MODELLING AND SIMULATION OF BROADLY NEUTRALIZING MULTISPECIFIC ANTIBODIES FOR HIV-1

Abstract

Human Immunodeficiency Virus (HIV) is a deadly virus that causes a life-threatening disease called HIV infection in humans, which can progress to a more stern condition known as Acquired Immunodeficiency Syndrome (AIDS). Currently available treatment options allow complete prevention of HIV infection in new cells, but fail to control the already infected or latent virus containing cells. As long as taken, the available treatment options only limit AIDs progression in HIV-patients without providing complete eradication of the virus. Therefore, in order to treat HIV an effective improvement of anti-viral treatment options is required. Recently, in animal investigations and current human therapeutic trials, broadly neutralizing antibodies (bNAbs) have shown a greater potential to protect against HIV-1. Passive delivery of monoclonal antibodies is also being considered as a possible HIV preventive method. According to recent investigations, it has been established that the passive injection of bNAbs is efficient in suppressing viremia in HIV-1 patients. In vitro, bNAbs have also been shown to neutralize the majority of HIV-1 strains with an IC50 of less than 1 mg/ml. As more broadly neutralizing monoclonal antibodies (mAbs) against HIV-1 enter clinical trials, it becomes clear that combinations of mAbs are required to prevent infection by the diverse array of globally circulating HIV-1 strains mainly to limit the emergence of resistant viruses. Multi-specific antibodies, which combine two or more HIV-1 entry-targeting moieties into a single molecule, have grown in popularity in recent years and offer an appealing solution for improving neutralization breadth and erecting a stronger barrier against viral resistance. Multi-specific HIV-1 antibodies have shown vastly improved antiviral potency in some cases due to increased avidity or enhanced spatiotemporal functional activity. Notably, recent literature highlights the necessity for revolution in conventional treatment approaches and the significance of using experimental as well as computational approaches for the design of multispecific antibodies. In comparison to a single antibody, the design of multispecific antibodies (based on the combinations of two or more bNAbs) represents a promising concept in reducing the risk and emergence of viral resistance. Therefore, in the current project the computational design of multispecific bNAbs is proposed to provide effective treatments options against HIV.