HIV-specific antibody responses in HIV-infected patients: From a monoclonal to a polyclonal view

HIV infections represent a major global health threat, affecting more than 35 million individuals worldwide. High infection rates and problems associated with lifelong antiretroviral treatment emphasize the need for the development of prophylactic and therapeutic immune intervention strategies. It is conceivable that insights for the design of new immunogens capable of eliciting protective immune responses may come from the analysis of HIV-specific antibody responses in infected patients. Using sophisticated technologies, several monoclonal neutralizing antibodies were isolated from HIV-infected individuals. However, the majority of polyclonal antibody responses found in infected patients are nonneutralizing. Comprehensive analyses of the molecular targets of HIV-specific antibody responses identified that during natural infection antibodies are mainly misdirected towards gp120 epitopes outside of the CD4-binding site and against regions and proteins that are not exposed on the surface of the virus. We therefore argue that vaccines aiming to induce protective responses should include engineered immunogens, which are capable of focusing the immune response towards protective epitopes.