNA but they don’t complete the maturation of the particle until the virus particles are in dying cells that no longer support oxidative phosphorylation and electron transport and they begin to die. That places the cells in the oxidising atmosphere at the very top of the skin and that’s the final step in the maturation of the virus particle. They crosslink through disulphides which can only form in the presence of oxygen, rather than the normal reducing atmosphere of regular living cells. So with the infectious particles that we’ve been able to generate we can re-establish new rounds of infection and passage the HPV for the first time.
What are the essential steps for keeping the HPV virus as a disease agent under control on a global scale?
The first essential stage is understanding the natural history of HPV in all of its manifestations, whether it’s in the genital infections, oral, respiratory tract or just cutaneous. This is the subject I spoke about a few minutes ago, the full range of natural history. Beyond that point I believe there are six components that have to be achieved. The first that I’ll mention is prophylactic vaccines, the ability to vaccinate and prevent the primary infection. There are clearly important achievements in the past ten years to develop and implement prophylactic vaccines. The major limitation, however, is distribution and uptake, that is acceptance globally. My greatest concern is that a very small fraction of eligible females have been vaccinated, at best I believe this number is about 5% or 7% of the young females in the world and essentially none of the boys. So the coverage is actually extremely low at this point. The logistical problem that the world is up against is there are approximately 128 million babies born each year and that would be an age cohort. At present it is logistically absolutely impossible to vaccinate that number of children as they come to the age group nine, ten, eleven, twelve. So vaccines at best are going to be a very, very long prospect. I can only look back at the issue of polio where we had effective vaccines, both the Salk and the Sabin, in the 1950s and we still have countries in the world with polio although that number has now been reduced to about three areas in the world. But still it has taken sixty years against a virulent virus that everyone fears. With HPV it’s a much more subtle virus and the acceptance of vaccination has been startlingly low in almost any country. So I think the vaccines, while important, are limited in how many people they’ll protect and lives they’re going to save. Notably anybody who has already acquired HPV is not going to benefit from a prophylactic vaccine, they’ve already got the infections and absent any other interception, such as screening and treatment, people with HPV today are going to live out their lives with the same risk as people had fifty years ago. So that limits the benefit of a prophylactic vaccine.
The second thing that’s essential in a management programme is screening. The Pap smear has been a remarkably effective tool for identifying serious disease and allowing surgical intervention. The Pap smear really was developed in the 1950s and widely implemented by the 1960s and ‘70s. Pap smear with associated cytology is obviously a highly accepted method of screening. However, the molecular tools that are available today with the developments that have come out of understanding the molecular biology of HPV have resulted in many new types of screening tools that are vastly more sensitive and specific and predictive. These certainly include the PCR and other amplification based tools to detect viral DNA or even viral RNA and those are heavily supplemented by antibody probes that can detect important protein biomarkers. As a package, collectively these molecular tools are remarkably more efficient than anything possible by cytology. Again the limitation is the number of cytologists or pathologists capable of devoting their time and attention and their lives to cytological screening. In contrast, the molecular tools can be automated, they are quantified and they can be taught and interpreted much, much more easily and therefore I strongly feel that they’re going to not just complement but ultimately replace cytology as a screening tool.
The third component is the big missing link right now and that’s therapeutics. Almost all papilloma virus lesions today are treated surgically or ablatively, either by LEEP, the electrocautery, or cold knife, but also with cryosurgery or laser surgery among other things. These are both damaging and invasive type treatments and they require also the access to appropriately trained colposcopists or surgeons. What is urgently needed are topical drugs, topical inhibitors of HPV infections at any and all stages of disease, from primary infection and persistent infection to low and high grade intraepithelial neoplasia, to carcinoma in situ and to cancer. So what is urgently needed is a series of inhibitors that can be applied topically to lesions at whatever stage of progression they may be at that will specifically and selectively target them for destruction. I believe that there’s ample opportunity for developing such inhibitors that could either stop progression or preferably eradicate lesions altogether and clear the tissue from the HPV at whatever stage of disease has occurred. Therapy is an essential follow-up to diagnosis. It doesn’t do any good to diagnose if you can’t also tell the patient that there’s multiple means of treatment of what has just been found.
