Le VIH, grâce à sa variabilité génétique, présente une grande capacité à échapper au système immunitaire et s’adapter à l’environnement. La recombinaison, source importante de cette variabilité, est illustrée par le grand nombre de formes recombinantes observées dans l’épidémie. Le laboratoire s’est intéressé à l’étude de ce mécanisme et des lois qui gouvernent l’apparition de ces formes et ce en se focalisant sur la recombinaison inter sous-types d’isolats primaires le long du gène de l’enveloppe. En plus de mettre en évidence les paramètres impliqués dans la génération et la sélection de ces formes dans la nature, le laboratoire a pu déterminer qu’une majorité des recombinants dans la région C2 du gène de l’enveloppe présente des défauts majeurs de fonctionnalité. Ces défauts étaient sans doute dus à une incompatibilité entre les deux portions de sous-types différents réassociées par la recombinaison. Afin d’identifier les régions impliquées dans cette perte de fonctionnalité, des chimères entre différents sous-types ont été construites et testées en entrée virale. Ces chimères présentent la région C2, V1V2 et V3 de sous-types différents du reste de la protéine. Les résultats obtenus ont permis de mettre en évidence que les régions V1V2 et C2 sont importantes pour le maintien de la fonctionnalité des protéines et que V1V2 est essentielle au maintien de l’interaction entre les sous-unités de l’enveloppe, la gp120 et la gp41. Cette étude a donc permis de déterminer que V1V2 et C2 font partie d’un réseau de coévolution important impliquant des interactions indispensables au maintien de la fonctionnalité de la protéine. / HIV presents a high genetic variability that is necessary for the virus to escape to the host immune response and to adapt to the environment. Recombination is an important source of this variability and contributes to the generation of recombinant forms in the epidemic. Using inter subtypes from primary isolates, the laboratory focused on the study of recombination along the envelope gene and the determination of the parameters involved in the generation and selection of these recombinant forms. Previous works in the laboratory showed that a majority of recombinants in C2 region of the envelope gene displayed an important loss of function. This loss was probably due to an incompatibility of the parts associated by recombination and that come from different origins. To identify the regions involved in the loss of functionality of these recombinants, chimeras where C2 and surrounding regions (V1V2 and V3) from a different subtype than the rest of the gene, were created and tested for their ability to mediate viral entry. The functionality tests showed that V1V2 and C2 are important to maintain the functionality of the protein. Indeed, V1V2 seem to be involved in the stability of the Env trimer by maintaining the interaction between the two subunits of the protein, gp120/gp41. This work shows that V1V2 and C2 regions are involved in a coevolution network and their interactions with other portions are essential to maintain the functionality of the protein.

This work introduces a combination of image processing and analysis methods that perform feature extraction, shape analysis and tomographic reconstruction of Electron Microscopy images. These have been implemented on images of the AIDS virus interacting with neutralizing molecules. The AIDS virus spike is the primary target of drug design as it is directly involved in infecting host cells. First, a fully automated technique is introduced that can extract sub-volumes of the AIDS virus spike and be used to build a statistical model without the need for any user supervision. Such an automatic feature extraction method can significantly enhance the overall process of shape analysis of the AIDS virus spike imaged through the electron microscope. Accurate models of the virus spike will help in the development of better drug design strategies. Secondly, a tomographic reconstruction method implemented using a shape based regularization technique is introduced. Spatial models of known features in the structure being reconstructed are integrated into the reconstruction process as regularizers. This regularization scheme is driven locally through shape information obtained from segmentation and compared with a known spatial model. This method shows reduced blurring, and an improvement in the resolution of the reconstructed volume was also measured. It performs better than popular current techniques and can be extended to other tomographic modalities. Improved Electron Tomography reconstructions will provide better structure elucidation and improved feature visualization, which can aid in solving key biological issues. / text