Coevolution of restriction factors and retroviruses

Les virus exploitent la machinerie cellulaire de l'hôte pour se répliquer. Ils doivent s'adapter pour infecter la cellule hôte de manière optimale tout en échappant à la vigilance du système de défense de l'hôte. Ainsi l'hôte et les virus se livrent à de constantes batailles évolutives. Mon travail de thèse a porté sur l'étude des signatures évolutives de facteurs de l'hôte agissant comme des 'facteurs de restriction' en bloquant la réplication rétrovirale chez les primates. Plus spécifiquement, mon travail a visé à utiliser des données évolutives pour renseigner les analyses fonctionnelles et la biologie. Nous avons étudié le facteur anti-VIH-1 nommé TRIM5a (i) chez les prosimiens pour mieux comprendre son rôle dans le contrôle d'un lentivirus endogène, (ii) dans son activité contre d'autres anciennes infections représentées par des rétrovirus endogènes humains et (iii) en tant que protéine capable de générer des mutants de la capside. Premièrement nous nous sommes intéressés à TRIM5a chez deux espèces de lémuriens dont Microcebus murinus qui porte le lentivirus endogène PSIV dans son génome depuis plusieurs millions d'années,. Nous avons observé que TRIM5a chez M. murinus a un spectre d'activité antivirale réduit à l'opposé de TRIM5a chez le Lemur catta - non porteur du PSIV endogène - qui bloque une large variété de rétrovirus dont le PSIV. De ce fait TRIM5a aurait pu contribuer à protéger certaines espèces de lémuriens vis-à-vis d'anciennes infections par le PSIV. A l'inverse du PSIV, des virus dérivés des rétrovirus endogènes humains HERV-K and HERV-H se sont révélés largement résistants à l'inhibition par TRIM5a. Ces données illustrent une absence de protection par TRIM5a face à d'autres anciennes infections rétrovirales. Puis, pour évaluer l'impact de la protéine TRIM5a humaine sur le VIH-1, nous avons testé l'effet de mutations des résidues sous sélection positive dans la capside du VIH-1 sur l'inhibition par TRIM5a. Nos résultats montrent que TRIM5a ne jouerait pas un rôle significatif dans l'évolution de la capside du VIH-1. Enfin notre travail a porté sur le facteur anti-VIH-1 SAMHD1 récemment découvert, que nous avons séquencé chez 25 espèces de primates. L'analyse évolutive des sites sous sélection positive et des expériences fonctionnelles ont permis d'identifier le domaine de SAMHD1 interagissant avec la protéine lentivirale Vpx. De même que d'autres protéines virales contrecarrent les facteurs de restriction en les menant à la dégradation, nous avons observé que Vpx induit la dégradation de SAMHD1 de manière spécifique à l'espèce. Ces découvertes contribuent à comprendre comment les facteurs de restriction et les virus co-évoluent pour se neutraliser l'un l'autre. - Viruses hijack the host cellular machinery to replicate. They adapt to infect optimally host cells while escaping host defense systems. Viruses and the host coevolve in an evolutionary struggle. My thesis work has been devoted to study the evolutionary signatures of host factors acting as restriction factors that block retroviral replication in primates. Specifically, my work aimed at using evolutionary data to inform functional analyses and biology. We studied the anti-HIV-1 factor TRIM5a (i) in prosimians to better understand its possible role in the control of an endogenous lentivirus, (ii) in its activity against other ancient infections - as represented by HERVs, and (iii) as a protein capable of generating escape mutants in the viral capsid. First, my work focused on two lemur species, one of which was the gray mouse lemur that carries the endogenous lentivirus PSIV integrated in its genome for several million years. TRIM5a from gray mouse lemur exhibited a limited antiviral spectrum as opposed to TRIM5a from ring-tailed lemur - not a host of PSIV - that is able to block diverse retroviruses notably PSIV. These results support the possible contribution of TRIM5a in protecting lemur species from ancient infection by PSIV. In contrast, chimeric viruses derived from two human endogenous retroviruses were broadly resistant to TRIM5a-mediated restriction, suggesting TRIM5a lack of activity against other types of ancient infections. To evaluate the recent impact of human TRIM5a on HIV-1 evolution, we tested whether variants at positively selected sites in the HIV-1 capsid affected the ability of human TRIM5a alleles to restrict HIV-1. Our results indicate that TRIM5a does not play a significant role in the evolution of HIV1 capsid. At last, our work concentrated on the newly discovered anti-HIV-1 restriction factor SAMHD1. We determined its coding sequence in a panel of 25 species of primates. Evolutionary analyses of positively selected sites in SAMHD1 domains and functional assays identified the domain of SAMHD1 interacting with the lentiviral protein Vpx. Similar to other viral countermeasures targeting cellular restriction factors, Vpx was responsible of the degradation of SAMHD1 orthologs in a species-specific manner. These findings contributed to understanding how restriction factors and viruses evolve to counteract each other.

The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity

Anatomical structures and mechanisms linking genes to neuropsychiatric disorders are not deciphered. Reciprocal copy number variants at the 16p11.2 BP4-BP5 locus offer a unique opportunity to study the intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated the variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain metrics, we show that the number of genomic copies negatively correlated to the gray matter volume and white matter tissue properties in cortico-subcortical regions implicated in reward, language and social cognition. Despite the near absence of ASD or SZ diagnoses in our 16p11.2 cohort, the pattern of brain anatomy changes in carriers spatially overlaps with the well-established structural abnormalities in ASD and SZ. Using measures of peripheral mRNA levels, we confirm our genomic copy number findings. This combined molecular, neuroimaging and clinical approach, applied to larger datasets, will help interpret the relative contributions of genes to neuropsychiatric conditions by measuring their effect on local brain anatomy.Molecular Psychiatry advance online publication, 25 November 2014; doi:10.1038/mp.2014.145.

