HIV-specific CD8 T Cell Cross-reactivity Following Ad5-based Vaccination Is Shaped by Vaccine Regimen and Prior Ad5 Exposure
Year: 2017
Type: conference-abstract
Abstract: A major obstacle to developing an HIV vaccine is its enormous viral diversity. As such, the ability of the CD8 T cell response to cross-recognize several variants of a single epitope could be an important factor in optimizing future vaccine design. Some prior work has indicated that CD8 cross-reactivity may play a role in viral control in individuals with protective HLA-I alleles; however, not much is known about CD8 cross-reactivity in the context of HIV vaccination. We examined the CD8 T cell cross-reactivity in recipients of two prior preventative HIV-1 vaccine studies, both of which used adenovirus serotype 5 (Ad5) vectors: HVTN 502 (MRKAd5) and HVTN 505 (VRC DNA with Ad5 boost). We measured the responses to vaccine-encoded epitopes and their common variants using IFNγ ELISpot assays. We also quantified the antigen sensitivities by measuring the IFNγ responses to log fold serial peptide dilutions. Overall, CD8 responses to variant epitopes had a lower magnitude and decreased antigen sensitivity than those targeting vaccine-encoded epitopes (P < 0.0001 and P = 0.014). A greater number of mutations, less conservative amino acid substitutions, and HLA-I driven mutations negatively affect the immunogenicity of cross-reactive responses (P < 0.0001, P = 0.0003, and P < 0.0001, respectively). Additionally, cross-reactive responses had a higher magnitude in MRKAd5 recipients with low pre-existing Ad5 titers than those with high pre-existing titers (P = 0.0230). Among that former MRKAd5 group, cross-reactive responses were decreased in magnitude and proportion in comparison with cross-reactive responses of VRC DNA/Ad5 recipients (P = 0.0052, P = 0.0488), even though both groups’ responses to vaccine-encoded epitopes had similar magnitudes. Our data show that cross-reactive responses are frequently elicited by vaccination and that this cross-reactivity is affected by the vaccine regimen and by pre-existing Ad5 titers. Future work will focus on analyzing the TCR clonotype repertoire responsible for these CD8 T cell responses and establishing the biologic and clinical significance of these vaccine-induced cross-reactive CD8 T cells. All authors: No reported disclosures.
Source: Open Forum Infectious Diseases
Institutions: University of Alabama at Birmingham, UAB Medicine
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,053
OpenAlex ID: W2763543209