3rd International AIDS Society Conference on HIV Pathogenesis and Treatment Rio de Janeiro - July 24 - 27, 2005

CROSS CLADE CD8+ T CELL RESPONSES IN PRIMARY HIV-1 CLADE B INFECTION

IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract No. TuOa0103

Malhotra U.¹, Nolin J.¹, Maenza J.¹, McElrath M.J.^1
1Fred Hutchinson Cancer Research Center, Seattle, United States of America

OBJECTIVES: To assess cross-clade recognition of HIV-1 Gag by CD8+ T-cell responses in primary clade B infection. The enormous HIV-1 sequence diversity is a major obstacle to vaccine development and optimization. The consensus sequence has at each site the modal amino-acid residue across a sequence alignment and reduces the genetic distance between the antigen and circulating viruses.

METHODS: We examined Gag responses by IFN-γ ELISpot to consensus-A, B, and C peptide-sets (15-mer overlapping by 11 aa) in 25 subjects infected for a median of 44 days, including 22 subjects who were untreated.

RESULTS: We observed no significant difference between either the breadth/magnitude of response detected with the three peptide-sets. The average magnitude with the B peptide-set was 926 vs. 821 SFC/10⁶ PBMC with the A (P = 0.5017) and C peptide-sets (P= 0.3934). The mean number of epitopes detected with the B peptide-set was 1.4 vs. 1.2 each with the A (P= 0.7274) and C peptide-sets (P= 0.72343). Eleven of 13 epitopes were recognized in all virus subtypes. Six of 11 cross-reactive epitopes were identical between virus sequences, while others contained amino-acid substitutions that were tolerated. Analysis of the optimal epitope sequences previously characterized with clade B HXB2 peptides in 18 subjects (Cao, McElrath et al, J Virol. 2003 Jun;77(12):6867-78) showed that 3 of the 6 optimal epitopes had identical consensus-A, B, and C sequences. The remaining epitopes, RK9, TW10, and DA9, contained amino-acid substitutions that were tolerated.

CONCLUSIONS: Extensive cross-clade T-cell responses exist in primary HIV-1 infection. Surprisingly, responses to both clade-specific and cross-clade peptides were detected with similar sensitivity, despite significantly smaller amino-acid diversity between isolate and clade-specific consensus-sequences compared to cross-clade sequences (3-8% vs. 15-30%). Finally, we conclude that new strategies to augment T-cell epitope coverage provided by consensus sequences, specifically in domains with moderate and high sequence variability, are needed.

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Basic | TuOa0103 | Uma Malhotra
13.3 525 13.3 HIV vaccine strategies

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