Gag- and Nef-specific CD4⁺ T cells recognize and inhibit SIV replication in infected macrophages early after infection

The precise immunological role played by CD4⁺ T cells in retroviral infections is poorly defined. Here, we describe a new function of these cells, the elimination of retrovirus-infected macrophages. After experimental CD8⁺ cell depletion, elite controlling macaques with set-point viral loads ≤500 viral RNA copies/mL mounted robust Gag- and Nef-specific CD4⁺ T cell responses during reestablishment of control with ≥54% of all virus-specific CD4⁺ T cells targeting these 2 proteins. Ex vivo, these simian immunodeficiency virus (SIV)-specific CD4 ⁺ T cells neither recognized nor suppressed viral replication in SIV-infected CD4⁺ T cells. In contrast, they recognized SIV-infected macrophages as early as 2 h postinfection because of presentation of epitopes derived from virion-associated Gag and Nef proteins. Furthermore, virus-specific CD4⁺ T cells displayed direct effector function and eliminated SIV-infected macrophages. These results suggest that retrovirus-specific CD4⁺ T cells may contribute directly to elite control by inhibiting viral replication in macrophages.