Structure of HIV-1 Rev oligomeric complexes on the RRE

Bhargavi Jayaraman, University of California, San Francisco
Mentor: Alan Frankel
Basic Biomedical Sciences
Postdoctoral Fellowship Award

All cells contain instructions in their genetic material that are required to perform various activities for sustenance and reproduction. These instructions exist in segments of the genetic material called genes. Cellular activities are controlled by a large number of molecules, mostly proteins, whose functions are dictated by their respective genes. In human cells (and most other cells), the genetic material (and consequently the genes) is located in a compartment called the nucleus. Instructions on genes are read by a set of proteins and messages (molecules called mRNA) are prepared in the nucleus. The mRNAs are then processed to a stage when they are ready to be read. Subsequently, they are sent into another compartment called the cytoplasm where they are read and proteins are made according to the instructions in them. If the mRNAs are not made correctly or processed completely, they are retained in the nucleus and are destroyed.

When HIV attacks human cells, its genetic material gets integrated with the human genetic material. The virus makes the human proteins read its genetic material and prepare its mRNAs. However, in contrast to the human mRNAs, not all of the HIV mRNAs require processing. In fact, for HIV to survive, reproduce and infect more cells, some of its mRNAs should not be processed but sent out as such to the cytoplasm. Since human cells destroy mRNAs that do not get processed, they will also destroy unprocessed viral mRNAs. In order to send the unprocessed viral messages out to the cytoplasm, the virus has evolved a strategy by producing a protein called Rev. Multiple molecules of Rev load themselves onto a specific region of these unprocessed viral mRNAs called Rev-Response-Element (RRE). This big molecular complex then enables the transport of the unprocessed viral mRNAs into the cytoplasm without getting destroyed or processed.

Since the transport of unprocessed viral mRNAs is an important step in viral reproduction in human cells, it is essential for us to know how this step is executed so that we can develop drugs to block it. Typically, in order to understand how a device/machine functions, we need to know how it looks, what its parts are and how they function. Similarly, it is necessary for us to understand what the Rev-RRE molecular complex looks like to come up with hypotheses of how it works to transport the viral mRNAs into the cytoplasm. My proposal aims at developing an understanding of the structure and architecture of the Rev-RRE complex by studying pieces of it at a time and then combining the information gained from each piece (akin to pieces in a jigsaw puzzle) to develop a model of the full complex.