Thousands of cats are housed in rescue shelters worldwide. Unfortunately, the welfare of these animals is often compromised. Environmental enrichment is' frequently used in an attempt to improve the physical and psychological well-being of sheltered cats. To date, the use of sensory enrichment for such animals has been overlooked. This thesis thus aimed to explore the potential value of sensory stimulation as a method of enrichment for cats residing in one of the leading feline rescue charities in the United Kingdom, Cats Protection. Four experiments were conducted; the first assessed the general behaviour exhibited by cats in the rescue shelter in order to establish baseline levels of activity, while the subsequent three experiments explored the effects of sensory enrichment (visual, olfactory and auditory) on the behaviour and welfare ofsuch animals. For all experiments, cats were studied for three hours a day for three days. Each animal's behaviour was recorded every five minutes over the three hours oftesting per day using time-sampling. Results from the experiments indicated that the cats were experiencing some degree of chronic stress likely to be associated with boredom. Some of the sensory stimulations had a positive effect upon the behaviour and welfare of the animals studied. Visual stimulation, particularly that combining elements of prey items and linear movement, was considered the most effective type of environmental enrichment. Olfactory stimulation in the form of catnip also offered welfare advantages, promoting play and behavioural diversity. Auditory stimulation had inconclusive results on the behaviour of the sheltered cats, and at this stage is not recommended as a form of environmental enrichment for such animals. Overall, it is concluded that certain types of sensory stimulation harbour enrichment potential for sheltered cats. Further long-term studies in this area are highly advocated, however, before generalised conclusions can be drawn.

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Strong adaptive evolutionary forces shape the interactions between pathogens and their hosts and typically lead to a stable co-existence. In this process of co-evolution, mammals have developed restriction factors that limit retrovirus infectivity, replication or assembly and narrow the spectrum of potential host species. These restriction factors are either constitutively expressed, such as APOBEC3 proteins, cytidine deaminases that interfere with reverse transcription, or form part of the type I interferon-induced innate immunity, such as TRIM5, a member of the tripartite motif protein family that induces degradation of retroviral capsid, blocks reverse transcription, or tetherin (BST-2, CD317), which inhibits release of nascent viral particles from infected cells. Conversely, viruses have evolved antagonists of restriction factors or proteins that limit IFN-induced gene expression, thus evading immune surveillance. The interaction between host and viral components is delicately balanced and has a significant impact on disease outcome. Feline immunodeficiency virus (FIV), a lentivirus closely related to human immunodeficiency virus (HIV), is a recent introduction into domestic cats and causes an immunodeficiency syndrome analogous to human AIDS. Interestingly, non-domestic cats such as lion or pumas have co-existed with lentiviruses for prolonged periods of time and FIV infections are largely benign. Although plasma viral and proviral loads are high in both domestic and non-domestic cats, in vitro studies have shown that FIV infection of non-domestic cat T lymphocytes is significantly less efficient than that of domestic cat T cells. Thus, this thesis tests the hypothesis that the differential disease outcome of FIV infections in felids is caused by differences in lentiviral restriction factor activities or their sensitivities to FIV restriction factor antagonists. Data presented in this study show for the first time that feline APOBEC3 proteins are expressed in tissues and cell types relevant for FIV infection. The APOBEC3 proteins A3H and A3CH exhibited a high antiviral activity against FIV lacking the APOBEC3 antagonist Vif in single-cycle replication assays, with no difference in activity being detected between domestic and non-domestic cat proteins. However, domestic cat A3CH was significantly more sensitive to antagonism by FIV Vif than lion or puma A3CH, which would allow efficient viral replication in domestic cat T lymphocytes and subsequently lead to T cell loss and immunodeficiency. Furthermore, this thesis provides evidence that felid tetherins can prevent FIV particle release from producer cells in single-cycle replication assays; however, stable expression of domestic and non-domestic cat tetherins in feline cell lines did not abrogate FIV replication. Indeed, syncytium formation indicative of viral cell-to-cell spread was significantly enhanced in type I interferon-treated feline cells infected with CD134-independent strains of FIV which often arise in chronic (late) stages of FIV infections in vivo. Finally, this work reports the generation of a synthetic domestic cat TRIM5α-cyclophilin A fusion protein which was highly efficient at preventing FIV pseudotype and productive infection. This novel feline restriction factor represents a potent antiviral defence agent with very low potential for toxicity and could in future be used in gene therapy approaches to treat FIV-infected cats.

