The progressive depletion of CD4 T cells underlies clinical progression to AIDS in untreated HIV-infected subjects. Most dying CD4 T cells correspond to resting nonpermissive cells residing in lymphoid tissues. Death is due to an innate immune response against the incomplete cytosolic viral DNA intermediates accumulating in these cells. The viral DNA is detected by the IFI16 sensor, leading to inflammasome assembly, caspase-1 activation, and the induction of pyroptosis, a highly inflammatory form of programmed cell death. We now show that cell-to-cell transmission of HIV is obligatorily required for activation of this death pathway. Cell-free HIV-1 virions, even when added in large quantities, fail to activate pyroptosis. These findings underscore the infected CD4 T cells as the major killing units promoting progression to AIDS and highlight a previously unappreciated role for the virological synapse in HIV pathogenesis. Galloway and Doitsh demonstrate that the mode of HIV-1 spread determines the outcome form of CD4 T cell death. Cell-to-cell spread of HIV-1 is required to deplete non-permissive cells via caspase-1-dependent pyroptosis. Free HIV-1 particles, even in large quantities, are unable to trigger innate immune recognition and pyroptosis.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)