An HIV vaccine--evolving concepts.

Classic preventive vaccines are designed to mimic the effects of natural exposure to microbes. They provide a high level of long-lasting protection against infection in the vast majority of recipients and serve as freestanding preventive measures. Although a classic preventive vaccine remains the ultimate goal of efforts to develop a vaccine for protection against the human immunodeficiency virus (HIV), the enormous genetic diversity and other unique features of the HIV envelope protein have thus far thwarted attempts to identify an effective candidate. However, we have learned from studies of HIV pathogenesis in humans and from animal models that a vaccine that induces strong T-cell–mediated immune responses in the absence of broadly neutralizing antibodies may prove beneficial even if infection is not completely prevented. Vaccine-induced T-cell responses may blunt initial viremia and prevent the early and massive destruction of memory CD4+ T cells that help control infection and prolong disease-free survival. Furthermore, secondary transmission may also be reduced if the vaccine helps to control viral replication; efficiency of transmission is directly related to plasma virus levels. T-cell vaccines represent uncharted territory, and their use may have outcomes that challenge researchers and regulators alike. If proven successful, a disease-modifying HIV vaccine would also present new challenges for the entire public health community, since it would not be a stand-alone preventive measure, as are most classic preventive vaccines. Instead, it would need to be delivered in the context of a comprehensive HIV-prevention program. OB S T AC L E S T O VAC C I NE DE V E L OPM E N T The development of more than two dozen antiretroviral therapies to combat HIV infection has resulted in a dramatic decrease in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS) in developed countries and, increasingly, in low- and middle-income countries as these therapies become more widely available. Despite ongoing prevention efforts, however, HIV continues to spread unabated in many parts of the world, with an estimated 14,000 new infections occurring daily. A safe and effective HIV vaccine would be an enormously valuable tool in the campaign to stop the spread of HIV. Most viruses against which successful vaccines have been developed undergo some level of initial replication and dispersal from the portal of entry before the virus reaches its target organ and triggers pathogenic sequelae. During this period, the virus remains vulnerable to eradication by the immune system. When prior immunization or exposure to a virus has elicited virus-specific immunologic memory, the increased speed and intensity of the immune response can prevent or mitigate disease. The nature of the interaction between HIV and the immune system is complex, and the relevance of different immune responses to the control of infection is only partially understood (Fig. 1). The primary stage of HIV infection begins with a burst