Identifying the neural correlates of executive functions in early cerebral microangiopathy: a combined VBM and DTI study.

Cerebral microangiopathy (CMA) has been associated with executive dysfunction and fronto-parietal neural network disruption. Advances in magnetic resonance imaging allow more detailed analyses of gray (e.g., voxel-based morphometry-VBM) and white matter (e.g., diffusion tensor imaging-DTI) than traditional visual rating scales. The current study investigated patients with early CMA and healthy control subjects with all three approaches. Neuropsychological assessment focused on executive functions, the cognitive domain most discussed in CMA. The DTI and age-related white matter changes rating scales revealed convergent results showing widespread white matter changes in early CMA. Correlations were found in frontal and parietal areas exclusively with speeded, but not with speed-corrected executive measures. The VBM analyses showed reduced gray matter in frontal areas. All three approaches confirmed the hypothesized fronto-parietal network disruption in early CMA. Innovative methods (DTI) converged with results from conventional methods (visual rating) while allowing greater spatial and tissue accuracy. They are thus valid additions to the analysis of neural correlates of cognitive dysfunction. We found a clear distinction between speeded and nonspeeded executive measures in relationship to imaging parameters. Cognitive slowing is related to disease severity in early CMA and therefore important for early diagnostics.

Systematic identification of genomic markers of drug sensitivity in cancer cells.

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.

Pollution and pollutant transport in the geosphere - An introduction to the symposium

Environmental research in earth sciences is focused on the geosphere, i.e. (1) waters and sediments of rivers, lakes and oceans, and (2) soils and underlying shallow rock formations,both water-unsaturated and -saturated. The subsurface is studied down to greater depths at sites where waste repositories or tunnels are planned and mining activities exist. In recent years, earth scientists have become more and more involved in pollution problems related to their classical field of interest, e.g. groundwater, ore deposits, or petroleum and non-metal natural deposits (gravel, clay, cement precursors). Major pollutants include chemical substances, radioactive isotopes and microorganisms. Mechanisms which govern the transport of pollutants are of physical, chemical (dissolution, precipitation, adsorption), or microbiological (transformation) nature. Land-use planning must reflect a sustainable development and sound scientific criteria. Today's environmental pollution requires working teams with an interdisciplinary background in earth sciences, hydrology, chemistry, biology, physics as well as engineering. This symposium brought together for the first time in Switzerland earth and soil scientists, physicists and chemists, to present and discuss environmental issues concerning the geosphere.

The newly defined "Greenstone Unit'' of the Aiguilles Rouges massif (western Alps): remnant of an Early Palaeozoic oceanic island-arc ?

In the southwestern part of the Aiguilles Rouges massif (pre-Alpine basement of the Helvetic realm, western Alps), a metavolcanic sequence, newly defined as the ``Greenstone Unit'',is exposed in two NS trending belts of several 100 metres in thickness. It consists of epidote amphibolites, partly epidote and/or calcic amphibole-bearing greenschists, and small amounts of alkali feldspar-bearing greenschists, which underwent low- to medium-grade metamorphism during Visean oblique collision. Metamorphic calcic amphiboles and epidotes show strong chemical zoning, whereas metamorphic plagioclase is exclusively albitic in composition (An 1-3). The SiO2 content of the subalkaline tholeiitic to calc-alkaline suite ranges continuously from 44 wt% to 73 wt%,but andesitic rocks predominate. The majority of samples have chemical compositions close to recent subduction-related lavas; some are even restricted to recent oceanic arcs (extremely low Ta and Nb contents, high La/Nb and Th/Ta ratios). But several basaltic to basalto-andesitic samples resemble continental tholeiites (low Th/Ta, La/Nb ratio). As it is very probable that both lava types are to some extent contemporaneous, it is proposed that the Greenstone Unit represents a former oceanic volcanic are which temporarily underwent extension during which emplacement of continental tholeiite-like rocks occurred. The cause of the extension remains ambiguous. Considering palaeotectonic significance and age of other metavolcanic units in the Aiguilles Rouges massif, the Greenstone Unit most likely formed in the Early Palaeozoic.

The age of movements along the insubric line West of Locarno (Northern Italy and southern Switzerland)

Permo-Mesozoic Canavese sediments are pinched in between the pre-Alpine high-grade metamorphic Ivrea Zone and the Alpine metamorphosed Sesia Zone along the Insubric Line W of Locarno. According to the ``illite crystallinity'' these sediments were deformed under anchi- and epizonal conditions. Synkinematically formed white mica in the mylonitized Canavese sediments yields the following K-Ar age ranges: 60-76 Ma at the southwestern end, 28-43 Ma in the central part and 19-26 Ma in the northeastern part of the Insubric Line W of Locarno. The youngest age group dates the main uplift and dextral strike-slip movements of the Insubric Line, comprising mylonites in the NE and cataclasites in the SW. This activity correlates with Late Oligocene to Early Miocene rapid cooling and uplift of the Central Alps.