"Human immunodeficiency virus (HIV) infection numbers are increasing world wide; more than 40 million people are living with HIV/AIDS. Research of the virus has resulted in treatments, that increase the life expectancy of infected individuals, but the viru s¿ high replication and mutation rates make it a formidable foe, that with time escapes treatment due to resistance mutations.
Clinically approved treatment strategies aim at the viral enzymes and at membrane fusion. One attractive target for antiretrovira l therapy would be the early replication, before the integration of the viral DNA into the cellular genome. After penetration of its target cell the virus depends on unknown cellular co-factors. The viral core needs to traverse the cytoplasm, and the preintegration complex needs to reach the nucleus. At the same time it is vulnerable to intracellular defense systems, such as restriction factors. Two classes of mammalian restriction factors for HIV have been described to date (Trim, APOBEC); there is evidence for more such factors. Identification of several mouse T cell lines that strongly restrict HIV infection at a post-entry step makes it possible to pinpoint the steps that are affected in these cells.
Using quantitative methods, the study of this block wi ll identify sensitive stages in retroviral replication. Moreover, we will employ a genetic screening system to identify cellular factors that are necessary for early viral replication events inside a host cell. Our previous work has characterized cells that are not susceptible for HIV replication due to a recessive block: these cells lack a factor(s) for HIV infection. Such a factor may be introduced with a cDNA library and selected for by its positive effect on HIV susceptibility. Isolation of such factors will help tremendously in our understanding of these events and in the identification of weak points in the viral life cycle; this may be used for novel strategies to fight the HIV/AIDS pandemic."
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