Background: Sequence variation within the HIV-1 genome represents a significant obstacle to the development of a successful vaccine. HIV-1 viruses have been divided into different clades based on the predominant sequence present in different regions of the world. Clade B virus is found primarily in North America and Europe; clades A, C, and D are more prevalent in Africa, where the bulk of infected individuals live. It is not clear if T-helper (Th) cell responses generated with sequences based on clade B virus will be effective in recognizing the prevalent virus strains found in Africa and Asia. The question has direct applicability to vaccine development and to the worldwide utility of vaccines in development.

Methods: We examined Th-cell responses to 5 clade B epitopes within HIV-1 Gag. We synthesized variants of the epitopes found in 5% or more of clade A, B, C, D, and AE sequences. Recognition of the variant epitopes was measured by ELISpot assay for the secretion of IFN-g by clones, PBMC, and T-cell lines specific for the given epitopes.

Results: CD4⁺ T-cell clones did not recognize many of the cross-clade variant peptides. Those variant peptides that were recognized elicited abrogated responses with only a few exceptions. We tested whether polyclonal responses measured in PBMCs or T-cell lines would improve recognition of the variant peptides. No significant increase in cross-clade recognition was seen at the polyclonal level. Finally, we measured whether or not the variant peptides could antagonize the clonal response to the index peptide. No antagonism of Th-cell responses was seen. When viewed at a population level, the variant peptides were rare enough that people in non-clade B endemic areas would still generate immune responses to the majority of circulating virus strains.

Conclusions: CD4⁺ T-cells showed abrogated responses to cross-clade variant peptides found in naturally occurring viruses. These abrogated responses were present at both the clonal and polyclonal level. Variant peptides did not block recognition of the index peptide. These results illustrate the difficulty in developing an HIV-1 vaccine with worldwide applicability. Even given these limitations, it appears that significant cross-clade responses would be seen in the epitopes we studied due to conservation of sequences in Gag across many of the HIV-1 clades.