The STEP study was a large, randomized, placebo-controlled, test-of-concept vaccine trial using an Ad5 vector expressing human immunodeficiency virus (HIV)–1 Gag, Pol, and Nef designed to induce T cell immunity to HIV-1. This trial was stopped and unblinded in 2007 after an interim analysis showed that the vaccine did not achieve efficacy for the 2 primary study end points, HIV-1 acquisition and plasma HIV-1 RNA levels 3 months after diagnosis of HIV-1 infection, and suggested that vaccinated individuals with high preexisting antibody titers against Ad5 might be at a higher risk of acquiring HIV-1 infection [1–2]. These results initiated reconsideration in the HIV-1 research field of the role of T cells in protection from HIV-1 infection and disease progression.

Fitzgerald et al, in this issue of the Journal, now provide follow-up data on the vaccine effect on markers of HIV-1 disease progression in 87 male participants in the STEP trial who became HIV-1-infected by November 2007. After a median of 24 months of postinfection follow-up, no effect of the vaccine on HIV-1 load setpoints, CD41 T cell counts, time to initiation of antiretroviral therapy, and AIDS-free survival was observed. Overall, these data provide further evidence that the HIV-1–specific T cell responses induced by the Ad5 vaccine had no protective effect on HIV-1 disease progression in the majority of individuals. Since the initial publication of the disappointing data from the STEP trial in 2008, the results of this trial, and their consequences for HIV-1 vaccine research, have been extensively discussed [3–11], and samples collected from the trial have been used to gain additional insights into the immune responses induced by the vaccine and into the consequences of the preinfection Ad5 serostatus on vaccine-induced immunity [1, 12–14]. In general, HIV-1–specific CD81 T cell responses induced by the vaccine were weak and directed against a very limited number of T cell epitopes. Only a median of 2 epitope-specific