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The long-standing quest for the development of vaccines that confer protection against highly mutable viruses such as HIV, hepatitis C, and influenza has elicited numerous structural and functional studies on virus-neutralizing human antibodies. These studies have aimed at translating the knowledge acquired on broadly neutralizing antibodies to the design of better immunogens for the induction of specific and protective immune responses. The last few months were marked by several seminal articles that investigate HIV-neutralizing human antibodies. These studies have characterized essential mechanistic details of the neutralization of HIV and imply that both exquisite specificity and degeneracy of the specificity of antibodies may be equally important for HIV neutralization. In this Opinion, we highlight and further discuss the potential of polyreactive (promiscuous) antibodies in defense against promptly evolving viruses. Despite having been somewhat neglected by mainstream immunologists in the last 20 years, polyreactive antibodies may come to light as new weapons against HIV.

“Rational Vaccine Design” for HIV Should Take into Account the Adaptive Potential of Polyreactive Antibodies