Background. The relative immunogenicity of human immunodeficiency virus type 1 (HIV‐1) proteins for CD8⁺ and CD4⁺ cell responses has not been defined.

Methods. HIV‐1–specific T cell responses were evaluated in 65 chronically HIV‐1–infected untreated subjects by interferon‐γ flow cytometry with peptides spanning the clade C consensus sequence.

Results. The magnitude of HIV‐1–specific CD8⁺ T cell responses correlated significantly with CD4⁺ cell responses, but the percentage of CD8⁺ T cells directed against HIV‐1 (median, 2.76%) was always greater than that of CD4⁺ cells (median, 0.24%). Although CD8⁺ T cell responses were equally distributed among Gag, Pol, and the regulatory and accessory proteins, Gag was the dominant target for CD4⁺ cell responses. There was no consistent relationship between virus‐specific CD8⁺ or CD4⁺ cell response and viral load. However, the median viral load in subjects in whom Gag was the dominant CD8⁺ T cell target was significantly lower than that in subjects in whom non‐Gag proteins were the main target ().

Conclusions. Gag‐specific responses dominate the CD4⁺ T cell response to HIV, whereas CD8⁺ T cell responses are broadly distributed, which indicates differential immunogenicity of these cells against HIV‐1. The preferential targeting of Gag by CD8⁺ T cells is associated with enhanced control of viral load.