Efficient interaction of HIV-1 with purified dendritic cells via multiple chemokine coreceptors.
Bottom Line: However, few late gag-containing sequences are detected, so that active viral replication does not occur.RANTES interacts with CCR5 and SDF-1 with CXCR4 receptors.DCs express more CCR5 and CXCR4 mRNA than T cells.
Affiliation: Theodor Kocher Institute, Bern, Switzerland.
HIV-1 actively replicates in dendritic cell (DC)-T cell cocultures, but it has been difficult to demonstrate substantial infection of purified mature DCs. We now find that HIV-1 begins reverse transcription much more efficiently in DCs than T cells, even though T cells have higher levels of CD4 and gp120 binding. DCs isolated from skin or from blood precursors behave similarly. Several M-tropic strains and the T-tropic strain IIIB enter DCs efficiently, as assessed by the progressive formation of the early products of reverse transcription after a 90-min virus pulse at 37 degrees C. However, few late gag-containing sequences are detected, so that active viral replication does not occur. The formation of these early transcripts seems to follow entry of HIV-1, rather than binding of virions that contain viral DNA. Early transcripts are scarce if DCs are exposed to virus on ice for 4 h, or for 90 min at 37 degrees C, conditions which allow virus binding. Also the early transcripts once formed are insensitive to trypsin. The entry of a M-tropic isolates is blocked by the chemokine RANTES, and the entry of IIIB by SDF-1. RANTES interacts with CCR5 and SDF-1 with CXCR4 receptors. Entry of M-tropic but not T-tropic virus is ablated in DCs from individuals who lack a functional CCR5 receptor. DCs express more CCR5 and CXCR4 mRNA than T cells. Therefore, while HIV-1 does not replicate efficiently in mature DCs, viral entry can be active and can be blocked by chemokines that act on known receptors for M- and T-tropic virus.
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Mentions: The presumed entry of HIV-1 into DCs was totally blocked with recombinant soluble CD4 or the blocking leu 3a anti-CD4 antibody (not shown). The role of chemokine coreceptors was first assessed with a panel of chemokines as blockers. For both blood-derived DCs and skin DCs, the entry of Ba-L was almost completely blocked by RANTES (Fig. 3, A and B) and less completely by MIP-1α, which are known ligands for the CCR5 coreceptor for M-tropic HIV-1 (17, 26, 27). No block of Ba-L entry was observed with SDF-1, a ligand for the CXCR4 receptor for T-tropic isolates (28, 29). Several chemokines did not block the entry of Ba-L (Fig. 3 A): the CC chemokines eotaxin, MCP-1 and MCP-3, and the CXC chemokines, IL-8, γIP-10, Mig, and PF-4.