Progress toward an AIDS vaccine: Prospects for protective immunity

uch can be asked of an AIDS vaccine. Ideally, vaccination would pre-empt the initial viremia associated with HIV infection, preventing illness, transmission, and the establishment of long-term viral reservoirs. If this goal of "sterilizing immunity" is not attainable, the vaccine-induced immune response would at least mitigate the effects of HIV infection by limiting viral replication. An optimal AIDS vaccine would induce long-lasting protection not only against the dominant viral subtype (clade) in a particular geographic region but against the nine or more clades of HIV-1 distributed around the world, as well as interclade recombinant strains, and would be effective regardless of the HLA genotype of the recipient. A great deal of attention and effort is also being devoted to the important work of building an international infrastructure to support the testing and ultimate availability and distribution of an AIDS vaccine. But the scientific questions remain: Can any AIDS vaccine currently in development be expected to achieve what is being asked? And how are we to decide which of the growing number of vaccine candidates should receive priority for evaluation in human trials? This article reviews key studies published over the past year, as well as research efforts presented at the international research conference "AIDS Vaccines 2001," held from 5 to 8 September in Philadelphia, that represent progress toward answering these questions. Introduction: HIV-specific responses and protection The immunologic correlates of protection against HIV in humans have yet to be characterized. Because the virus integrates into the host genome and persists for the lifetime of the infected cell and its progeny, it would appear that a humoral immune response directed against the viral envelope would provide the best chance for sterilizing immunity by preventing initial cellular infection. However, despite evidence of protection in a chimpanzee model (1), the development of envelope subunit vaccines has fallen on controversy with the recognition that these vaccines fail to elicit neutralizing antibody responses to primary HIV isolates (as opposed to tissue-culture laboratory adapted strains) in humans (2). Preliminary results are expected within the next year from two phase III efficacy studies of envelope subunits, one based in the United States and one in Thailand (3). Basic researchers continue to pursue the development of envelope-based constructs that might elicit broadly neutralizing antibodies (such as oligomeric structures or variable-loop deletions). However, the majority of human vaccine trials currently in development are based on evidence that cellular immunity may play a protective role even in the absence of neutralizing antibodies. New evidence from monkeys HIV-specific cellular responses Several studies in nonhuman primates published or presented in the past year support the correlation between vaccine-induced, HIV-specific cellular immunity and protection against subsequent challenge with pathogenic SHIV (SIV core/HIV-1 envelope) recombinants. For example, in macaques immunized with a replication-incompetent adenovirus vector expressing SIV Gag, protection against SHIV challenge correlated with prechallenge cytotoxic T lymphocyte (CTL) response to an immunodominant CTL epitope (4). In macaques immunized with gag/env DNA augmented by a plasmid expressing an IL-2/Ig hybrid cytokine, HIV-specific CTL responses correlated with viral load set point following challenge; in some animals, clinical progression was delayed more than 1.5 years following challenge (5, 6). Macaque trials of a regimen consisting of gag/pol/env DNA priming followed by boosting with a recombinant modified vaccinia Ankara vector expressing Gag-Pol-Env found similarly that vaccine-induced cellular responses correlated with control of viral load following challenge (7, 8). With regard to route of administration, intrarectal immunization of macaques with HIV/SIV peptides resulted in the induction of SIV-specific CTL and lymphoproliferative responses in the gut and was associated with control of viral load, both in the blood and in gut mucosal reservoirs, following intrarectal challenge (9, 10).