Resistance of HIV-infected macrophages to CD8+ T lymphocyte-mediated killing drives activation of the immune system.

Abstract

CD4+ T lymphocytes are the principal target of HIV infection, but infected macrophages also contribute to viral pathogenesis. Killing of infected cells by CD8+ cytotoxic T lymphocytes (CTLs) leads to control of viral replication. Here we demonstrate that CTL killing of macrophages is impaired compared to killing of CD4+ T cells, resulting in inefficient HIV suppression. Macrophage killing depends on caspase-3 and granzyme B, whereas rapid killing of CD4+ T cells is caspase-independent and does not require granzyme B. Moreover, impaired killing of macrophages is associated with prolonged effector-target contact time and greater CTL interferon-γ expression, inducing macrophage production of pro-inflammatory chemokines that recruit monocytes and T cells. Similar results were observed when macrophages presented other viral antigens, suggesting a general mechanism for macrophage persistence as antigen-presenting cells that enhance inflammation and adaptive immunity. Inefficient CTL killing of macrophages may contribute to chronic inflammation, a hallmark of chronic HIV disease.