AEGiS-08CROI: Differential regulation of CCR5 and cxcr 4 on macrophages and microglia: implications for HIV-1 pathogenesis in the CNS and other tissue reservoirs.

8th Conference on Retroviruses and Opportunistic Infections

Chicago, IL - February 4 - 8, 2001

Differential regulation of CCR5 and cxcr 4 on macrophages and microglia: implications for HIV-1 pathogenesis in the CNS and other tissue reservoirs

Conf Retroviruses Opportunistic Infect 2001 Feb 4-8; 8:44 (abstract no. 6)

J. Wang¹, K. Crawford², and D. Gabuzda¹
¹Dana-Farber Cancer Institute, and ²Ctr. for Blood Res., Boston, MA.

BACKGROUND: Macrophages, microglia, and other mononuclear phagocytes are targets for HIV-1 infection and serve as vehicles for virus dissemination and persistence.

METHODS: To understand host factors that influence HIV-1 pathogenesis in the CNS and other tissue reservoirs by regulating expression and function of HIV-1 coreceptors, we investigated the regulation of CCR5, CXCR4, and CD4 on macrophages (MDM) and microglia.

RESULTS: The regulation of CCR5 expression on MDM and microglia in response to IL-10 (upregulation), TNF-α, and LPS (downregulation) was similar, whereas CCR5 expression was differentially regulated by other cytokines including IL-2 and IL-4. IL-2 upregulated CD4 expression on microglia, but not on monocytes or MDM. Furthermore, IL-2 upregulated CD4 expression on microglia, whereas CD4 expression on monocytes and MDM was downregulated. CXCR4 expression was also differentially regulated by certain cytokines, including IL-10, which upregulated CXCR4 on monocytes and MDM but downregulated CXCR4 on microglia. The functional consequences of these findings were investigated in virus replication assays and other studies. IL-10 significantly increased replication in microglia but markedly decreased virus replication in MDM. Single cycle infection assays indicated that these effects were due to effects on virus entry.

CONCLUSIONS: These results suggest that cytokines regulate HIV-1 coreceptors and influence virus entry and replication in mononuclear phagocytes in a manner that is cell- and tissue-dependent. Our findings also suggest that increased levels of IL-10 in the late stages of AIDS may contribute to disease progression in the CNS by enhancing the entry and replication of R5 HIV-1 strains.

2001-02-04
6

Copyright © 2001 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.