Feline immunodeficiency virus (FIV) is an important pathogen of domestic cats which in some cases can lead to feline AIDS. It shares many similarities with its human counterpart and is studied to understand correlates of immune-protection and mechanisms of disease progression in cats, both to improve the welfare of infected cats and as an animal model for the pathogenesis of HIV infection in humans. FIV is believed to evolve during the course of infection as a result of the error prone nature of reverse transcriptase and recombination between viral variants, but relatively little is known about this process in naturally occurring infection. Ultimately, it remains unknown why some infected cats remain healthy while others progress to AIDS rapidly. The studies reported in this thesis addressed this lack of knowledge by examining sequential blood samples obtained during the course of natural FIV infection in a population of 44 privately owned domestic cats. Employing Bayesian coalescent framework, it was demonstrated that the FIV env gene is relatively stable genetically. Although not necessary a prerequisite, this is likely to explain why many naturally infected cats can remain healthy and do not progress to AIDS. By determining the cell tropism of isolated viral variants, it was shown that sick cats were more likely to harbour viruses of the “late” phenotype than healthy animals, similar to the co-receptor switch observed during the progression of HIV infection. Intra-host diversity analyses highlighted a likely role for the leader region of the env gene in viral pathogenesis. Furthermore, recombination was demonstrated to be abundant in natural infection, indicating a requirement for the current phylogenetic classification of FIV to be revised. By assessing the strength and breadth of neutralising antibodies (NAbs), it was shown that NAbs did not appear to influence the course of natural FIV infection, arguing against a role in controlling infection and disease progression. Following an examination of samples collected from a group of privately owned Australian vaccinates, it was shown that the Fel-O-Vax FIV vaccine did not induce cross-reactive neutralising antibodies. Furthermore, in the country where commercial FIV vaccine is licenced, we identified and characterised the virus strain which was likely able to establish infection in vaccinated cat and raised concerns of vaccine’s efficacy. Overall this study broadens our understanding of natural FIV infection, and highlights that much can be learned, not from the similarities but rather by studying the differences between the feline and human lentiviruses. Such comparative studies are likely to contribute to design of highly desirable, safe and fully efficacious lentiviral vaccines.

Feline Osteoarthritis (OA) is a pathological change of a diarthrodial articulation which primarily occurs in older cats. The aims of this study were:- 1) to define the radiographic features of OA in the cat for each individual appendicular joint; 2) to relate the radiographic features to the gross pathologic and histopathologic features; 3) to explore underlying causes of OA in cats, 4) to identify the presence of Protease Activated Receptor-2 (PAR-2) and matriptase in feline articular cartilage and synovial membrane and to determine their role in OA pathogenesis. The present study has defined five radiographic features of OA for each appendicular joint:- presence of osteophytes, enthesiophytes, areas of abnormal mineralisation,synovial effusion and joint remodelling. The study furthermore suggested that increases in radio-opacity beneath the semilunar notch, along the femoral trochlea, beneath the tibial plateau and on the femoral head/neck are also important radiographic features. The radiographic prevalence was highest in the elbow (23.9%, 93/389) and stifle (23.9%,93/389) joints, followed by the hip (21.1%, 82/389), tarsal (17.7%, 69/389), shoulder(6.7%, 27/389) and carpal (6.4%, 25/389) joints. The results from this study demonstrate that the presence of a radiographically apparent supinator sesamoid bone(SSB), meniscal mineralisation (MM) and two fabellae are related to cartilage pathology and can be indicators of OA. Prevalence rates for gross pathology changes were highest in the elbow (20.2%,102/506) joint, followed by the stifle (19.6%, 99/506), hip (18.4%, 93/506), shoulder (17.8%, 90/506), tarsal (15.0%, 76/506), and carpal (9.1%, 46/506) joints. Eight key gross pathologic features were identified- cartilage discolouration, cartilage fibrillation,cartilage ulceration, cartilage erosion, osteophytes, thickening of joint capsule, synovium discolouration and joint remodelling. The radiographic and gross pathologic total scores were positively correlated in each appendicular joint and the joint most likely to have cartilage damage without radiographic evidence of OA is the shoulder (71.1%, 64/90) followed by the elbow (39.1%, 9/23), hip (32.4%, 11/34), stifle (26.1%,6/23), carpal (23.1%, 21/91) and tarsal (14.9%, 7/47) joints. Four possible underlying conditions that lead to secondary OA were identified:- radioulnar incongruity, hip dysplasia (HD), cranial cruciate ligament (CCL) disease and primary meniscal mineralisation. The identification of PAR-2 and matriptase proteins and gene expression in feline articular tissues is a novel and important finding supporting the hypothesis that serine proteases are involved in the articular cartilage degradation seen in feline OA.

This research focused on three areas of interest regarding feline amputees; owner perception of how their cats adapt to limb amputation, the possibility of phantom sensation, and changes in gait. In general owners felt their cats had an acceptable quality of life; however a proportion believed their cat experienced pain. Anecdotally, owners reported that their cats continued to attempt to use the missing limb following amputation. This prompted the investigation of noninnate forelimb behaviours potentially indicative of phantom sensation; such behaviours apparently persist for months or years after amputation. The impact of phantom sensation on feline welfare is not known, although in humans phantom sensation is a risk factor for phantom pain. Alterations in gait and posture in humans are associated with pain and osteoarthritis. The kinetic changes in feline gait were assessed using a pressure sensitive walkway; this provided its own challenges as the software was designed for large bipeds. As such, a proportion of this work was devoted to developing methods to reliably extract data for small quadrupeds. The results detail how feline amputees alter their weight distribution and paw placement when moving. Observation of amputee cats suggests that they move their limbs differently to those of normal cats, and this was confirmed in a kinematic study using markers to track the motion of each limb. Prior to this research very little was known about how cats coped with limb amputation. The results will better inform the veterinary profession and owners of feline amputees about expected changes, and potentially inform future work on the impact of limb amputation on the welfare of cats. On balance, although there may be some areas of concern, the welfare of cats is acceptable following amputation.