BetaHPV colonize the skin shortly after birth and are widespread. This is not a problem for healthy people – but for immunocompromised patients. A Cologne research team is now testing a new vaccination approach.
infections with High-risk HPV type of genus alpha (such as HPV16 or HPV18) are acquired shortly after the onset of sexual activity. They can cause anogenital carcinomas and carcinomas of the head and neck area. Currently approved HPV vaccines are based on the HPV L1 major capsid protein, which assemble into virus-like particles (VLPs) and induce type-specific neutralizing antibodies. They are used before the first sexual intercourse to prevent infection and thus the development of HPV-related lesions in the mucous membrane.
More white skin cancer
Prof. Baki Akgül from the Institute of Virology at Cologne University Hospital has now published the first preclinical data on a vaccination strategy against oncogenic papilloma viruses of the skin, the HPV types of the beta genus (betaHPV). The associated scientific Work has recently appeared. BetaHPV colonize the human skin in the first few weeks after birth and are very widespread in the general population. As a rule, different betaHPV can be detected on the skin of every human being, which means they are ubiquitous and part of the normal microbiological flora. However, the multiplication of the viruses is controlled and inhibited by the immune system, so that no disease develops.
However, in immunocompromised patients such as organ transplant recipients or HIV-infected people, there is increased virus replication in the skin, which causes many betaHPV-associated diseases such as warts and actinic keratoses as skin cancer precursors or even squamous cell carcinomas (white skin cancer) arise. As a result, these patients are much more likely to develop white skin cancer than the healthy general population.
New vaccine: A technical challenge
In contrast to the high-risk alphaHPV types, there are currently no prophylactic vaccines that can be administered to prevent skin cancer. Because HPV are able to actively suppress their recognition by innate immune system receptors called pattern recognition receptors (PRR), they can evade the innate immune response. 52 betaHPV types are currently known, with no high-risk types being defined, all of which are potentially involved in the development of squamous cell carcinoma on the skin. Due to the large number of types and the lack of classification into high and low risk types, the question arises as to whether the development of prophylactic pan-betaHPV vaccines based on VLPs represents a practicable strategy at all.
Since the protein sequences of the various HPV types are very different, a universal VLP-based vaccine that covers all HPV types with a multivalent L1-VLP-based vaccine poses a technical challenge. Akgül’s working group is pursuing a remedy here together with colleagues from the Institute for Clinical Chemistry and Clinical Pharmacology at the University Hospital in Bonn, developed a novel approach for targeted immune activation against betaHPV. “Our working hypothesis was to test whether the targeted re-activation of the PRR in betaHPV-positive precancerous lesions causes self-immunization against beta-HPV without having to know the exact persistent HPV types on the patient’s skin,” says accul.
Therapeutic activation of the PRR by specific ligands in the presence of high levels of virus could restore physiological activation of the immune system, leading to endogenous self-immunization and consequent virus eradication. Now, the efficacy of such a treatment to prevent betaHPV-induced skin tumors has been demonstrated in a proof-of-concept approach in the preclinical HPV8 transgenic mouse model that develops skin tumors spontaneously but also after mechanical wounding. Treatment with poly(I:C), a synthetic double-stranded RNA that activates the innate immune system, completely prevented the development of skin tumors in all treated animals. In addition, increased numbers of total and activated CD4 and CD8 T lymphocytes were detected in the skin of HPV8 transgenic mice treated with poly(I:C), but not in untreated control mice.
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Experiments depleting T cells in poly(I:C) treated animals have shown that CD4 T cells play an important role in poly(I:C) tumor prevention. Thus, poly(I:C) could be identified as a promising candidate for self-immunization to protect against betaHPV-induced skin tumors. In further experiments in animal models, it should now be clarified against which betaHPV genome sections or proteins the immune response is directed. Subsequently, these valuable findings regarding the use of specific immune stimulators as a future vaccination strategy in skin cancer prophylaxis in high-risk patients will be tested in clinical studies.
Image source: Drew Dizzy Graham, Unsplash
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