Specific antibodies protect us from a viral infection – or not? Scientists from the German Cancer Research Center (DKFZ) examined the immune response of mice to papillomaviruses and found a previously unknown mechanism by which the pathogens outwit the immune system: at the beginning of the infection cycle, they produce a longer version of a virus envelope protein. The body forms antibodies against it – which are, however, ineffective in the fight against the original structure of the pathogen.
The human immune system has a variety of defense strategies available to combat pathogens. This happens, among other things, through the formation of antibodies that fight viruses and bacteria. But over time, the pathogens have developed sophisticated methods to escape the immune system.
Several such strategies are already known to scientists. In the case of human papillomaviruses (HPV), these have so far only referred to the so-called “innate”, ie already existing immunity and not to the acquired immunity, which only develops after the pathogen has penetrated. Under the leadership of Daniel Hasche, Frank Rösl and his colleagues at the DKFZ have now discovered a new mechanism with which so-called cutaneous, skin-specific papilloma viruses mislead the immune system.
Infected from birth
Certain cutaneous HPVs, such as HPV5 or HPV8, occur as natural infections on the skin. These infections do not occur sexually, but are transmitted to the newborn by the mother during childbirth. Family members are usually populated with the same HPV types. An infection usually goes unnoticed because the body can successfully fight the pathogens. However, certain cutaneous HPV types can stimulate their host cells to divide, depending on the individual status of the immune system, the genetic background, age and other external factors such as UV radiation. This leads to skin changes and, in rare cases, the development of squamous cell carcinoma, also known as white skin cancer.
The experiments were carried out on a specific mouse species (Mastomys coucha), which, like humans, is infected with cutaneous papilloma viruses shortly after birth and forms specific antibodies against the virus. In combination with UV radiation, infected animals develop white skin cancer.
The animal’s immune system forms antibodies against the two viral proteins L1 and L2, which make up the virus envelope. These antibodies can prevent the viruses from entering the host cell and thus neutralize the virus. However, the experiments showed that the viruses produce a longer variant of the L1 protein in addition to the usual proteins. This is not able to actually participate in the construction of the viral envelope. Instead, it serves as a kind of bait against which the immune system is directed and forms specific antibodies.
Immune system produces “useless” antibodies
However, the scientists were able to show that these antibodies are unable to successfully combat the papilloma virus. Instead of neutralizing the infectious agent by binding to L1, they only bind the non-functional bait protein. While the immune system is busy producing these “useless” antibodies, the original virus can continue to multiply and spread throughout the body. Only after a few more months do neutralizing antibodies appear which are directed against the normal variant of the L1 protein and thus against the actually infectious viruses.
“Whether rodent or human – in almost all HPV types that can trigger cancer, the L1 gene is designed in such a way that a longer variant of the protein could also be formed. This also applies to high-risk HPV types, such as HPV16 or HPV18, which can cause cervical cancer. It therefore seems to be a widespread mechanism that allows viruses to multiply and spread efficiently in the early infection phase, ”explains Daniel Hasche. “The fact that antibodies against papilloma viruses are detectable does not necessarily have to go hand in hand with protection against infection. This will have to be taken into account in the future when evaluating and interpreting epidemiological studies, ”Frank Rösl points out.
Yingying Fu, Rui Cao, Miriam Schäfer, Sonja Stephan, Ilona-Braspenning-Wesch, Laura Schmitt, Ralf Bischoff, Martin Müller, Kai Schäfer, Sabrina E. Vinzón, Frank Rösl and Daniel Hasche: Expression of different L1 isoforms of Mastomys natalensis papillomavirus as a mechanism to circumvent adaptive immunity. eLife 2020, https://doi.org/10.7554/eLife.57626