Universitą degli studi di Pavia
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Kissova research activity
Role of host-pathogen interactions between viral proteins and cellular cofactors in promoting HIV-1 pathogenesis and indentification of novel targets for antiretroviral therapy.
Viruses, as obligatory intracellular parasites, hijack the cellular transcription and translation machineries to promote the production of progeny virions. Central to this ability, are the protein-protein interactions taking place between viral and cellular factors. As a consequence of these interactions, the homeostatic cellular functions are altered, leading to efficient viral replication and signifcantly contributing to viral pathogenesis. This research project is aimed to the characterization of the interactions between the HIV-1 proteins Vif and Rev and, respectively, the cellular proteins Hck and DDX3. Hck is a non-receptorial tyrosine kinase of the Src family, preferntially expressed in lymphocytes (the target cells for HIV-1). Hck promotes cellular proliferation, thus driving viral replication. HIV-1 can hyperactivate Hck through the interaction with its early protein Nef. Recent data showed that a late viral protein, Vif, interacts with Hck inhibiting its activity and that such a negative regulation is essential for the completion of the HIV-1 replication cycle. We aim to clarify the significance of such dual antagonistic regulation of Hck, in order to design possible inhibitors of thr Vif/Hck interaction as novel anti-HIV agents. Another cellular cofactor under study in our laboratory, is the nuclear export factor DDX3. DDX3 interacts with the viral protein Rev (a splicing inhibitor), enabling unspliced and partially spliced viral transcripts to be exported from the nucleus to the cytoplasm. We want to underdstand the molecular determinants of the Rev/DDX3 interaction, in order to develop a possible antiretroviral strategy based on the inhibition of the Rev-DDX3 axis.
Viruses, as obligatory intracellular parasites, hijack the cellular transcription and translation machineries to promote the production of progeny virions. Central to this ability, are the protein-protein interactions taking place between viral and cellular factors. As a consequence of these interactions, the homeostatic cellular functions are altered, leading to efficient viral replication and signifcantly contributing to viral pathogenesis. This research project is aimed to the characterization of the interactions between the HIV-1 proteins Vif and Rev and, respectively, the cellular proteins Hck and DDX3. Hck is a non-receptorial tyrosine kinase of the Src family, preferntially expressed in lymphocytes (the target cells for HIV-1). Hck promotes cellular proliferation, thus driving viral replication. HIV-1 can hyperactivate Hck through the interaction with its early protein Nef. Recent data showed that a late viral protein, Vif, interacts with Hck inhibiting its activity and that such a negative regulation is essential for the completion of the HIV-1 replication cycle. We aim to clarify the significance of such dual antagonistic regulation of Hck, in order to design possible inhibitors of thr Vif/Hck interaction as novel anti-HIV agents. Another cellular cofactor under study in our laboratory, is the nuclear export factor DDX3. DDX3 interacts with the viral protein Rev (a splicing inhibitor), enabling unspliced and partially spliced viral transcripts to be exported from the nucleus to the cytoplasm. We want to underdstand the molecular determinants of the Rev/DDX3 interaction, in order to develop a possible antiretroviral strategy based on the inhibition of the Rev-DDX3 axis.
