Abstract Feline immunodeficiency virus (FIV) is an important infectious agent of domestic cats worldwide. It has been classified into the Lentivirus genus of the Retroviridae family, together with human immunodeficiency virus (HIV). Five FIV subtypes (A, B, C, D and E) have been described based on sequence variation of the V3-V5 region of the envelope (env) gene. There is considerable sequence diversity within and between subtypes, which has been a major obstacle in the development of a successful vaccine. However, an FIV vaccine that incorporates inactivated whole viruses from subtypes A and D is now commercially available. Although the vaccine has been shown to be efficacious in protecting against challenge with homologous and a heterologous (subtype B) subtypes, its effectiveness against other viral variants is unknown. Therefore, identifying the type and diversity of FIV strains in different regions is important to establish the potential efficacy of the vaccine in areas where vaccination is to be implemented. The proviral DNA sequence of the V3-V5 region of the env gene was determined for 102 FIV-infected cats from locations in Australia, New Zealand and South Africa. Subtype A was the predominant subtype in Australia and South Africa, although subtype B and C were also identified in each of these countries, respectively. Both subtypes A and C were also present in New Zealand. Of interest, there were some samples in New Zealand and South Africa that demonstrated subtype assignment discrepancies when different regions of the genome were analysed, suggesting co-infection and/or recombination. Cats infected with FIV exhibit varying degrees of immunological impairment. Currently, prognosis for an FIV-infected cat is based on clinical signs alone, which is a relatively subjective measure. In HIV-infected patients it is recognised that viral RNA load correlates with disease stage and prognosis. This PhD research tested whether viral RNA load may be a useful prognostic marker in FIV infection. A real-time PCR assay was developed to quantify plasma viral RNA load in 42 FIV-infected cats at three different clinical stages (1:healthy, 2:unwell without signs of immunodeficiency, 3:unwell with signs of immunodeficiency). In cats older than 5 years of age, log-transformed viral RNA loads were significantly higher in cats in category 3 compared to cats in category 1. There were no significant differences in the viral RNA load of older cats in category 2 compared to category 1. There were no cats younger than 5 years of age in category 3 and there was no significant difference in viral RNA load between young cats in categories 1 and 2. Of the 15 cats for which follow-up data was available, eight showed no change in clinical signs, and seven showed a worsening of clinical signs with six of these showing a progression of clinical category including death. One of the cats in category 2 that progressed clinically had one of the highest viral RNA loads of cats in that category. Three of four cats from category 3 that were followed had either died or been euthanised. Two of these cats had among the highest viral RNA loads in the whole study, while the remaining cat (for which the definitive cause of death was not confirmed) had a relatively low viral RNA load. In summary, measurement of viral RNA load was found to be a potentially useful clinical and prognostic marker but further work is required to better assess its usefulness to veterinarians. Serum acute phase proteins were investigated as possible candidate markers of FIV disease with the aim of developing a more simplified assay that could be used as a prognostic marker for FIV infection. Blood samples from 43 FIV-infected and 25 FIV-negative cats were assayed for the concentration of four acute phase proteins. Both healthy and sick cats were included in the study. Compared to healthy cats, sick cats had significantly higher concentrations of serum amyloid A (P<0.05). Alpha 1-acid glycoprotein and haptoglobin were also found to be in higher concentrations in sick cats (P<0.1). Other variables such as age and gender were also associated with acute phase protein concentrations. With respect to FIV infection, it was found that in sick cats, serum amyloid A, in combination with the age of the cat, was the best predictor of FIV viral RNA load. Alpha 1-acid glycoprotein and haptoglobin were not significantly associated with FIV viral RNA load. Although health status did not influence albumin levels, they were found to be significantly lower in FIV-positive cats in comparison to FIV-negative cats (P<0.05). The frequent monitoring of viral RNA loads and CD4+ lymphocyte counts that is performed on HIV-infected patients is cost prohibitive in veterinary patients. This study showed that there is potential for the use of acute phase protein concentrations (in particular serum amyloid A) as alternative prognostic tools in FIV-infected cats. Further work, particularly longitudinal studies, is required to more definitively define changes in viral RNA load and acute phase protein concentrations throughout the course of FIV infection.

