Insights into the Mode of Action of the Human Cytomegalovirus

There is form of the human cytomegalovirus that is responsible for herpes – this virus is referred to as the herpesvirus human cytomegalovirus (HCMV).  This virus can have severe repercussions for infants and those individuals who are immune-compromised such as AIDS patients.  The entire HCMV genome was completely sequenced twenty years ago.  In spite of this accomplishment, the understanding of the complete array of proteins that are produced by this virus has not been fully elucidated.  This is because of the fact that although the genome is quite small – 240 kilobases (kb) – it has been estimated that there are between 165 and 252 open reading frames (ORFs).  An ORF is the part of a reading frame in the genome that contains no stop codons – stop codons terminate transcription.

A gene is defined as that part of the genome (DNA) that contains the information for the production of a protein product.  Transcription is the first step in the process that converts the information contained within the reading frame into what is referred to as messenger RNA (m-RNA).  It is the m-RNA that migrates to the highly specialized cell organelles, the ribosomes, where proteins are ultimately produced.  This phase is called translation.  It seems that the translation products of HCMV are far more complex than previously believed.

To help unravel this apparent mystery, Dr. Noam Stern-Ginossar and colleagues at the Department of Cellular and Molecular Pharmacology at Howard Hughes Medical Institute of California at San Francisco infected human foreskin fibroblasts (HFFs) with a clinical strain of HCMV.  They subsequently harvested cells 5, 24 and 72 hours post infection and analyzed the full range of translation protein products. 

As a result of this very intensive analysis, they were able to identify 751 translated ORFs - hundreds of which had not been identified before.  The explanation that best fits the results is that transcription involves the use of alternative start sites with the net effect being the production of multiple and distinct protein products.  This result was not anticipated by the investigators and demonstrates a level of complexity that far exceeded expectations.

This kind of work is significant in that it provides important insights into the full scope of the functional and antigenic – a measure of the capacity to produce an immune response – potential of HCMV.