Background:  Infection and death of HIV-specific CD4⁺ T cells are dramatic and ongoing during HIV infection, and contribute weak HIV-specific CD4⁺ T-cell responses. Triggering the lymphocyte co-stimulatory molecule, glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR), potentiates effector T-cell responses in part by protecting T cells from apoptosis, but the role of triggering GITR in HIV disease has been unstudied.

Methods:  We compared CD4⁺ T cell expression of GITR by flow cytometry in HIV-infected and -uninfected subjects with the Mann-Whitney test. In addition, we examined the impact of agonistic monoclonal antibody triggering of GITR on the percentage of CD4⁺ and CD8⁺ T cells demonstrating intracellular expression of tumor necrosis factor-alpha (TNF-a) and interferon-gamma (IFN-g) to HIV p55 and control antigens in 12 HIV-infected subjects using the Wilcoxon test. We then related the magnitude of the response to GITR triggering to the peripheral CD4⁺ count using Pearson correlations. Lastly, we examined the effect of GITR triggering on CD4⁺ T cell apoptosis by assessing intracellular expression of activated caspase-3 on CD4⁺ T cells expressing TNF-a to HIV p55 and other antigens using a Mann-Whitney test.

Results:  The percentage of CD4⁺ T cells expressing GITR at baseline was greater in HIV-infected subjects (34.70% vs 10.59%, p = 0.035), but, in contrast to healthy controls, phytohemagglutinin (PHA) failed to induce additional GITR expression in HIV-infected subjects (34.70% vs 45.03%, p = 0.402). Antibody triggering of GITR increased the percentage of HIV p55-specific CD4⁺ T cells secreting TNF-a (0.51% vs 1.00%, p = 0.008) and IFN-g (0.37% vs 0.51%, p = 0.034). CD4⁺ T cell cytokine secretion to pooled peptides to cytomegalovirus (CMV), Epstein Barr virus (EBV), and influenza (CEF) was unaffected by GITR triggering, as were CD8⁺ T-cell responses to all antigens. The magnitude of the HIV-specific TNF-a response to GITR triggering correlated directly with the absolute peripheral CD4⁺ T-cell count (p = 0.009, Pearson R = 0.714). Lastly, expression of the intracellular apoptosis marker activated caspase-3 was reduced preferentially in HIV-specific CD4⁺ T cells after GITR triggering (12.15 vs 10.45, p <0.001).

Conclusions:  Despite HIV-related impairments in GITR expression on CD4⁺ T cells, GITR triggering enhances HIV-specific CD4⁺ T-cell cytokine secretion, and protects HIV-specific CD4⁺ T cells from apoptosis. GITR triggering is thus a novel and modifiable host response that protects CD4⁺ T cells from apoptosis during HIV infection.