In den letzten 26 Jahren konnte ein starker Anstieg von HIV-1 auf globaler Ebene beobachtet werden. Die außergewöhnliche Vielfalt von HIV-1 wird begründet durch die hohe Mutationsrate, starke Replikation, häufige Rekombination und strategische Verteilung von N-linked glycosylation sites. In der vorliegenden Arbeit wurde die genetische Variation von HIV-1 mit besonderem Fokus auf der Rekombination und den N-linked glycosylation sites untersucht.

Les protozooses digestives restent une des premières causes de morbidité, de malnutrition et de mortalité dans le monde. Cependant, la biologie de certains protozoaires entériques comme Blastocystis est mal connue et il reste négligé par les autorités sanitaires. Ce parasite colonise le tractus intestinal de l’Homme et de nombreux animaux. Son principal mode de transmission est la voie oro-fécale et sa prévalence peut dépasser 50% dans les pays en développement. Il présente une large diversité génétique avec 17 sous-types (STs) identifiés à ce jour. Un large faisceau de données récentes suggère que l’infection à Blastocystis est associée à une variété de troubles gastro-intestinaux et de l’urticaire.Dans le cadre de ma thèse, des études épidémiologiques ont été menées dans différents pays (Liban, Sénégal, France) afin de déterminer la prévalence de ce parasite dans la population humaine et identifier des facteurs de risque d’infection. En parallèle, à travers une enquête dans des zoos français, des réservoirs animaux de transmission zoonotique du parasite ont été proposés. D’autre part, les mécanismes impliqués dans la colonisation de l’hôte par Blastocystis ont été étudiés.Dans le cadre des enquêtes épidémiologiques, le parasite a été recherché dans les selles par PCR en temps réel et l’amplicon obtenu séquencé pour le sous-typage. La première étude menée au Liban a montré une prévalence de 19% dans la population générale mais cette prévalence atteint 60% dans une population d’écoliers vivant dans la même région. Une prévalence de 100% a été obtenue dans une cohorte d’enfants sénégalais. Ces fortes prévalences s’expliquent par des conditions d’hygiènes très précaires. Le ST3 était prédominant dans ces deux pays suivi des ST1 et ST2. Dans une étude multicentrique menée en France, une prévalence globale de 18,3% a été obtenue avec une prédominance du ST3 suivi des ST1, ST4 et ST2. Cette distribution est aussi celle observée dans une majorité de pays européens. Dans l’étude française, des variables (voyage récent, âge, saison) ont été identifiés comme des facteurs de risque de transmission du parasite. Le contact avec des animaux peut représenter un autre facteur de risque du fait du potentiel zoonotique du parasite. Dans une large étude épidémiologique réalisée dans deux zoos français sur plus de 160 espèces animales, la prévalence globale de Blastocystis dépasse 30% avec des variations importantes selon les groupes d’animaux. En comparant la distribution des STs entre l’Homme et les différents groupes d’animaux, les primates, les artiodactyles (bovins et cochons) et les oiseaux représenteraient les principaux réservoirs potentiels d’infection pour l’Homme.Une association entre l’infection à Blastocystis et l’appendicite a été mise en évidence chez une enfant au Maroc confirmant la pathogénie et le potentiel invasif et inflammatoire du parasite. De plus, 26 autres membres de sa famille ont présenté des symptômes digestifs suggérant une épidémie de blastocystose d’origine hydrique. L’hypothèse d’une relation entre ST de Blastocystis et pouvoir pathogène a été émise d’où l’intérêt d’une étude de génomique comparative afin d’identifier des facteurs de virulence pouvant être spécifiques d’un ST. A ce jour, aucune différence n’a pu être mise en évidence entre le génome de ST4 séquencé durant ma thèse et celui de ST7 disponible dans les bases de données alors qu’ils présentent une virulence différente in vitro. Enfin, l’impact de la colonisation par Blastocystis sur la composition du microbiote intestinal humain a été évalué. Une approche par séquençage à haut-débit a permis de comparer les compositions des microbiotes de patients infectés ou non par Blastocystis montrant une diversité bactérienne plus élevée chez les patients colonisés par le parasite. Ces données suggèrent que la colonisation par Blastocystis ne serait pas associée à une dysbiose intestinale généralement observée dans les maladies infectieuses intestinales. / Digestive protozoan infections are a major cause of morbidity, malnutrition and mortality worldwide. However, the biology of some enteric protozoa as Blastocystis is not well known and these microorganisms remain still neglected by the health authorities. Briefly, this parasite colonizes the intestinal tract of humans and various animals. Its main mode of transmission is the fecal-oral route and its prevalence can exceed 50% in developing countries. It exhibits a large genetic diversity with 17 subtypes (STs) identified to date. Recent data suggest that infection with Blastocystis is associated