Understanding the role of nuclear envelope protein.. (Lentiviral entry)
Understanding the role of nuclear envelope proteins in the regulation of entiviral infectivity in non-dividing cells
Start date: Sep 1, 2013,
End date: Aug 31, 2015
One of the most striking characteristics of lentiviruses and one that distinguishes them from onco-retroviruses is their ability to infect nondividing cells. As a result, primate lentiviruses such as HIV-1 can establish a productive infection in terminally differentiated cells such as macrophages and microglia in the brain or in memory T-cells that are not cycling. The prevailing view is that those viruses are indifferent to the cell cycle status of the target cells and can infect dividing and non-dividing cells indiscriminately. We have identified proteins of the inner nuclear envelope that are required for a step in the viral life cycle subsequent to nuclear entry but prior to integration of viral cDNA into host cell chromatin. Upon silencing these nuclear lamina proteins, the majority of viral cDNAs in the nucleus are converted to inactive circular forms. These results suggest a model in which nuclear envelope proteins counteract the action of enzymes in the nucleus that otherwise circularize and inactivate linear viral cDNAs. Because these inner nuclear envelope proteins are spatially disordered upon nuclear envelope breakdown at mitosis, our findings suggest that lentiviruses have evolved a specific route of entry into non-dividing cells.We have recently established that at least one of those nuclear lamina proteins is phosphorylated upon infection. Blocking phosphorylation resulted in the same effect as silencing the protein thus pointing at a complex regulation allowing nuclear entry. We propose to characterize the viral and cellular determinants that regulate this nuclear step in the viral replication cycle and further define how the inner envelope proteins regulate lentiviruses in the nucleus. We will extend our analysis to identify the cellular proteins and their possible post-translational modification that regulate the transit of viral cDNA through the nuclear envelope for lentivivuses and compare it to ncoretroviruses.
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