Only two HIV vaccines have been taken through efficacy trials so far. In the first HIV vaccine efficacy trial started ten years ago, recombinant gp120 protein, the CD4-binding subunit of the HIV envelope, was used as vaccine antigen [1]. The vaccine neither prevented HIV acquisition nor reduced the viral load in those acquiring HIV infection. Although the vaccine was able to induce antibodies to gp120, these did not neutralize field isolates of HIV. Differences in the conformation between the monomeric gp120 subunit of the vaccine and the functionally active trimeric envelope spike on the surface of virus particles, HIV diversity, as well as various antibody escape mechanisms of the HIV envelope (reviewed in [2]), have been proposed to explain the inefficacy of the antibody-based gp120 vaccine. Given the difficulties of antibodybased HIV prevention strategies, the second HIV efficacy trial, the STEP study, tested whether the second arm of the adaptive immune response, cytotoxic T cells, would be able to provide protection. To induce cytotoxic T cell responses, replication-deficient adenoviral vectors transfering the gag, pol, and nef genes of HIV were used. Since all the three vaccine antigens used in this study are intracellular proteins that are usually not expressed on the surface of HIV-infected cells or HIV particles, vaccine-induced HIV-specific antibodies should not be able to contribute to protection. Thus, the study was specifically designed to explore the efficacy of HIV-specific cytotoxic T cells. A total of 3,000 volunteers with a high risk of acquiring HIV infection were either immunized three times intramuscularly with replication-deficient adenoviral vectors transfering the gag, pol, and nef genes of HIV, or received a placebo. As observed in non-human primate studies and previous phase I clinical trials, the adenoviral vector vaccine induced substantial HIV-specific cytotoxic T cell responses in most of the vaccinees [3]. However, at a planned interim analysis, 19 individuals in the vaccine arm and 11 individuals of the placebo arm acquired HIV infection during a follow-up of approximately 620 person years in both groups [4]. Incidences of 3.07 and 1.77 per 100 volunteers in the vaccine and placebo group, respectively, indicate that there was no beneficial effect of the vaccine on HIV acquisition. The HIV virus particle transmitted to an individual cannot be targeted by the vaccinees’ cytotoxic T cells, because they require presentation of HIV-derived peptides on autologous MHC-I molecules. When looking at the different stages in the establishment of HIV infection after mucosal exposure (Figure 1), the earliest stage cytotoxic T cells could exert their beneficial effect is the killing of the first HIV-infected cell, presumably in the lamina propria of the exposed mucosa. However, given the low density of T cells in this compartment, it seems highly unlikely that an HIV-specific cytotoxic T cell encounters this single HIV-infected cell. Rather, it can be assumed that additional replication cycles and local spread of the virus or virus-infected cells to the draining lymph nodes occur prior to encounter with HIV-specific T cells. Subsequent activation and expansion of the HIV-specific T cells might be too slow to prevent further spread of the virus. Thus, rather then preventing HIV infection, the benefit of the cytotoxic T cells might be the reduction of viral load. However, the interim analysis of the STEP study also failed to provide any evidence for lower viral loads in the vaccine group [4]. Therefore, neither non-neutralizing gp120-specific antibodies nor HIV-specific cytotoxic T cells induced by the adenoviral vector vaccine were sufficient to provide protection.

The incidence of HIV infections …