We investigated whether HIV-1 antigen-specific CD4⁺ T cells expressed the viral coreceptor CCR5 during primary HIV-1 infection (PHI). In the peripheral blood of subjects with very early PHI (< 22 days after onset of symptoms), there was a 10- to 20-fold increase in the proportion of highly activated (CD38⁺⁺⁺) and proliferating (Ki-67⁺) CD4⁺ T cells that expressed CCR5⁺, and were mostly T-cell intracellular antigen-1 (TIA-1)⁺ perforin⁺ granzyme B⁺. Inthe same patient samples, CD4⁺ T cells producing interferon (IFN)–γ in response to HIV group-specific antigen (Gag) peptides were readily detected (median, 0.58%) by intracellular cytokine assay—these cells were again predominantly CD38⁺⁺⁺, Ki-67⁺, and TIA-⁺⁺, as well as Bcl-2^low. On average, 20% of the Gag-specific CD4⁺ T cells also expressed interleukin-2 (IL-2) and were CD127 (IL-7R)⁺. Taken together, these results suggest that Gag-specific T-helper 1 (Th1) effector cells express CCR5 during the primary response and may include precursors of long-term self-renewing memory cells. However, in PHI subjects with later presentation, antigen-specific CD4⁺ T cells could not be readily detected (median, 0.08%), coinciding with a 5-fold lower level of the CCR5⁺CD38⁺⁺⁺ CD4⁺ T cells. These results suggest that the antiviral response to HIV-1 infection includes highly activated CCR5⁺CD4⁺ cytotoxic effector cells, which are susceptible to both apoptosis and cytopathic infection with HIV-1, and rapidly decline.