Immune control of viral infections is heavily dependent on helper CD4⁺ T cell function. However, the understanding of the contribution of HIV-specific CD4⁺ T cell responses to immune protection against HIV-1, particularly in clade C infection, remains incomplete. Recently, major histocompatibility complex (MHC) class II tetramers have emerged as a powerful tool for interrogating antigen-specific CD4⁺ T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4⁺ T cell epitopes in clade C virus infection, constructed MHC class II tetramers, and then used these to define the magnitude, function, and relation to the viral load of HIV-specific CD4⁺ T cell responses in a cohort of untreated HIV clade C-infected persons. We observed significantly higher frequencies of MHC class II tetramer-positive CD4⁺ T cells in HIV controllers than progressors (P = 0.0001), and these expanded Gag-specific CD4⁺ T cells in HIV controllers showed higher levels of expression of the cytolytic proteins granzymes A and B. Importantly, targeting of the immunodominant Gag41 peptide in the context of HLA class II DRB1*1101 was associated with HIV control (r = -0.5, P = 0.02). These data identify an association between HIV-specific CD4⁺ T cell targeting of immunodominant Gag epitopes and immune control, particularly the contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infection. Furthermore, these results highlight the advantage of the use of class II tetramers in evaluating HIV-specific CD4⁺ T cell responses in natural infections.