with a variety of gastrointestinal disorders and urticaria. As part of my thesis, epidemiological studies have been conducted in different countries (Lebanon, Senegal, France) to determine the prevalence of this parasite in the human population and identify risk factors for infection. In parallel, through a survey in French zoos, animal reservoirs of zoonotic transmission of Blastocystis have been proposed. Moreover, mechanisms involved in the colonization of the host by the parasite were studied.As part of, epidemiological, the parasite was identified in faecal samples by real-time PCR and the resulting amplicon was sequenced for subtyping. The first study conducted in Lebanon in the Tripoli area showed a prevalence of 19% in the general population but this prevalence reached 60% in a population of school children living in the same region. A prevalence of 100% was obtained in a cohort of Senegalese children. The high prevalence observed in these countries can be explained by poor hygiene conditions in connection with the faecal peril. In terms of distribution of STs, the ST3 was predominant in both countries followed by ST1 and ST2. In a multicenter study conducted in France, an overall prevalence of 18.3% was obtained with a predominance of ST3, followed by ST1, ST2 and ST4. This distribution is quite similar to that observed in most European countries. In the French study, parasite prevalence was significantly higher in summer than in winter. Other variables such as a recent trip and age have been identified as risk factors for transmission of the parasite. The contact with animals may represent another risk factor because of the zoonotic potential of the parasite. In a large epidemiological study conducted in two French zoos and including over 160 animal species, the overall prevalence of Blastocystis exceeds 30% with significant variations between animal groups. By comparing the distribution of STs between humans and different groups of animals, primates, artiodactyls (cattle and pigs) and birds represent major potential reservoirs of infection for humans.An association between infection with Blastocystis and appendicitis was demonstrated in a child in Morocco confirming the pathogenicity and invasive and inflammatory potential of the parasite. In addition, 26 other family members presented digestive symptoms suggesting waterborne outbreak of blastocystosis. The hypothesis of a relationship between Blastocystis ST and pathogenicity was suggested hence the interest of a comparative genomics study to identify virulence factors that may be present or absent for some STs. No difference was found between the ST4 genome sequenced during my thesis and the ST7 genome available in the database while these STs have different virulence in vitro. Finally, the unknown impact of colonization by Blastocystis on the composition of the human intestinal microbiota was evaluated. The compositions of the bacterial microbiota of 96 patients infected or not by Blastocystis were obtained by high-throughput sequencing and compared. A higher bacterial diversity was found in colonized patients compared to non-infected patients. These data suggest that colonization by Blastocystis would not be associated with dysbiosis generally observed in intestinal infectious diseases but rather to a healthy intestinal microbiota.

Le système de types de la logique d'ordre supérieur permet d'exclure certaines expressions indésirables telles que l'application d'un prédicat à lui-même. Cependant, il ne suffit pas pour vérifier des critères plus complexes comme l'absence de divisions par zéro. Cette thèse est consacrée à l’étude d’une extension de la logique d’ordre supérieur appelée sous-typage par prédicats (predicate subtyping), dont l'objet est de rendre l'attribution de types aussi expressive que l'attribution de prédicats. A partir d'un type A et d'un prédicat P(x) de domaine A, le sous-typage par prédicats permet de construire un sous-type de A, noté {x : A | P(x)}, dont les éléments sont les termes t de type A tels que P(t) est démontrable. Le sous-typage par prédicats est au coeur du système PVS.Ce travail présente la formalisation d'un système minimal incluant le sous-typage par prédicats, appelé PVS-Core, ainsi qu'un système de certificats vérifiables pour PVS-Core. Ce deuxième système, appelé PVS-Cert, repose sur l'introduction de termes de preuves et de coercions explicites. PVS-Core et PVS-Cert sont munis d'une notion de conversion correspondant respectivement à l'égalité modulo beta et à l'égalité modulo beta et effacement des coercions, choisi pour établir une correspondance simple entre les deux systèmes.La construction de PVS-Cert est semblable à celle des PTS (Pure Type Systems) avec paires dépendantes et PVS-Cert peut être muni de la notion de beta-sigma-réduction utilisée au coeur de ces systèmes. L'un des principaux théorèmes démontré dans ce travail est la normalisation forte de la réduction sous-jacente à la conversion et de la beta-sigma-réduction. Ce théorème