Functions of HIV accessory genes

The Rekosh Lab studies a small regulatory protein called Rev, as a model for understanding basic molecular mechanisms of posttranscriptional gene regulation with specific emphasis of RNA nucleo-cytoplasmic export, localization and translation. This is part of an ongoing collaborative effort with another Cancer Center investigator, Dr. Marie-Louise Hammarskjold, that has lasted over 20 years. Rev is synthesized by Human Immunodeficiency Virus (HIV) after infection, and a primary function of this protein is to facilitate the nucleo-cytoplasmic export of mRNAs that retain complete introns. Cellular mRNAs with retained introns are usually restricted by the cell from exiting the nucleus and since many HIV mRNAs have this property, Rev is essential for HIV replication.  To perform its export function, Rev binds to a specific element present in some HIV mRNAs called the Rev Response Element. This RNA-protein complex then interacts, through the leucine-rich nuclear export signal in Rev, with cellular factors such as CRM1 and Ran-GTP to facilitate mRNA export.  The laboratory has also shown that Rev also functions in the cytoplasm, where it promotes the translation of intron-containing RNA. Other work has led to the discovery that many cellular genes, including some involved in regulation of cell growth, also produce alternatively spliced mRNAs that retain introns. Many of these mRNAs have been shown to require special cis-acting RNA elements to mediate their export and these elements interact with specific cellular proteins that are the subject of ongoing studies. Our hypothesis is that these differentially spliced mRNAs may create novel protein isoforms. Some of these might act as natural transdominant negative proteins that serve to regulate the activity of the primary protein product. Thus the regulation of export and translation of mRNA with retained introns represents a novel mechanism for post-transcriptional control of gene expression that is likely to play an important role function in both viral and cellular gene regulation.