Background:  While most HIV-infected elite controllers with undetectable viremia (<75 copies/mL) in the absence of therapy have strong immune responses to HIV, likely contributing to the control of viral replication, it is unclear whether these responses may also result in generalized T cell activation, contributing to CD4⁺ T cell depletion.
Methods:  We sampled 58 elite controllers, 66 untreated non-controllers (>10,000 copies HIV RNA/mL plasma), and 127 HIV⁺ patients with undetectable viremia on HAART from a clinic-based cohort (SCOPE), and 38 exposed but HIV^– individuals, and assessed relationships between measures of adaptive HIV-specific immune responses, the percentage of activated (CD38⁺HLA-DR⁺) T cells, and CD4⁺ T cell count.
Results:  Elite controllers had a higher median percentage of Gag-specific interferon (IFN)⁺ interleukin (IL) -2⁺ CD4⁺ T cells than non-controllers (p <0.001), HAART-suppressed (p <0.001), and HIV^– (p <0.001). Elite controllers also had the highest percentage of Gag-specific IFN⁺IL-2⁺ CD8⁺ T cells of all the groups (p <0.001). Compared to HIV^–, elite controllers had an abnormally high median percentage of activated CD4⁺ T cells (3.7% vs 1.6%, p <0.001) and CD8⁺ T cells (15% vs 4%, p <0.001). Elite controllers also had a higher percentage of activated CD8⁺ T cells than the HAART-suppressed (15% vs 9%, p =0.001). Among elite controllers, higher Gag-specific CD4⁺ T cell responses were associated with higher HIV-specific antibody levels (ρ 0.56, p = 0.004), but also higher CD4⁺ T cell activation (ρ 0.34, p = 0.01) and CD8⁺ T cell activation levels (ρ 0.51, p <0.001). While the median CD4⁺ T cell count in elite controllers was 683 cells/mm³, 9 (16%) had CD4⁺ T cell counts <350 cells/mm³ and 4 (7%) had AIDS. Among elite controllers, higher CD4⁺ and CD8⁺ T cell activation was strongly associated with lower CD4⁺ T cell counts (ρ –0.59, p <0.001 and –0.44, p <0.001, respectively). The extent of low-level viremia below 75 copies/mL—as estimated with ultra-sensitive methods (TMA)—was not associated with HIV-specific T cell responses, T cell activation, or CD4 cell counts (p >0.2 for all comparisons).
Conclusions:  Vigorous HIV-specific immune responses observed in most elite controllers, while likely contributing to the control of virus replication, are associated with abnormally high generalized T cell activation levels, potentially contributing to CD4⁺ T cell depletion even in the absence of readily detectable viremia.