The long-term goals of our project "HIV Neutralization Inhibitors: Engineering, characterization, and functions" are to identify and engineer protein and small molecule therapeutics, probes and vaccine immunogens that can be translated for the treatment and long-acting inhibition of HIV/AIDS. Though great progress has been achieved in developing treatments for and extending the life expectancies of HIV infected individuals, we do not have a cure or vaccine for this disease and many challenges remain including the development of drug resistance to currently used therapeutics, the high cost and availability of treatment, and the need for prevention strategies that are available to all. Among envelope viruses, the HIV spike protein in particular is unique in that its heterotrimeric structure is shrouded in a dense network of high-mannose oligosaccharides, now known as the ‘glycan shield’. Paradoxically, the carbohydrates that comprise the glycan shield are human glycans that are attached during translation and maturation of the viral genome. This leads to shielding of the virus from the immune system and complicates vaccine design and development. Because the high-mannose glycan shield is unique to viral proteins, mannose-binding lectins can potently inhibit HIV replication and infection. Thus, one subproject in our research group involves engineering of carbohydrate-binding proteins that specifically target the glycan shield of enveloped viruses such as HIV and coronaviruses. We have established proof of concept for our approaches (submitted for publication) and current work includes design and construction of bispecific antibody chimeras to rationally target multiple sites on the envelope proteins. Other subprojects include discovery of natural product inhibitors and peptide-based probes of HIV-1cell entry, and structural and mechanistic studies of HIV-1 Envelope-coreceptor interactions.