Chemokines of the C-C family, namely RANTES, MIP-la, and MIP-lb, have been very recently shown to be produce by activated CD8+ T-cells and to suppress HIV replication in the PMI cell line or in in vitro infected PHA blasts (Cocchi, Science, Dec 1995), suggesting the possibility of their therapeutic applications. However, no information was provided on the ability of these chemokines to suppress HIV replication in cells obtained from infected individuals. We have investigated the ability of several C-C chemokines and of the C-X-C chemokine interleukin-8 (IL-8)to modulate HIV replication in PBMC obtained from HIV infected individuals that were depleted of CD8+ cells by immunomagnetic beads. Cells were then either stimulated with PHA plus IL-2, or cocultivated with allogeneic PHA blasts of uninfected individuals in the presence or absence of chemokines (100 ng/ml). RANTES potently suppressed HIV replication in 5/6 cultures established from patients' CD8-depleted PBMC, whereas MIP-la inhibited virus production only in part (50-80%). No consistent modulatory effects on virus expression were observed in parallel cultures supplemented with other chemokines, such as MCP-3, IP10, or IL-8. In sharp contrast, MCP-1 induced a clear-cut upregulation of HIV replication in 4/6 cultures established from cells of infected individuals. Production of MCP-1 and RANTES has been observed in a chronically infected cell line after selective stimulation with phorbol esters or cytokines, thus providing a potential model for investigating the molecular pathways involved in chemokine-dependent regulation of HIV expression. In conclusion, our results suggests that chemokines encompass both suppressors (RANTES, MIP-1a) and activators (MCP-1) of HIV replication, and therefore caution should be exerted in planning their manipulation in protocols of clinical intervention.

CD8-Positive T-Lymphocytes/*CYTOLOGY Chemokines/*PHYSIOLOGY HIV/*PHYSIOLOGY Human Lymphocyte Depletion Monocytes/*VIROLOGY Virus Replication/*PHYSIOLOGY ABSTRACT

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