Immunology and the elusive AIDS vaccine.

Immunology and the elusive AIDS vaccine.

Developing a human immunodeficiency virus (HIV) vaccine is critical to end the global acquired immunodeficiency syndrome (AIDS) epidemic, but many question whether this goal is achievable. Natural immunity is not protective, and despite immunogenicity of HIV vaccine candidates, human trials have exclusively yielded disappointing results. Nevertheless, there is an indication that success may be possible, but this will be dependent on understanding the antiviral immune response in unprecedented depth to identify and engineer the types of immunity required. Here the authors outline fundamental immunological questions that need to be answered to develop a protective HIV vaccine, and the immediate need to harness a much broader scientific community to achieve this goal.

This thorough review of the state of our knowledge of HIV-related immunology points out that an effective HIV vaccine is an achievable goal but that there are ‘knowable unknowns’ that must be explored to gain the knowledge that is essential for translation into vaccine-induced protection. There are signals that vaccination may work from the Thai RV144 trial and from monkey studies but huge gaps in our knowledge remain, starting with the means by which the vast majority of HIV exposures do not result in infection. Making the case for ‘re-embracing CD4 T cells’ because basic rules of immunology indicate that it will be impossible to generate long-lived, stable, high-level vaccine-induced immunity without them, the authors also bring B cells and antibody back into focus. They argue that unexplored interactions between B cells, antibody responses, and T cells are ‘knowable unknowns’ critical to HIV vaccine strategies. The possibility of creating an evolutionary trap by driving HIV into a fitness dead-end, targeting epitopes in fitness-critical regions of viral proteins, is appealing, but the overarching call for attracting experts from other fields to tap into the wealth of current knowledge on HIV pathogenesis is perhaps the most compelling argument. Their insights could enhance our understanding of HIV immunology and that would have spin-offs beyond HIV for hepatitis B, hepatitis C, malaria, cancer, and tuberculosis, all of which face similar immunological issues.