Many acute viral infections are cleared by neutralizing antibodies induced by the replicating viruses. These antibodies bind to viral particles and block the ability of the particles to attach to and subsequently infect cells. Our emerging understanding of antibody responses in HIV-infected individuals suggests that such immune responses are not likely to be critical in blocking HIV spread. While high-titer anti-HIV antibodies certainly develop in infected individuals, these antibodies display only weak HIV-neutralizing activity. Moreover, the partial containment of replicating HIV usually seen during the first weeks following initial infection precedes the development of antibodies that can neutralize the virus. These observations imply that the virus-specific antibody response does not play a critical role in either the chronic or early containment of HIV replication in the infected individual. Nevertheless, there is reason to suppose that neutralizing antibodies will be important in the development of an effective HIV vaccine and that they can be elicited by immunization. A limited number of mAb’s have been developed that neutralize diverse HIV-1 isolates, confirming that shared, neutralization-sensitive viral domains exist. Infection by cell-free virus can probably only be blocked immunologically by antibodies that target such viral epitopes. Moreover, studies in the SHIV/macaque model clearly indicate that passively administered neutralizing antibodies can prevent an AIDS virus infection if sufficiently high levels of circulating antibody are achieved (4). Thus, if such antibodies can be elicited through vaccination, they should be effective in blocking transmission of virus. It is problematic, however, that the neutralization-sensitive domains of the virus have proven poorly immunogenic. Configuring a subunit immunogen that can elicit an antibody response that neutralizes a diversity of HIV isolates stands as perhaps the greatest challenge facing HIV vaccine development at this time. The immunologic mechanisms responsible for containing HIV replication are very different from those responsible for controlling many of the other viruses for which effective vaccines have been developed. These other viruses are contained primarily or solely by neutralizing antibody. HIV, on the other hand, appears to be controlled predominantly by cell-mediated immunity. Thus, soon after the indentification of HIV as the etiologic agent in AIDS, it was shown that CD8+ lymphocytes can inhibit HIV replication in CD4+ T cells in vitro (5). Later work showed that a virus-specific CD8+ CTL response precedes the early, partial control of HIV replication in acutely infected individuals (6). Moreover, the clinical status of chronically HIV-infected individuals is associated with the levels of circulating virus-specific CD8+ CTLs, high levels being predictive of a stable immunologic function (7). In fact, newly developed, highly quantitative assays for detecting these cell populations have recently demonstrated extremely high levels of HIV-specific CTLs in both acutely and chronically infected individuals (8). A definitive and direct demonstration of the importance of CD8+ lymphocytes in the control of viral infection came from work in the SIV/macaque model, where monkeys depleted of CD8+ lymphocytes by mAb infusion and then infected with SIV never controlled early viral replication. These animals went on to die with a rapidly progressive AIDS-like disease (9). Taken together, these findings make a strong argument for the importance of CD8+ CTLs in controlling HIV replication, and they suggest that an effective HIV vaccine must elicit such an immune response.

Immune studies in normal mice and humans have clearly …