The Shope Papillomavirus (SPV), also known as the Cottontail Rabbit Papillomavirus (CRPV), is a DNA virus belonging to the Papillomaviridae family, classified within the genus Kappapapillomavirus. It primarily infects the North American cottontail rabbit (Sylvilagus genus) but can also infect other lagomorph species. The infection manifests physically as keratinous masses that protrude from the animal’s skin. These growths are a form of neoplastic transformation resulting from the virus’s ability to drive uncontrolled cell division in the host’s epithelial tissue. Studying SPV has provided fundamental insights into the mechanisms by which viruses induce cancer, which has had profound implications for human health.
Historical Discovery and Scientific Importance
The existence of “horned rabbits” in the Midwestern United States sparked scientific curiosity in the early 1930s. American virologist Richard E. Shope investigated reports from hunters describing rabbits with horn-like protrusions on their heads and necks. Shope successfully isolated a filterable agent from these growths, demonstrating it could transmit the condition to healthy rabbits. This agent was identified as the Shope Papillomavirus in 1933, representing a breakthrough in cancer research.
Shope’s work established the first conclusive evidence that a virus could directly cause a tumor in a mammal. This discovery fundamentally shifted the understanding of cancer causation, which had previously been viewed as purely genetic or environmental. The finding created the field of viral oncology and provided a mammalian model to study how infectious agents initiate tumor development. The ability to experimentally induce the condition allowed for controlled study of the transformation process, paving the way for subsequent cancer research.
Clinical Presentation in Host Animals
Infection with SPV leads to the development of papillomas. These lesions start as small, raised foci before growing into large, rough, and highly keratinized masses. They are most commonly observed on the hair-bearing skin of the rabbit, especially around the face, neck, and shoulders. The hardened masses can become large enough to obstruct the animal’s vision or interfere with its ability to feed, potentially leading to starvation.
The prognosis varies significantly between the natural host and other species. In the wild cottontail rabbit (Sylvilagus genus), the tumors often exhibit regression as the immune system clears the infection. However, when the virus infects non-natural hosts like domestic rabbits (Oryctolagus cuniculus), the tumors are more aggressive and rarely regress. These non-regressing lesions have a high rate of malignant transformation, progressing to invasive squamous cell carcinoma in up to 75% of cases. Transmission of SPV in the wild is primarily facilitated by biting arthropod vectors, such as ticks and mosquitoes, which carry the virus from an infected rabbit to a new host.
Molecular Basis of Tumor Induction
The induction of tumors relies on a small set of genes expressed early in the viral life cycle. These genes code for viral proteins known as E6 and E7, which are functional homologs to the oncogenes found in high-risk human papillomaviruses. The E6 protein operates by targeting the host cell’s tumor suppressor protein, p53, for destruction. The p53 protein is normally responsible for halting the cell cycle or initiating programmed cell death (apoptosis) in response to DNA damage.
By stimulating the degradation of p53, the viral E6 protein removes this cellular safeguard, allowing damaged cells to survive and proliferate. Simultaneously, the viral E7 protein interferes with the function of another major tumor suppressor, the retinoblastoma protein (Rb). The Rb protein normally acts as a brake on the cell cycle by binding to and inactivating transcription factors that promote cell division. When E7 binds to Rb, it releases these transcription factors, pushing the host cell into continuous, uncontrolled growth. The combined action of E6 and E7 deregulates the host cell cycle, creating an environment of cellular immortality and unchecked proliferation characteristic of cancer. This molecular strategy of neutralizing two major tumor suppressors is a conserved mechanism across the papillomavirus family, underscoring the functional similarity between the rabbit and human viruses.
Significance as a Model for Human Cancer
The study of SPV has served as a foundational model for understanding Human Papillomavirus (HPV) and its link to human cancers. SPV was the first papillomavirus identified, and its pathogenesis closely mirrors the progression of high-risk HPV infections in humans. The genetic and functional homology between the rabbit virus and high-risk HPV types, particularly the shared mechanism of E6 and E7 oncoproteins, made the rabbit model ideal for preclinical research.
Scientists used the SPV-infected rabbit model extensively to test the efficacy of novel antiviral and anti-tumor compounds before human trials. The most significant translational success resulting from this model is the development of the prophylactic HPV vaccine. The initial proof-of-concept experiments for creating a vaccine based on virus-like particles (VLPs) of the major capsid protein (L1) were first conducted using the SPV system. The ability of the rabbit’s immune system to generate neutralizing antibodies in response to the SPV VLPs provided the data necessary to develop the highly effective vaccines currently used to prevent HPV infection in humans. The SPV model continues to be employed for investigating viral-host interactions and immune responses to papillomaviruses, providing a framework for developing new diagnostics and therapeutic strategies against HPV-related cancers.