New Approaches to Vaccine Adjuvants: Inhibiting the Inhibitor

D evelopment of an effective HIV-1 vaccine has been an elusive goal for over 20 years despite being an urgent global priority. The agonizingly slow progress is not from lack of effort, but is a consequence of the insidious biology of the virus. HIV-1 has many features that make vaccine development challenging, if not impossible [1]. Pessimism is based in part on the empirical observation that there has never been a confi rmed case of viral clearance and recovery from HIV-1 infection, and from the mounting evidence that HIV-1 superinfection (see Glossary) is common (in other words, if natural infection does not protect against infection with other HIV strains, why would we expect vaccination to offer protection?) [2]. The high replication error rate of HIV-1 is the basis for two of the greatest challenges in vaccine design. First, extreme genetic diversity makes vaccine antigen selection diffi cult. Second, the high mutation rate provides many opportunities for the virus to escape vaccine-induced immune responses. In addition, HIV-1 glycoprotein (gp)160 can directly cause dysfunction of antigen-presenting cells, and HIV-1 can infect CD4 + T cells, which cripples the key elements required to initiate the adaptive immune response to viral pathogens. After cells are infected, there are virus-specifi c mechanisms that disrupt the normal regulation of immune activation, and HIV-1 can also become latent or infect immunoprivileged sites and remain hidden from the immune response. The list of barriers to vaccine development continues with the multitude of structural features of gp160 that evade antibody neutralization [3]. Therefore, an effective HIV-1 vaccine will need to induce immune responses that can swiftly respond to infection and effi ciently clear or control infection at very low levels of replication. To do this may require better vaccine adjuvants or delivery vehicles than are currently available. In a new study in PLoS Medicine , Song et al. explore new approaches to enhancing vaccine-induced immune responses [4]. The fi eld of vaccine adjuvants has been rapidly evolving since the discovery of the Toll-like receptor (TLR) family of pattern recognition molecules [5]. Traditionally, adjuvants have been developed empirically from natural substances found to cause infl ammation. Since cytokines were found to be the effector molecules for many adjuvant effects [6], there has been an effort to build the optimal vaccine adjuvant effect one cytokine at a time. However, this approach underestimated the complexity and timing of events necessary to augment …