Vaccine and Infectious Disease Division

T-cell responses to HIV proteins are biased toward variable sequences

An effective HIV vaccine designed to elicit T-cell responses must either induce broad responses to a wide variety of epitopes, or protein pieces, in order to cover the extensive sequence variability in circulating HIV-1 strains, or it must be focused on a few highly conserved epitopes expected to be present in the majority of circulating strains likely to be encountered by a vaccinated individual.  A lingering question of the HVTN 502 “Step study” is why this vaccine regimen failed to prevent HIV transmission or reduce viral load in vaccinees who became infected, despite inducing robust T-cell responses as measured by standard immunogenicity assays. To address this question, VIDD staff scientist Dr. Fusheng Li, VIDD co-directors Drs. Julie McElrath and Steven Self, Center President and Director Dr. Larry Corey and colleagues investigated the epitopes from the Step study vaccine that induced T-cell responses and determined how frequently they were found within recently sequenced clade B isolates of HIV-1.

The researchers found that although the vaccine induced a large number of T-cell responses in most participants, these responses tended to be targeted to variable epitopes more frequently than would be expected from an unbiased sampling of the vaccine sequences. In contrast, responses to the most highly conserved epitopes from the vaccine sequences were detected at a lower frequency than would be expected. Interestingly, this bias toward responding more frequently to variable epitopes is similar to what occurs in natural HIV infection, implying that these conserved epitopes could somehow by masked from recognition by the immune system. Discovering mechanisms to unmask these epitopes could be crucial for the development of an effective T-cell focused HIV vaccine.

Li F, Finnefrock AC, Dubey SA, Korber BT, Szinger J, Cole S, McElrath MJ, Shiver JW, Casimiro DR, Corey L, Self SG. Mapping HIV-1 vaccine induced T-cell responses: bias towards less-conserved regions and potential impact on vaccine efficacy in the step study. PLoS ONE. 2011;6(6):e20479.