No abstract

The need to broaden research directed at answering fundamental questions in HIV vaccine discovery through laboratory, nonhuman primate (NHP), and clinical research has recently been emphasized. In addition, the importance of attracting and retaining young researchers, developing better NHP models, and more closely linking NHP and clinical research is being stressed. In an era of a level budget for biomedical research at the U.S. National Institutes of Health (NIH), HIV/AIDS vaccine research efforts will need to be carefully prioritized such that resources to energize HIV vaccine discovery can be identified. This article summarizes progress and challenges in HIV vaccine research, the priorities arising from a recent summit at NIAID, and the actions needed, some already under way, to address those priorities.

Since the discovery of human immunodeficiency virus (HIV) in 1983, significant progress has been made toward the discovery, development, and licensing of anti-HIV drugs. In vitro screens against whole virus are now being complemented by screens against specific viral targets, resulting in the development of clinical candidates acting at several critical stages of the viral life cycle. Despite these advances, clinical therapy remains largely palliative. In addition, it has recently been recognized that HIV resistance to most drugs may pose even greater obstacles. Moreover, emerging data on immunopathogenesis raise the possibility that even if virus was eliminated from an infected individual, the patient's immune system might not be capable of restoration to normal function. In the face of such obstacles, deeper insights into the pathogenic mechanisms of disease, aggressive exploitation of those mechanisms for therapeutic gain, and continued commitment of both public and private sectors to support and collaborate in this research are needed.

Selected Obstacles to HIV-Vaccine Development and Their Implications. Obstacles The window of opportunity for the immune system to clear the initial infection is narrow, since HIV integrates and establishes latent infection within days or weeks. Destruction of CD4+ T cells begins early after infection. Enormous genetic diversity and mutations that occur with replication enable HIV to avoid immune surveillance. Conserved antibody targets on the outer envelope protein are "hidden" from immune recognition. Implications Rational, empirical approaches to vaccine development have not been successful to date. Fundamental questions regarding HIV disease and the host response to the virus need to be answered. Fresh new ideas beyond the scope of classic vaccinology are urgently needed.