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Analysis of retroviral assembly and maturation using cryo-electron tomography

de Marco, Alex

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Retroviruses are a family of membrane-enveloped RNA viruses that can retrotranscribe and integrate their genome in the host cell chromatin. During the active production of virions the structural polyprotein Gag assembles together with the genomic RNA to form immature particles, which bud out from the host cell. After budding the Gag protein undergoes proteolytic maturation and is cleaved into MA, CA, NC, p6 and two spacer peptides, SP1 and SP2. This leads to dramatic changes in the core morphology and the gain of infectivity. The immature retro-virions are known to have Gag organized into a round, incomplete hexameric lattice with a spacing of ~7.5nm. The core of mature virions is organized into a mixture of hexamers and pentamers which are organized along a lattice with a spacing of ~9.6nm. The shape of the core in the mature virions is genus-dependent, but can be cylindrical, conical or round. During my PhD I have studied the immature Gag assembly across four retroviral genera in order to understand the structural requirements for the assembly of the immature retroviral lattice, and to shed more light on the principles of HIV-1 maturation. The major conclusions of my studies are the following: The CA region of Gag is the most structurally conserved across genera. The presence of a domain upstream of CA is not critical for the assembly although it stabilizes the lattice. In order to maintain an immature lattice is important to have a Gag multimerization domain downstream of CA. The region between CA and NC, which is highly variable, is not critical for the assembly but it can stabilise the lattice and therefore affect the structural changes that occur during the maturation. The maturation in retroviruses is an extremely fast process. In order to investigate the structural changes occurring during the maturation in HIV-1 I analysed the products of partial Gag maturation, which were obtained through selective mutations of the cleavage sites in Gag. This confirmed that the order in which Gag cleavages occur is important for a correct processing. The immature Gag lattice is destabilized only if both sides of the CA-SP1 region are cleaved. Furthermore, it showed that the condensation of the RNP has an effect on the core morphology in the mature virion.

Item Type: Dissertation
Supervisor: Gavin, Dr. Anne-Claude
Place of Publication: EMBL, Heidelberg
Date of thesis defense: 11 June 2012
Date Deposited: 12 Nov 2013 10:51
Date: 2013
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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