Narrowed TCR diversity for immunised mice challenged with recombinant influenza A-HIV Env(311-320) virus

Understanding CD8+ T cell responses generated by live virus vectors is critical for the rational design of next generation HIV CTL-based vaccines. We used recombinant influenza viruses expressing the HIV Env(311-320) peptide in the neuraminidase stalk to study response magnitude, cytokine production and repertoire diversity for the elicited CD8+ D(d)Env(311) CTL set. The insertion of the CD8+ D(d)Env(311) epitope into the NA stalk resulted in a decrease in viral fitness that was reflected in lower lung viral titres. While not affecting the magnitude of endogenous primary influenza-specific responses, the introduction of the D(d)Env(311) CD8+ T cell epitope altered the hierarchy of responses following secondary challenge. The CD8+ K(d)NP(147) response increased 9-fold in the spleen following secondary infection whereas the CD8+ D(d)Env(311) response increased 15-fold in the spleen. Moreover, this study is the first to describe narrowing of CD8+ TCR repertoire diversity in the context of an evolving secondary immune response against influenza A virus. Analysis of Vbeta bias for CD8+ D(d)Env(311) T cell responses showed a narrowing of CD8+ Vbeta8.1/8.2 D(d)Env(311) TCR repertoire diversity. This work further emphasizes the importance of understanding vaccine-induced CD8+ T cell responses.