Primary macrophages from HIV-infected adults show dysregulated cytokine responses to Salmonella, but normal internalization and killing

BACKGROUND: Adults with advanced HIV are susceptible to invasive and recrudescent infections with nontyphoidal salmonellae. OBJECTIVES: To examine whether persistence and recurrence of salmonella infection results from HIV-related defects in macrophage internalization and intracellular killing or from ineffective type 1 cytokine responses. Such defects could be a direct consequence of macrophage HIV infection or secondary to reduced enhancement of macrophage effector functions by interferon-gamma (IFNgamma) as CD4 cell count falls. DESIGN: Ex-vivo scientific case-control study. METHODS: Primary ex-vivo human alveolar macrophages (huAM) from HIV-negative and HIV-positive subjects were challenged with Salmonella typhimurium under unprimed and IFNgamma-primed conditions to study internalization and intracellular killing of bacteria and cytokine responses of huAM. RESULTS: Priming of huAM with IFNgamma reduced bacterial internalization but enhanced microbicidal activity against intracellular salmonellae. HuAM from HIV-positive subjects showed unimpaired internalization and intracellular killing of salmonellae, with and without IFNgamma priming. Opsonic and mannose receptor (CD206)-mediated entry was not required for optimal internalization. HuAM from HIV-positive subjects, however, exhibited increased secretion of tumour necrosis factor alpha (TNFalpha), interleukin (IL)-10 and IL-12 in response to S. typhimurium challenge, regardless of IFNgamma priming. This cytokine dysregulation showed a trend to a curvilinear relationship with peripheral CD4 cell count, with marked decline at values < 250 cell/mul. CONCLUSIONS: Dysregulation of proinflammatory cytokine release, including IL-12, by macrophages during salmonella infection may underlie the susceptibility to severe salmonellosis in patients with AIDS. This defect was not reversed by IFNgamma and may represent a proinflammatory effect of HIV infection upon the macrophage or the alveolar milieu.