147 Rational Design of Envelope Surface Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1

Advances in our basic scientific understanding of the immune system and mechanisms of HIV pathogenesis have provided the tools to rationally design an effective vaccine for AIDS. Cross-reactive neutralizing antibodies (NAb) are found in the sera of many HIV-1 infected subjects, but the virologic basis of their neutralization remains poorly understood. We have used knowledge of HIV-1 Envelope (Env) structure to developed antigenically resurfaced glycoproteins specific for the structurally conserved site of CD4 receptor binding. These probes identified sera with such NAbs from infected donors and enabled the isolation of B cells that recognized the CD4-binding site (CD4bs). By expressing immunoglobulin genes from individual B cells, we identified three monoclonal antibodies, including a pair of somatic variants that neutralized over 90% of circulating HIV-1 isolates. Exceptionally broad HIV-1 neutralization can be achieved with individual antibodies targeted to the functionally conserved CD4bs of gp120, an insight critical to the development of an AIDS vaccine. In other studies, we have continued to study basic mechanisms of pathogenesis of HIV and have recently made progress in defining the molecular basis for CD4 cell killing/depletion by HIV. The status of the rational immunogen design and novel therapeutic interventions that prevent HIV infection will be discussed.