So you have vaccines, screening and therapies that are three key components that have been based on a thorough understanding of the natural history of HPV. Now beyond that you need three other things. The first is physician education, which can be achieved through continuing medical education, not only to doctors but to any healthcare providers including nurse midwives and anyone else who is likely to encounter the types of lesions that HPV infections can cause.
Beyond that you need public education achieved through the media and today the media could include a video, it could include print media and now especially it can include social media, communication among people. I would regard that as a very crucial stage in spreading the word and convincing the public as to the needs and to the possibilities. The other group that needs to be brought in are the decision makers and these would be government officials such as Ministry of Health, but also the funding branches of governments who are in a position to implement the necessary funds for paying for clinics, for vaccines, for screening, for treatment.
Another element that has played a major role is advocacy groups, primarily composed of patients or their families and they’ve had a very important role in lobbying decision makers for making appropriate choices in policy. That then moves to the issue of national healthcare policies which are going to differ from country to country or region to region but essentially must be addressed with the best means possible for different economies, different societies, different social points of view. But ultimately it’s essential for each country or region to make their own choices as to implementation of what is possible.
A critical challenge for the world is the diverse points of view regarding the value of life, the value of women, the value of children. I think this is something where universal peer pressure can move everyone to the respect for human life and health and with it the dignity that can come. So these are huge international problems in generating policies that can really reduce the burden of HPV infection and disease on the world.
So, to summarise, the second group of needs, it’s professional and public education, it’s legislative decisions regarding funding, whether it be for development of clinics or programmes or for ongoing basic research and development. Then it’s a question of implementing appropriate public health policies, both locally and then as part of the world community.
The other crucial component of such management and control is, of course, the role of the pharmaceutical and biotechnology industries in developing safe, affordable and effective products. It’s very clear that industries, as well as non-profits, have to co-ordinate and co-operate to achieve what’s possible. So I see this entire package of needs to be coherent and requiring co-ordination but I am absolutely confident that together it will eliminate HPV as a serious burden of disease, cancer and death.
How can we get this message out?
One of the best mechanisms for promoting awareness and sharing knowledge and engaging both the public policy people and also the clinicians and the basic research scientists is international congresses such as the one we’re having right here in Santiago. I would also highlight that there are regional meetings taking place all over the world each year on essentially every continent. All of these are ultimately feeding in to the International Papilloma Virus Society and again I would point out that our very next congress is in Seattle, Washington, USA from August 20th – 25th of year 2014 with the meeting in 2015 taking place in Lisbon, Portugal. I would hope that interested contributors to the meeting would come and share their own research and development and clinical understanding. The meetings typically have four major tracks of presentations, the first being in the basic sciences which would include the molecular biology of the papilloma viruses, both human and animal papilloma viruses, and the development and understanding of immunologic tools for managing and understanding HPV infections.
The second major track is clinical, that is the experience of clinicians in understanding and treating lesions that appear on patients. HPV being a major cause not only of anogenital tract infections but it’s becoming more and more clear how many of the infections of the oropharynx, nasal passages, base of the tongue and tonsils and larynx are associated with HPV infections.
The third track would be epidemiology assessments of both the screening programmes and the vaccine programmes. These are crucial to validating what we’ve achieved so far and guiding alterations in policy for both vaccines and screening.
Then finally public health implementation from very diverse societies and economies around the world is another huge component of the papilloma virus conferences, both in terms of establishing policy and then assessing the successes or weaknesses of the policies that have been followed. Again, the International Papilloma Virus Society conferences always begin with a two day, or sometimes three day, workshops for clinical training and for public health training. Then those two continuing medical education approved training workshops then transition into the basic research component of the meeting which will last another four days typically for the exchange of information on an annual basis concerning the basic sciences, immunology, clinical sciences, epidemiology and public health. So the society has really concentrated heavily on all aspects of bringing HPV infections and diseases under control and has achieved an immense amount in the past 30-35 years of meeting together essentially every year. The society has met in 17 different countries on 5 continents and we will continue to move from city to city, country to country, continent to continent in our upcoming meetings. So people are very welcome to join in on the conference or follow it from a distance. I think this is one of the major opportunities for keeping current with what has been achieved by such a large number of people. The papilloma meetings typically have representatives from over 80 countries, every imaginable discipline and very often about 2,000 or 2,200 participants at the meeting. So it’s truly a venue for global exchange of such information and everyone is very welcome to come and participate.
