Rational design of vaccines to elicit broadly neutralizing antibodies to HIV-1.

For the majority of licensed vaccines, neutralizing antibodies have provided the best correlate of vaccine efficacy. Although a variety of immune mechanisms may contribute to protection, immunity is in part caused by inactivation of the infecting virus that aborts productive replication. In the case of HIV, it has been difficult to define such antibodies because the virus has evolved a multitude of mechanisms to evade humoral immunity. Because of its error-prone DNA-dependent RNA polymerase and its ability to undergo RNA recombination, the virus has generated unprecedented diversity (Korber et al. 2000). The number of common determinants shared by naturally circulating strains is therefore diminished. In addition, HIV envelope glycoprotein (Env) displays a low spike density on the virion surface (Klein et al. 2009; Klein and Bjorkman 2010), potentially reducing the efficiency of cross-linking and the advantage of antibody avidity that enhances the neutralization of many viruses. Its high carbohydrate content further masks critical structures that may be sensitive to neutralization (Wyatt et al. 1998). Finally, other mechanisms, including conformational flexibility, strain-specific amino acid variability, and decoy forms of the HIV Env, such as the free monomer (Douek et al. 2006), stimulate nonneutralizing antibody responses to irrelevant viral structures. Thus, the definition of serotypes that has proven a successful approach for many vaccines has not been available to guide the design of broadly neutralizing antibody immunogens. These challenges have prompted efforts to understand the immunobiology of HIV-1 Env, with an emphasis on understanding the structural basis for HIV-1 Env neutralization. In addition, the definition and characterization of monoclonal antibodies that mediate such broad neutralization, as well as the structural basis for its interaction with HIV envelope, have provided opportunities for the design of HIV-1 vaccines that stimulate the production of antibodies that are directed against specific conserved regions of the virus. Rational design of immunogens that elicit broadly reactive neutralizing antibodies is facilitated by the identification of HIV-infected individuals with broadly neutralizing sera, from which individual monoclonal antibodies can be isolated. Two strategies have led to the identification of such antibodies. First, individual B cells have been isolated, grown in microcultures, and the secreted antibodies have been tested for neutralization. Antibodies that neutralize diverse HIV-1 viruses were identified, and the immunoglobulin genes from the cells of interest were cloned and expressed. The neutralization specificity was then confirmed for the cloned expressed IgG genes. A second approach built on knowledge of structure to design resurfaced and stabilized HIV Env cores that were used as probes to select individual B cells targeted to a specific site. The immunoglobulin genes from these B cells were then rescued by PCR amplification. The neutralization breadths of expressed antibodies were defined against a panel of genetically diverse circulated viruses. Finally, targeted approaches to other specific regions of the virus, including the membrane-proximal region (MPR), CD4-induced (CD4i), and Env glycans have all provided specific targets for which immunogens can be specifically designed. Taken together, these approaches have enabled the design of probes that allow detection of antibodies to specific viral structures at the same time that they serve as prototype immunogens to elicit these responses. Nonetheless, impediments remain to the elicitation of such antibodies, including the ability to overcome the elimination of autoreactive B cells and to stimulate the relevant necessary somatic mutations that give rise to antibodies of the appropriate specificity. Finally, elucidation of the critical structures that confer relevant antigenicity while defining the determinants required for immunogenicity represents a key scientific question whose solution will facilitate the success of this rational vaccine design strategy.