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Uncoating and nuclear transport of the HIV preintegration complex

Applicant Trono Didier
Number 49920
Funding scheme Project funding (Div. I-III)
Research institution Dépt Microbiologie et Médecine Moléculaire Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Molecular Biology
Start/End 01.09.1997 - 30.09.2002
Approved amount 1'303'697.00
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Lay Summary (English)

Lead
Lay summary
Our group has been interested for a number of years in characterizing molecular events that are key to the replication and survival of human immunodeficiency virus (HIV) in the human body. Our long-term goal is to shed light on the pathogenesis of HIV-induced disease and to facilitate the development of novel AIDS therapies. One area that has attracted much of our attention is the path followed by HIV from the cell outer membrane to the nucleus, the sanctuary where the virus genetic information is irreversibly established. The replication of all retroviruses requires that a retro-transcribed copy of the viral genome integrate into the host cell chromosome. Oncoretroviruses such as murine leukemia virus need cell division to perform this operation, because the size of the retroviral preintegration complex, which comprises the viral genome and a few structural proteins and enzymes, prevents its passive diffusion through an intact nuclear envelope. In contrast, human immunodeficiency virus type 1 (HIV-1) and other lentiviruses can infect nondividing cells owing to the karyophilic properties of their preintegration complex, which govern its active transport through the nucleopore. Integration per se is mediated by the viral integrase (IN), a recombinase responsible for the cutting-and-joining reaction that leads to the covalent ligation of the viral genome with the cellular DNA, that is, to the formation of the provirus. Over the last few years, we have contributed to identifying the viral elements that mediate the nuclear import of HIV, as well as their cellular partners. An important by-product of these studies has been the development of a novel gene delivery system known as lentiviral vector, a promising tool for the gene therapy of a variety of diseases including hemophilia, cystic fibrosis, Parkinson, Alzheimer, diabetes mellitus, cancer, viral hepatitis, and AIDS itself. In the recent past, using morphological techniques developed in our laboratory, we have discovered that an early interplay takes place between the incoming virus and the cell gene expression machinery. We are now dissecting the molecular components of this interplay, a possible key to the efficiency with which HIV and lentiviral vectors express their genome. In parallel, we are defining the minimal conditions that turn T lymphocytes, the main targets of virus in the body, from a state of resistance to one of susceptibility to the immediate early steps of HIV infection. For further information, please consult our web site (www.tronolab.unige.ch).
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
68021 Molecular exploration of the immediate early phase of HIV infection 01.10.2002 Project funding (special)

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