4. HIV replication

Viral and cellular factors contribute to HIV RNA metabolism and morphogenesis

We have demonstrated that the HIV specific codon bias represents an essential prerequisite for Rev-dependent regulation of late lentiviral gene expression. Careful analysis has revealed that the accumulation of distinct AU rich sequence elements in lentiviral transcripts reduces RNA half lifes and limits nuclear-cytoplasmic translocation of these mRNAs. However, addition of the 5' untranslated region increases nuclear stability of these RNAs >50 fold and renders these RNAs susceptible to nucleo-cytoplasmic translocation. Accordingly, following fusion of a 3' RNA export element (RRE) and coexpression of the shuttle protein Rev, late lentiviral RNAs are readily exported into the cytoplasm essentially involving the export machinery (CRM1/Exportin, Ran-GTP etc.), which is also employed by e.g. small nuclear RNAs. Applying these rules to non-lentiviral reporter genes, screening systems could be established which now allow the identification of additional cellular proteins interacting with the viral/cellular export machinery as basis for the identification of peptidic or small molecule based drug candidates. Furthermore, understanding the critical contribution of the HIV codon bias on late lentiviral gene expression allowed us to design safer and more efficient HIV candidate vaccines (see chapter 5).

Once translocated into the cytoplasm, late lentiviral RNAs are translated to yield late gene products, namely Gag, Pol and Env.  We were amongst the first groups demonstrating that the HIV-1 Gag protein comprises all necessary informations to trigger the assembly and release of immature virus particles. Using subviral and viral reporter systems, we contributed to the delineation of several functional domains mediating e.g. trafficking of the Gag precursors to the cytoplasmic membrane, the assembly and release of viral particles, controlled maturation of these particles, the CypA mediated disassembly of virion cores as well as the transportation of the preintegration complex into the nucleus. Almost all of these steps need assistance by cellular interacting proteins. Altogether, these insights facilitated the setup of assay systems, which  allow to screen for assembly inhibitors targeting viral and cellular proteins. At the same time, these results provided the basis for the construction of recombinant virus-like particles as basic compounds for vaccine design.


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