Differential regulation of CC chemokine gene expression in human immunodeficiency virus-infected myeloid cells

Abstract

The importance of chemokine expression on HIV infection has been emphasized by the discovery that infection of CD4+ T cells by M-tropic strains of HIV-1 is antagonized by the chemokines RANTES, MIP-1α and MIP- 1β, which are natural ligands of CCR5, a major coreceptor for macrophagetropic (M-tropic) isolates of HIV-1. Similarly, the CCR2b ligands MCP-1 and MCP-3 inhibit productive infection of PBMCs by both CCR5- and CXCR4-dependent strains of HIV-1, suggesting that expression of the MCP-1 chemokine may affect HIV infection via signaling through the CCR2 receptor and subsequent desensitization of the CCR5 and/or CXCR4 signaling pathway. Given the major role played by chemokine receptors in HIV-1 fusion/entry and the regulatory effects of chemokines on HIV-1 infection, we examined the pattern of chemokine gene expression in HIV-l-infected myeloid cells and in primary monocyte/macrophages. Chronic HIV-1 infection of U937 monocytic cells increased the expression of RANTES, MIP-1α MIP-1β, and IL-8 chemokine genes, but strongly inhibited PMA/PHA- and TNFα-induced MCP-1 gene transcription. HIV-I -mediated inhibition of MCP-1 transcription and secretion was further confirmed in de novo HIV-1-infected U937 cells and correlated with a delay in HIV- and signal-induced NF-κB binding to the MCP- 1 promoter. The inhibition of MCP-1 gene expression may provide a mechanism by which HIV-1 escapes the early influence of chemokine expression in monocytic cells.