Type I Interferon Upregulates Bak and Contributes to T Cell Loss during Human Immunodeficiency Virus (HIV) Infection

The role of type i interferon (ifn) during pathogenic hiv and siv infections remains unclear,with conflicting observations suggesting protective versus immunopathological effects. we therefore examined the effect of ifnα/β on t cell death and viremia in hiv infection. ex vivo analysis of eight pro- and anti-apoptotic molecules in chronic hiv-1 infection revealed that pro-apoptotic bak was increased in cd4+ t cells and correlated directly with sensitivity to cd95/fas-mediated apoptosis and inversely with cd4+ t cell counts. apoptosis sensitivity and bak expression were primarily increased in effector memory t cells. knockdown of bak by rna interference inhibited cd95/fas-induced death of t cells from hiv-1-infected individuals. in hiv-1-infected patients,ifnα-stimulated gene expression correlated positively with ex vivo t cell bak levels,cd95/fas-mediated apoptosis and viremia and negatively with cd4+ t cell counts. in vitro ifnα/β stimulation enhanced bak expression,cd95/fas expression and cd95/fas-mediated apoptosis in healthy donor t cells and induced death of hiv-specific cd8+ t cells from hiv-1-infected patients. hiv-1 in vitro sensitized t cells to cd95/fas-induced apoptosis and this was toll-like receptor (tlr)7/9- and type i ifn-dependent. this sensitization by hiv-1 was due to an indirect effect on t cells,as it occurred in peripheral blood mononuclear cell cultures but not purified cd4+ t cells. finally,peak ifnα levels and viral loads correlated negatively during acute siv infection suggesting a potential antiviral effect,but positively during chronic siv infection indicating that either the virus drives ifnα production or ifnα may facilitate loss of viral control. the above findings indicate stage-specific opposing effects of type i ifns during hiv-1 infection and suggest a novel mechanism by which these cytokines contribute to t cell depletion,dysregulation of cellular immunity and disease progression. © 2013 fraietta et al.