Bioorganic approaches towards HIV vaccine design

The worldwide epidemic of HIV/AIDS urges the development of an effective vaccine. With the identification of HIV as the cause of AIDS about two decades ago, it was once expected that a preventive vaccine would follow closely behind. But the early promise of HIV envelope gp120 as a preventive vaccine was not fulfilled. Broadly neutralizing antibodies and HIV-specific cytotoxic T lymphocytes (CTL) are two immune effectors that an effective HIV vaccine may have to elicit. Experiments in animal models have proved that sufficient levels of neutralizing antibodies can clean up the virus and protect the animals from viral challenge. Therefore, the induction of a broadly neutralizing antibody response remains a principal goal in HIV vaccine development. To achieve persistent infection, HIV has evolved elegant strategies to evade host immune surveillance. These include envelope oligomerization, rapid mutation, heavy glycosylation, and conformational changes. Each level of the HIV's defenses provides an additional dimension of complexity that has to be taken into account in order to come up with a vaccine conferring strong and long lasting immunity. Important progresses have been made in recent years in understanding the structure of HIV envelopes and the molecular mechanism of HIV evasion to the immune system. This in turn has greatly facilitated a rational design of immunogens capable of eliciting broadly neutralizing antibodies against HIV. The present review provides an overview of the major scientific obstacles we are facing in the development of an effective HIV vaccine, and discusses recent progresses in the field with a focus on current approaches toward a neutralizing antibody-based HIV vaccine. The bioorganic aspects of the approaches are emphasized.