An example of such a single clade vaccine is MRKAd5 developed by the Merck Research Laboratories, which showed no efficacy in the first T-cell vaccine STEP trial in 2007 13, 14. When the power of the virus variability became more appreciated and selleck chemicals respected, many vaccine designs mixed variants of the same protein derived from several different HIV-1 clades into

a single formulation. One such vaccine is currently in a recently expanded phase IIb proof-of-concept trial designated the HIV Vaccine Trials Network (HVTN) protocol 505 15. More advanced T-cell-based vaccine strategies have taken full advantage of the Los Alamos National Laboratory (LANL) HIV Sequence Database, which has the

most complete data set of known HIV-1 isolates. The first in silico approach that emerged computed centralized sequences 16. This approach uses either consensus (average) or centre-of-phylogenetic tree whole protein sequences or extrapolates individual amino acid positions in the whole proteins to common clade or group ancestors. This captures the intraclade variation, but is likely to be too stretched to comprehensively cover the whole main group of HIV-1 variants. The best coverage of the ‘non-conserved’ strategies computes mosaic proteins, which are artificial sequences assembled in silico using an iterative algorithm 17. Known 9-amino acid stretches were chosen because this is the most typical length of an epitope recognized by CD8+

T killer cells and by computing mosaic proteins Ibrutinib supplier the coverage of all common variants of these sequences is maximized. For example, a tetravalent mosaic protein of Gag optimized click here on the main group sequences covers about 74% of the main group Gag-derived 9-mers as a perfect match. Both computed designs described are supported by a strong rationale; nevertheless, they do not refocus the immune responses away from the dominant, hypervariable regions towards the subdominant but invariant regions of HIV-1 18, 19. This means that the induced T-cell responses, although increased in depth, are just as likely to focus on variable regions and this opens the possibility of selecting novel escape variants not yet included in the LANL database. Recent deep sequencing of natural T-cell escape mutations showed that a very large number of alternative amino acids were generated by mutation during infection and ‘tested’ in these variable epitope positions 20. In essence, perhaps the best solution to a T-cell vaccine immunogen is one that consists of conserved regions made of mosaic sequences. The first mosaic vaccine is scheduled to enter clinical evaluation in year 2012. Even the most conserved regions of the HIV-1 proteome are not immunologically inert.