16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

INCORPORATION OF SEQUENCE DIVERSITY INCREASES THE RATE OF DETECTION OF HIV-SPECIFIC T CELL RESPONSES

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WeAa0202

Frahm N.¹, Yusim K.², Fisher W.², Muldoon M.³, Linde C.¹, Hewitt H.¹, Faircloth K.¹, Walker B.¹, Brander C.¹, Korber B.^2
1 Massachusetts General Hospital, Harvard Medical School, Partners AIDS Research Center, Charlestown, MA, United States, ² Los Alamos National Laboratory, Theoretical Biology and Biophysics, Los Alamos, NM, United States, ³ University of Manchester, School of Mathematics, Manchester, United Kingdom

BACKGROUND: Detection of HIV-specific T cell responses oftentimes relies on antigen test sets based on consensus or isolate-specific sequences, although it has been shown that response rates can be increased significantly by using autologous peptides. However, cost and time of establishing autologous peptide sets are prohibitive, prompting us to develop an alternative method for the detection of more accurate T cell responses. Central to this approach is the observation that sequence diversity in specific positions of HIV proteins is generally limited to a few residues, likely reflecting functional constraints on the virus. In addition, residues appear to 'toggle' between preferred residues, so that amino acid substitutions at specific positions are frequently conserved even across different HIV clades.

METHODS: We designed a peptide test set that incorporates sequence diversity directly into the peptide synthesis step, resulting in a combinatorial peptide library with limited diversity. For conserved proteins, 95% of sequences contained in the LANL database can be covered by this approach with a reasonable number of peptides contained in each synthesis mix, while for more variable proteins lower sequence coverage will be achieved. Peptide sets spanning Gag-p24, Pol and the central part of Nef were tested in 17 HIV clade B-infected subjects by IFN-γ ELISpot.

RESULTS: Comparison of responses to 'toggled' versus consensus peptides revealed significantly increased detection rates of T cell responses, even in the most conserved proteins of HIV, p24 and Pol. Additionally, the magnitude of the responses detected with 'toggles' was also significantly increased compared to the consensus peptides.

CONCLUSIONS: The data thus show that toggled peptides represent a powerful tool for the detection of more comprehensive breadth and magnitude of T cell responses, therefore providing additional insight as to which regions of HIV are targets of the virus-specific cellular immune responses, and hence may reflect potential vaccine candidates.

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2006-08-13
WeAa0202

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