Approaches to inhibit HIV through enhancement of Tetherin restriction
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Although humans have evolved a range of natural defenses to protect us from viral infections, successful pathogens, such as the human immunodeficiency virus (HIV), have frequently devised ways to overcome them. Understanding how HIV does this is an important area to study, as it may suggest ways that we can either enhance our own natural anti-viral defenses, or block the ability of HIV to thwart them. Recently, a new host defense mechanism has been discovered that is based on the human BST-2 or ‘Tetherin’ protein. When Tetherin is present on the surface of cells, it stops newly-made HIV particles from leaving the cell, in effect by tethering them to the cell surface. HIV-1 counteracts Tetherin through the action of one of its components, the Vpu protein. We have discovered that Vpu works because it stops Tetherin from reaching the surface of human cells. Although we don’t yet fully understand how Vpu does this, we are interested in finding drugs that could block Vpu’s ability to counteract Tetherin. If such a drug could be found, it would allow our cell’s natural defense, Tetherin, to reduce the spread of HIV in a patient’s body. As a first stage to finding such anti-Vpu drugs, we are developing a system that will allow us to rapidly screen large collections of chemical compounds to find those rare drugs that could block the Vpu-Tetherin interaction. An important practical requirement for such screens is that we can develop a sensitive and automated assay system to do this search. Towards this goal, we have recently made ‘mini-Tetherin’ derivatives that also contain so-called reporter genes, capable of being detected when they are present at the cell surface. We predict that in the presence of Vpu, these reporter proteins will be blocked from getting to the cell surface and their signal will be diminished. However, if a drug is added that blocks the Vpu-Tetherin interaction, it will in turn prevent Vpu from blocking the mini-Tetherin-reporters, thereby freeing them to return to the cell surface. The signal produced by the returned mini-Tetherin reporter will be detected in our automated screen and will result in the corresponding drug being selected for further studies. By using large libraries of drugs and a high throughput screen, we will be able to rapidly search through collections of 1,000s of drugs, in order to identify those rare compounds that block the Vpu-Tetherin interaction. Any compounds we identify will be further investigated in detail, in order to confirm their anti-HIV activity and to understand how they work. Although these experiments would be just the very first stages in what can be a long process to develop a new anti-HIV drug, such compounds would be exciting finds because they would represent a totally new class of anti-HIV drugs, in an area in which there are currently none known. Ultimately, such drugs will be working by simply allowing one of our own natural cellular defense mechanisms to do its job.