CD28 costimulation increases CD8+ cell suppression of HIV replication

A subset of CD8+ T lymphocytes that expresses CD28, a membrane receptor for B7 differentiation Ags found on APCs, is primarily responsible for the noncytotoxic suppression of HIV replication in CD4+ cells of HIV-infected individuals. Optimal inhibition of HIV production by CD8+ cells occurs after triggering the CD28 molecule on the cells with anti-CD28 Abs during stimulation. Blocking the interaction of the CD28 and B7 molecules with a CTLA4Ig fusion protein abrogates the ability of autologous macrophages to enhance this CD8+ cell antiviral activity. This blocking effect can be reversed by treating the CD8+ cells with anti-CD28 Ab. The increase in antiviral activity following CD28 costimulation correlates with enhanced IL-2 production and IL-2R expression by CD8+ cells. Prevention of IL-2 binding to its receptor, using anti-IL-2 or anti-IL-2R Abs, reduces the ability of CD8+ cells to suppress HIV replication following CD28 costimulation. Importantly, engagement of the CD28 molecule during stimulation of CD8+ cells from individuals with AIDS restored the ability of their cells to suppress HIV replication. Thus, triggering the CD28 molecule during stimulation of CD8+ cells could clinically benefit HIV-infected symptomatic patients.