The goal of this proposal is to obtain a detailed functional understanding of the HIV-1 capsid proteins with respect to virus morphogenesis and replication. The results obtained from this study are likely to be useful for the design of novel antiviral drugs. Methods used will include the construction of mutant proviruses by site-directed mutagenesis and their characterization in tissue culture.
The specific aims of this proposal are: 1. To define the amino acid sequences required for myristylation of the HIV-1 capsid precursor. To determine whether proteolytic processing observed in the absence of myristylation is due to an intracellular assembly of capsid precursor molecules. 2. To determine the effect on virus morphology and infectivity of alterations in proteolytic processing of the capsid precursor. To analyze the consequences of a possible budding-independent intracellular activation of the HIV-1 protease. 3. To analyze whether virions with a defect in the protease or in a particular proteolytic cleavage site are able to enter target cells and to initiate provirus synthesis. 4. To study the role of the matrix protein pl7 assembly of the capsid precursor membrane and its role in the organization of the viral envelope shell and the ordering of the envelope glycoprotein at the viral surface. 5. To analyze the functional significance of the most conserved regions in the major capsid protein p24 with special emphasis on a predicted and highly conserved amphipathic alpha-helical structure to determine whether functions other than capsid formation can be assigned to this protein. 6. To analyze the role of the conserved """"""""zinc-finger"""""""" motif in the nucleocapsid protein p9 for viral RNA encapsidation as well as to determine which regions of the protein confer specificity to the RNA-protein interaction. 7. To determine whether the C-terminal component of the capsid precursor, p6, is required for replication and if so, at what stage of the viral life cycle.
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| Ma, Yu May; Boucrot, Emmanuel; Villen, Judit et al. (2007) Targeting of AMSH to endosomes is required for epidermal growth factor receptor degradation. J Biol Chem 282:9805-12 |
| Calistri, Arianna; Sette, Paola; Salata, Cristiano et al. (2007) Intracellular trafficking and maturation of herpes simplex virus type 1 gB and virus egress require functional biogenesis of multivesicular bodies. J Virol 81:11468-78 |
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