Nuclear import of the HIV-1 pre-integration complex: mechanism and therapeutic implications [ 2003 - 2005 ]

Research Grant

Researchers: Dr Sabine Piller (Principal investigator) ,  Prof David Jans

Brief description The human immunodeficiency virus (HIV) has a unique feature distinguishing it from other retroviruses the ability to replicate in non-dividing cells such as in macrophage-microglia cells which are among the prime target cells for virus infection. The viral genome needs to be integrated into the host cell chromosome in order to infect cells productively. The host cell s genome is not normally accessible because it is located inside the nucleus, separated from the rest of the cell by the barrier of the nuclear envelope (NE). However, HIV has found a way to transport its genome to the nucleus in a complex together with other viral-cellular proteins, the pre-integration complex (PIC), through the intact NE of non-dividing cells. This is a crucial step of viral infection and if blocked could prevent the establishment and spread of HIV infection. Thus far it is unclear how the large HIV PIC accesses the nucleus and which viral and cellular proteins are essential for the navigation of the PIC through the NE and into the nucleus. Using fluorescent labels on the key components of the HIV PIC including the DNA in combination with confocal laser scanning microscopy and a novel optical single-transporter recording technique, we will be able to visualize the PIC on its way through the NE for the first time. Mutational analyses will further identify the key residues of viral proteins and the cellular nuclear transport machinery utilized during the transport. The results of this study will literally provide a clear picture of nuclear import of the HIV PIC. The future aim of elucidating this essential step in HIV replication is to identify new targets for anti-retroviral drug interventions that may be less prone to side effects and development of resistance than the currently available drug regimens.

Funding Amount $AUD 425,250.00

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant