AEGiS-11IAC: Secretion of multiple chemokines in U1 cells: auto-crine upregulation of viral expression by MCP-1.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

Secretion of multiple chemokines in U1 cells: auto-crine upregulation of viral expression by MCP-1.

Int Conf AIDS 1996 Jul 7-12; 11:6 (abstract no. Mo.A.145)
Biswas P, Delfanti F, Vicenzi E, Sozzani S, Moro M, Mantovani A, Poli G; San Raffaele Scienific Institute, Milan, Italy. Fax: 39-2-2643-7989.

OBJECTIVE: To investigate the role of chemokines on HIV expression in the latently infected promonocytic UI cell line that is characterized by virus inducibility by several cytokines.

METHODS: HIV expression was measured in culture supernatants by the reverse transcriptase (RT) activity assay. Chemokine secretion: RANTES, MIP-1a and MIP-1b were measured by a commercially available ELISA kit, whereas MCP-1 and IL-8 were determined by home made ELISAs. Standard Northern Blot analyses were performed to evaluate chemokine messages.

RESULTS: Unstimulated UI cells produced detectable levels of RANTES, MCP-1 and IL-8, but not of MIP-1a and MIP-1b. PMA stimulation resulted in the secretion of all five chemokines, whereas IL-6 and IFN-g selectively induced high levels of MCP-1, but not IL-8 or MIP-1a/b, and downregulated RANTES accumulation in culture supernatants. These results were confirmed by Northern blot analyses of the messages for MCP-1 and RANTES. We further investigated whether MCP-1 secretion induced by IL-6 and IFN-g was a mediator of HIV expression. An anti-MCP-1 neutralizing mAb inhibited at least in part HIV expression induced by IL-6. However, exogenous recombinant MCP-1 did not induce HIV expression by UI cells, suggesting that IL-6 may also regulate MCP-1 receptors, therefore allowing the cells to respond to the endogenously produced chemokine.

CONCLUSIONS: Endogenous secretion of MCP-1 induced by IL6 and IFN-g may be responsible for HIV expression induced by these cytokines in UI cells. These findings, together with the observation that MCP-1 activates, whereas RANTES and MIP-1a suppress HIV replication in primary CD8-depleted PBMC from HIV(+) individuals (see abstract by G. Poli et al.), shed new light on the role of chemokines in the pathogenesis of HIV infection. A balance between opposite regulatory effects exerted by chemokines of the same C-C family may contribute to determine the extent of virus replication in infected individuals.

Keywords: AEGIS, Monocyte Chemoattractant Protein-1, Chemokines, RANTES, HIV Infections, Up-Regulation, Virus Replication, Interleukin-8, Interleukin-6, Cytokines, Anti-HIV Agents, Reverse Transcriptase Inhibitors, HIV Protease Inhibitors, secretion, virology, genetics, ICA11

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MoA145