Discovery of a New Approach to Attacking HIV
By Jeffrey Laurence, M.D.
September 21, 2006—Dr. Susana Valente’s tenure as an amfAR Fellow is only halfway through, but she has already published a key paper on a novel approach to attacking HIV. Working under the mentorship of Dr. Stephen Goff at Columbia University, her article in the August issue of the scientific journal Molecular Cell describes three key findings stemming from a single body of amfAR-funded work.
First, Dr. Valente identified a small protein fragment capable of drastically reducing HIV growth within a cell without endangering the cell's ability to survive. Second, identification and extraction of this protein validated the discovery method used, which was pioneered by the Goff lab and holds great promise for uncovering other naturally-occurring inhibitors of HIV. Third, her work on the mechanism of action of this protein identified a step in the control of HIV growth that has not previously been the target of efforts for anti-HIV drug discovery, mediated by a region of the virus known as the 3'-LTR.
Valente and Goff began their work with the knowledge that HIV, like all viruses, requires normal cellular partners to enable its growth, and hypothesized that many key partners had not yet been identified. Using techniques of modern molecular biology, they first made a “library” of all 25,000 or so genes in a normal human cell. They then screened the library for the presence of any gene that might make proteins or proteins fragments that are critical for HIV's growth. Dr. Goff and other investigators, including several funded by amfAR, had already discovered and characterized several such genes as part of a long-standing amfAR research initiative targeting natural host resistance factors against HIV. Many of these genes are under active investigation with respect to development of new anti-HIV agents. The newest candidate identified by Valente and Goff is known as N-86-hnRNPU, as it was derived from the N, or amino, end of an 86 amino acid fragment of the normal cell protein, heterogeneous nuclear ribonuclear protein U. Although its precise mechanism of action will require further study, it appears to block the reproduction of HIV by preventing the export of HIV protein-encoding messenger RNAs from an infected cell’s nucleus to its cytoplasm, where viral proteins would normally be made and assembled into infectious particles.
Drs. Valente and Goff concluded their article by predicting that new lines of investigation opened by discovery of N-86-hnRNPU could “lead to important antiviral approaches in clinical settings.”
Dr. Laurence is amfAR’s senior scientific consultant.