permet d'une part de construire un algorithme de vérification du typage (et des preuves) pour PVS-Cert et d'autre part de démontrer un résultat d'élimination des coupures, utilisé à son tour pour prouver plusieurs propriétés importantes des deux systèmes étudiés. Par ailleurs, il est également démontré que PVS-Cert est une extension conservative du PTS lambda-HOL, et qu'en conséquence PVS-Core est une extension conservative de la logique d'ordre supérieur.Une deuxième partie présente le prototype d'une instrumentation de PVS pour produire des certificats de preuve. Une troisième et dernière partie est consacrée à l'étude de liens entre logique classique et constructive avec la définition d'une traduction par double négation minimale ainsi que la présentation d'un algorithme de constructivisation automatique des preuves. / The type system of higher-order logic allows to exclude some unexpected expressions such as the application of a predicate to itself. However, it is not sufficient to verify more complex criteria such as the absence of divisions by zero. This thesis is dedicated to the study of an extension of higher-order logic, named predicate subtyping, whose purpose is to make the assignment of types as expressive as the assignment of predicates. Starting from a type A and a predicate P(x) of domain A, predicate subtyping allows to build a subtype of A, denoted {x : A | P(x)}, whose elements are the terms t of type A such that P(t) is provable. Predicate subtyping is at the heart of the proof system PVS.This work presents the formalization of a minimal system expressing predicate subtyping, named PVS-Core, as well as a system of verifiable certificates for PVS-Core. This second system, named PVS-Cert, is based on the introduction of proof terms and explicit coercions. PVS-Core and PVS-Cert are equipped with a notion of conversion corresponding respectively to equality modulo beta and to equality modulo beta and the erasure of coercions, chosen to establish a simple correspondence between the two systems.The construction of PVS-Cert is similar to that of PTSs (Pure Type Systems) with dependent pairs and PVS-Cert can be equipped with the notion of beta-sigma-reduction used at the core of these systems. One of the main theorems proved in this work is the strong normalization of both the reduction underlying the conversion and beta-sigma-reduction. This theorem allows, on the one hand, to build a type-checking (and proof-checking) algorithm for PVS-Cert and, on the other hand, to prove a cut elimination result, used in turn to prove important properties of the two studied systems. Furthermore, it is also proved that PVS-Cert is a conservative extension of the PTS lambda-HOL and that, as a consequence, PVS-Core is a conservative extension of higher-order logic.A second part presents the prototype of an instrumentation of PVS to generate proof certificates. A third and final part is dedicated to the study of links between classical and constructive logic, with the definition of a minimal double-negation translation as well as the presentation of an automated proof constructivization algorithm.

There is a gender gap in United States politics; men are over represented, and prioritize issues/policies differently compared with women. Stereotypes may be associated depending on group memberships. Stereotypes of men (competent) are consistent and stereotypes of women (warm) are inconsistent with politicians (competent). I examined stereotypes of major/non-major political parties, and how party affiliation affects whether stereotypes about men/male politicians/women/female politicians predict female politicians’ traits. Stereotype valence ascribed to political parties is important because people vote for a positively viewed party/representative. I assessed the strength and valence of stereotypes associated with political parties, and found major parties were viewed more positively than non-major parties, and the Democratic and Republican parties were viewed more positively than the Independent Party (Study 1). I found warmth and competence attributes ascribed to women/female politicians/men/male politicians predicted Karen Johnson’s warmth and competence depending on whether Karen Johnson was a major or non-major party candidate. When men/male politicians were perceived as competent Karen Johnson was perceived as competent, but no relationship between men/male politicians’ warmth and Karen Johnson’s warmth emerged. When women/female politicians were perceived as warm/competent, Karen Johnson was perceived as warm/competent. As a major candidate, Karen Johnson was perceived as warm/competent when women/female politicians were perceived as warm/competent. However, when Karen Johnson was a non-major candidate, there was no relationship between women’s competence and Karen Johnson’s competence, and when women/female politicians were perceived as warm, Karen Johnson was perceived as warm (Study 2). Women in office and members of multiple social groups are discussed.