The Shope Papillomavirus (SPV) naturally infects rabbits, primarily the North American cottontail. This virus causes distinctive, often dramatic, tumorous growths on the skin of its host animals. SPV is historically significant because its investigation provided some of the first evidence that a non-cellular agent could cause tumor formation in a mammalian host, laying the groundwork for understanding oncoviruses—infectious agents capable of inducing cancer.
The Shope Papillomavirus and Rabbit Tumors
The Shope Papillomavirus, also known as Cottontail Rabbit Papillomavirus (CRPV), is a non-enveloped, circular, double-stranded DNA virus. It is predominantly found in its natural reservoir, the wild eastern cottontail rabbit (Sylvilagus floridanus), throughout the Midwestern United States. Infection leads to the proliferation of keratin-producing cells in the skin, which results in the formation of large, dark, wart-like growths called papillomas.
These growths often appear on the head, neck, and ears of the infected rabbit, sometimes taking on a hardened, horn-like appearance. This dramatic physical manifestation is thought to be the source of historical myths like the “jackalope.” Transmission of the virus in the wild primarily occurs through mechanical transfer by biting arthropods, such as ticks and mosquitoes.
The insects carry the virus from an infected animal and introduce it into the skin of a new host, often requiring a small abrasion or wound for successful infection. The resulting papillomas are usually benign in the wild cottontail host; however, they can grow large enough to impede the rabbit’s ability to eat, leading to starvation.
A biological feature of SPV is its potential for malignant transformation, which differs depending on the host species. In the natural cottontail host, approximately 25% of papillomas will progress to an invasive squamous cell carcinoma (SCC). However, when the virus experimentally infects a non-natural host, such as the domestic rabbit (Oryctolagus cuniculus), the rate of malignant transformation is much higher, with some sources indicating up to 75% of lesions can become cancerous.
The Landmark Discovery of Viral Carcinogenesis
The scientific investigation into this rabbit disease was spearheaded by the American virologist Richard Shope in the early 1930s. Shope began his work after receiving reports from hunters in Iowa describing rabbits with unusual “horn” protrusions. At the time, the prevailing scientific consensus largely dismissed the idea that viruses could cause solid tumors in mammals, despite earlier work on avian species.
Shope’s contribution was the demonstration that a filterable agent—something smaller than bacteria—was the infectious cause of these rabbit tumors. He achieved this by grinding up portions of the rabbit papillomas, creating a suspension, and passing it through a fine filter that excluded all bacteria and cells, yet the resulting filtrate remained infectious. By inoculating this cell-free filtrate into the skin of domestic rabbits, Shope successfully reproduced the papillomas, confirming the viral nature of the disease.
This finding established the Shope Papillomavirus as the first recognized DNA tumor virus. The work provided a tangible, reproducible model for studying the viral origins of cancer, paving the way for the field of tumor virology. Shope’s ability to isolate the infectious agent and transmit the disease experimentally established the rabbit model as a powerful tool for cancer research that persists to this day.
How SPV Transformed Cancer Research
The discovery of the Shope Papillomavirus established a precedent for the entire class of oncogenic viruses. This prompted researchers to search for similar agents in other animals and humans. This search eventually led to the identification of several human oncoviruses, including Epstein-Barr virus, Hepatitis B and C viruses, and, most notably, the Human Papillomavirus (HPV).
The SPV system provided an invaluable animal model due to the high degree of genetic and functional similarity between the rabbit virus and high-risk HPV types. For instance, the SPV genome contains genes that function analogously to the oncogenes in HPV. Specifically, the viral genes E6 and E7, which are present in both SPV and high-risk HPV, are responsible for disrupting the host cell’s normal growth controls.
Research using the SPV model helped clarify how these oncogenes drive malignant transformation. The E6 protein works to degrade p53, a cellular protein that normally suppresses tumors, while the E7 protein neutralizes the function of the retinoblastoma (Rb) protein, which regulates the cell cycle. By disabling these two major cellular checkpoints, the virus forces the host cell into uncontrolled division, a characteristic of cancer.
The most visible legacy of SPV research is its direct contribution to the development of the prophylactic HPV vaccine. Early studies using the SPV system demonstrated that the virus’s outer shell protein, called L1, could spontaneously assemble into non-infectious, virus-like particles (VLPs). The rabbit model showed that immunizing an animal with these L1 VLPs generated protective antibodies, a finding that served as the foundational evidence for the current, highly effective HPV vaccines.