The development of bifunctional molecules recruiting the innate immune system as novel antivirals

Human immunodeficiency virus type 1 (HIV-1) infection remains a major public health concern because present HIV-1 medications do not offer a cure and must be continuously administered to prevent life-threatening disease and virus transmission. In addition, patients need to be regularly monitored for the emergence of drug-resistant viruses. In the absence of a HIV vaccine that would allow the immune system to destroy the invading virus, the human body has a few proteins with broad antiviral function, known as restriction factors. These factors form part of the innate immune system and can provide potent blocks to virus infection that are effective against more than one viral disease. Unique molecular patterns within the component parts of the attacking virus are detected by the innate immune system and trigger the production of interferons that signal neighbouring cells to heighten their antiviral defenses and make restriction factors.
HIV-1, like all successful human viruses, has evolved the means to prevent the production of interferon and exclude restriction factors from the parts of the cell where the virus multiplies. Nevertheless, following the success of targeted protein destruction in new cancer therapies where small bifunctional molecules move cancer promoting proteins to the cell’s discard pathway, we believe recruiting restriction factors to sites of HIV-1 reproduction could produce antiviral drugs with important new properties and broad specificity. Moreover, the complexity of a virus’s interaction with restriction factors and the innate immune system is a larger hurdle to the development of viral drug resistance than that provided by current HIV drugs.
This study will establish whether a bifunctional molecule can circumvent virus defences and obstruct HIV-1 infection by recruiting restriction factors directly to virus components. We will also explore whether a bifunctional can reveal the virus’s molecular patterns that are normally hidden from recognition by the interferon system and investigate if restriction factors can target the long-lived HIV-1 infected cells that form a barrier to a cure for this disease. In addition, we will employ bifunctional molecules to reposition restriction factors to novel locations within cells that are shared in the replication of different virus families and determine their ability to act as broad-spectrum antivirals.