HIV-1 exposed dendritic cells show increased pro-inflammatory cytokine production but reduced IL-1ra following lipopolysaccharide stimulation

Objectives: Dendritic cells (DC) are potential first target cells in sexual ly transmitted HIV-1 infection. They are also considered to be central in t he activation of naive T cells, which thereupon can become permissive for H IV-I. In addition, activated DC express effector molecules, which likely co ntribute to the direction of T helper (Th1/Th2)-specific immune responses. Methods: The capacity of cytokine and chemokine production in in vitro DC i nfected and uninfected with HIV-1 was assessed by enzyme-linked immunosorbe nt assay (ELISA) and by in situ immunocytochemical detection at the single cell level. Fluorescent in situ 5'-nuclease assay (FISNA) was used for quan titative evaluation of HIV-1 gag-positive cells. Results: Macrophage-tropic HIV-1 effectively infected 20-40% of in vitro cu ltured DC. However, this activity alone did not induce detectable cytokine or chemokine protein expression in DC. In contrast, lipopolysaccharide (LPS ) stimulation of these HIV-1-infected DC resulted in a significantly increa sed level of cells producing tumour necrosis factor alpha (TNF-alpha) and i nterleukin (IL) 1 beta but reduced frequencies of cells producing IL-1 rece ptor antagonist (IL-1ra) compared with the LPS-stimulated but uninfected DC cultures (P < 0.05). Furthermore, an extensive production of the beta-chem okines [RANTES, macrophage inflammatory proteins (MIP) 1 alpha and 1 beta] was detected in DC in response to both LPS and HIV-1 plus LPS. Conclusions: These findings indicate that HIV-I infected DC may have an inc reased proinflammatory activity. Elevated production of cytokines such as T NF-alpha and IL-1 beta and reduced IL-1ra may contribute to enhanced replic ation of HIV-1 in bystander T cells. Cram-negative bacterial infection and gut-associated bacterial translocation in HIV-1-infected individuals may al so result in endotoxin-mediated reactivation of HIV-1 in bystander CD4 CD45 RO T cells caused by the increased production of proinflammatory cytokines in DC. (C) 1999 Lippincott Williams & Wilkins.