Mosaic HIV-1 Gag antigens can be processed and presented to human HIV-specific CD8+ T cells

Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Charlestown, MA 02129, USA.
The Journal of Immunology (Impact Factor: 4.92). 06/2011; 186(12):6914-24. DOI: 10.4049/jimmunol.1004231
Source: PubMed


Polyvalent mosaic HIV immunogens offer a potential solution for generating vaccines that can elicit immune responses against genetically diverse viruses. However, it is unclear whether key T cell epitopes can be processed and presented from these synthetic Ags and recognized by epitope-specific human T cells. In this study, we tested the ability of mosaic HIV immunogens expressed by recombinant, replication-incompetent adenovirus serotype 26 vectors to process and present major HIV clade B and clade C CD8 T cell epitopes in human cells. A bivalent mosaic vaccine expressing HIV Gag sequences was used to transduce PBMCs from 12 HIV-1-infected individuals from the United States and 10 HIV-1-infected individuals from South Africa; intracellular cytokine staining, together with tetramer staining, was used to assess the ability of mosaic Gag Ags to stimulate pre-existing memory responses compared with natural clade B and C vectors. Mosaic Gag Ags expressed all eight clade B epitopes tested in 12 United States subjects and all 5 clade C epitopes tested in 10 South African subjects. Overall, the magnitude of cytokine production induced by stimulation with mosaic Ags was comparable to clade B and clade C Ags tested, but the mosaic Ags elicited greater cross-clade recognition. Additionally, mosaic Ags induced HIV-specific CD4 T cell responses. Our studies demonstrate that mosaic Ags express major clade B and clade C viral T cell epitopes in human cells, as well as support the evaluation of mosaic HIV-1 vaccines in humans.

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    • "This in silico recombination is done using a machine learning algorithm that selects a set of protein sequences that resemble natural proteins, but in combination optimize the coverage of the diversity of epitope sequences that exist worldwide in HIV-1 strains (Barouch et al., 2010; Fischer et al., 2007; Thurmond et al., 2008). The potential utility of these mosaic proteins for immunogens in humans was recently demonstrated when Ndhlovu et al. showed that processing of mosaic proteins generates epitope peptides that are recognized by human CD8þ T cells (Ndhlovu et al., 2011). Moreover, this strategy is also being explored for immunization against other pathogens, including Chlamydia (Nunes et al., 2010), Hepatitis C (Yusim et al., 2010), Ebola (Grard et al., 2011), and type 2 porcine reproductive and respiratory syndrome viruses (Shi et al., 2010). "
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