Vaccines teach the immune system to recognize a specific harmful organism and fight off the disease when the body faces the real thing. Despite extraordinary advances in understanding both HIV and the human immune system, a fully successful HIV vaccine continues to elude researchers.

The most difficult challenges today for HIV vaccine researchers are:

• HIV attacks CD4+ T cells, the most important part of the immune system that coordinates and directs the activities of other types of immune cells that combat intruding microbes. For a vaccine to be effective, it will need to be able to activate these cells-a difficult feat if they're being infected and destroyed by the virus.
• Scientists have not identified the correlates of immunity, or protection, for HIV and are still trying to design vaccines to induce the appropriate immune responses necessary for protection. Unlike other viral diseases for which investigators have made successful vaccines, there are no documented cases of complete recovery from HIV infection. Therefore, HIV vaccine researchers have no human model of recovery from infection and subsequent protection from re-infection to guide them.
• In an infected person, HIV continually mutates and recombines to evolve into new strains of virus that differ slightly from the original infecting virus. This extensive diversity of HIV poses a challenge to vaccine design as an HIV vaccine would need to protect against many different strains of the virus circulating throughout the world. Conventional vaccines have had to protect against one or a limited number of strains.
• Ideally, an HIV vaccine will marshal two kinds of immune responses to fight HIV: T cells and antibodies secreted by B cells. These immune responses would prevent the establishment and spread of the virus from the original site of infection and decrease the effects of the disease in those who do become infected. However, scientists have not yet been able to stimulate both types of responses. To date, researchers have only stimulated T cell responses weakly with experimental HIV vaccines, and have had difficulty stimulating the production of antibodies that protect against a broad range of HIV strains.
• Researchers lack the knowledge about which HIV immunogens, pieces of HIV used to construct an experimental HIV vaccine, will get the immune system to recognize HIV during an actual encounter and protect against disease.
• Lack of a practical animal model to predict the effectiveness of an HIV vaccine in people hampers HIV vaccine development. Currently, researchers rely on experiments using non-human primate models infected with the simian cousin of HIV, known as SIV, and an engineered combination of SIV and HIV, known as SHIV, to somewhat mimic disease progression. Evaluating experimental vaccines in these animals requires a SIV or SHIV analog instead of the actual HIV vaccine candidate used in clinical trials in humans.