L'infection par le VIH : rôle des facteurs viraux.

Abstract

L’étude de la dynamique de la population virale a montré que la présence de cellules sanctuaires infectées, quiescentes, empêchait l’éradication du virus par les thérapies actuelles. Une meilleure connaissance du mode d’entrée du virus et de sa réplication devrait permettre d’envisager de nouveaux modes d’intervention antivirale : les inhibiteurs de la transcriptase inverse restent les mieux connus, mais on peut espérer agir aussi sur la protéine NCp7 de la nucléocapside virale et sur les protéines de la matrice virale. En effet, NCp7 chaperonne la transcriptase inverse et est impliquée dans la libération de la particule virale, et les protéines de la matrice sont actives au niveau de l’entrée du noyau viral (complexe de préintégration) dans le noyau cellulaire. En outre, la compréhension du rôle des protéines accessoires Vpu et Nef dans l’endocytose de CD4, les transports intracellulaires et le bourgeonnement demeurent des objectifs importants pour pouvoir développer des virus atténués et mettre au point des vaccins contre le VIH.

Although many discoveries have led to the development of treatments, AIDS still remains irrevocably a lethal disease. Virus resistance to antiviral agents is a major hurdle to overcome in the search for an efficient therapeutic intervention. Viral population turnover dynamics in the host has revealed that some infected latent non-dividing cells become sanctuaries of viral replication. Opposite to productively infected cells, that contribute to the replenishment of the viral population, these chronically infected cells are not easily accessible to current treatments. The recent finding that chemokine receptors act as the enigmatic HIV viral co-receptors for viral entry has opened the way to possible new antiviral products. Comprehension of the key mechanisms of viral membrane fusion has now been greatly enhanced by the discovery of CXCR4 and CCR-5 as major factors in viral replication and tropism. Although preliminary results on the specific regions of co-receptors implicated in their various functions have been investigated, it remains uncertain if such regions can be clearly defined. Possible effects of chemokine receptor use by HIV on signal transduction are also being studied. Following the translocation of the viral core into the cytoplasm, several events are potential targets for antiviral intervention. The active transport of the pre-integration complex to the nucleus is a landmark event in HIV replication. Inhibition of such a phenomenon could directly prevent the infection of non-dividing cells (such as macrophages), and contribute to the elimination of the latently infected 'sanctuary' cells. The best known AIDS antiviral therapy remains against reverse transcription. Insights into the role of viral nucleoprotein NCp7 in efficient RT action and infectious particle formation have proposed new, broader multi-target intervention, based on inhibiting the multifunctional NCp7 protein. Finally, the role of the accessory proteins Vpu and Nef is currently under investigation. The understanding of the mechanisms behind the effect of these two proteins on viral infectivity, release and budding, specifically through interactions with CD4 or with other cellular partners, will give clues to possible development of stable, attenuated viruses for use as anti-HIV vaccines. [References: 24]