Mechanisms of deaminase-independent inhibition of .. (MDIIHIVIA)
Mechanisms of deaminase-independent inhibition of HIV infection by APOBEC3 proteins
Date du début: 1 mai 2013,
Date de fin: 30 avr. 2015
"The human immunodeficiency virus (HIV) continues to be a major public health issue. Current treatments can slow down disease progression, but high costs, severe side effects and the emergence of drug-resistant strains all call for the development of new treatment regimes. The detailed understanding of virus-host interactions is of utmost importance for this endeavor. The cytidine deaminase APOBEC3 (A3) proteins, and in particular APOBEC3G (A3G), are potent host restriction factors that can be packaged into assembling HIV-1 virions and severely compromise viral infectivity. To evade this powerful restriction, HIV-1 relies on the vif (viral infectivity factor) protein, which has evolved to promote proteasome-dependent A3G degradation. Despite intensive research and the high potential of the vif-A3G axis for therapeutic intervention, the precise mechanisms of A3G packaging and HIV inhibition are not fully understood. As a polynucleotide editing enzyme, A3G induces hypermutation in the viral genomic DNA. Additionally, it has recently become evident that A3G also interferes with the process of reverse transcription in a deaminase-independent way. The research proposed here is designed to elucidate the molecular basis of A3G-mediated inhibition of cDNA synthesis during reverse transcription using a combination of experimental approaches and systems. This involves: 1) The assessment of reverse transcription efficiency in the presence and absence of A3 proteins in vitro as well as in physiologically relevant human CD4+ T cells. Importantly, this will include a novel assay designed to map 3’ termini of nascent viral cDNA products. 2) Mapping of A3G binding sites on viral genomic RNA and identification cellular RNA binding partners using CLIP (crosslinking and immunoprecipitation) assays. 3) A detailed investigation of A3G’s interaction with components of the reverse transcription complex (RTC)."
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