Rev Proteins of Human and Simian Immunodeficiency Virus Enhance RNA Encapsidation

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Abstract
The main function attributed to the Rev proteins of immunodeficiency viruses is the shuttling of viral RNAs containing the Rev responsive element (RRE) via the CRM-1 export pathway from the nucleus to the cytoplasm. This restricts expression of structural proteins to the late phase of the lentiviral replication cycle. Using Rev-independent gag-pol expression plasmids of HIV-1 and simian immunodeficiency virus and lentiviral vector constructs, we have observed that HIV-1 and simian immunodeficiency virus Rev enhanced RNA encapsidation 20- to 70-fold, correlating well with the effect of Rev on vector titers. In contrast, cytoplasmic vector RNA levels were only marginally affected by Rev. Binding of Rev to the RRE or to a heterologous RNA element was required for Rev-mediated enhancement of RNA encapsidation. In addition to specific interactions of nucleocapsid with the packaging signal at the 5′ end of the genome, the Rev/RRE system provides a second mechanism contributing to preferential encapsidation of genomic lentiviral RNA. The AIDS pandemic is still an important public health problem, particularly in developing countries. A comprehensive understanding of the HIV replication cycle might allow development of new therapeutics. Despite 20 years of extensive research, the intracellular fate of the different RNAs produced during virus replication is not fully understood. It is known that the viral regulatory protein Rev binds to large viral RNAs and shuttles them from the nucleus to the cytoplasm by a cellular export pathway. We now provide evidence for a more far-reaching role of Rev. We observed that Rev enhances packaging of viral RNA into viral particles to a much larger extent than its effect on viral RNA levels in the cytoplasm. Thus, an early nuclear event (binding of Rev to the viral RNA) seems to be intimately linked to RNA encapsidation occurring at a late step of the viral replication cycle. Since Rev is not part of the viral particles, Rev seems to act indirectly, possibly by targeting the viral RNA to a cytoplasmic compartment favourable for RNA encapsidation. Thus, further studies on the function of Rev might also advance our understanding of cytoplasmic RNA trafficking and subcytoplasmic compartmentalization.

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