Cross-Reactive CD8 T-Cell Responses Elicited by Adenovirus Type 5-Based HIV-1 Vaccines Contributed to Early Viral Evolution in Vaccine Recipients Who Became Infected.

Because of HIV's vast sequence diversity, the ability of the CD8 T-cell response to recognize several variants of a single epitope is an important consideration for vaccine design. Cross-recognition of viral epitopes by CD8 T cells is associated with viral control during HIV-1 infection, but little is known about CD8 cross-reactivity in the context of HIV-1 vaccination. Here, we evaluated vaccine-induced CD8 cross-reactivity in two preventative HIV-1 vaccine efficacy trials, the MRKAd5 and DNA/rAd5 studies. Cross-reactive CD8 responses elicited by vaccination were similar in magnitude and frequency to those induced during acute HIV-1 infection. Although responses directed against variant epitopes were less avid than responses to vaccine-matched epitopes, we did not detect any difference in response polyfunctionality (the proportion of cells producing multiple effector molecules). And while depth, or the frequency of cross-reactive responses, did not correlate with viral loads in recipients who became infected, cross-reactivity did appear to influence early viral evolution. In comparing viral sequences of placebo versus vaccine recipients, we found that viral sequences from vaccinees encoded CD8 epitopes with more substitutions and greater biochemical dissimilarity. In other words, breakthrough sequences of vaccinees would be less cross-recognized by vaccine-induced responses. Additionally, vaccine-induced CD8 T cells poorly cross-recognized variant epitopes encoding HLA-I-associated adaptations, further supporting our conclusion that these responses play a role in driving early HIV-1 viral evolution.