Divergent regulation of HIV-1 replication in PBMC of infected individuals by CC chemokines: suppression by RANTES, MIP-1 alpha, and MCP-3, and enhancement by MCP-1

We investigated the role of different CC chemokines, including regulated up on activation normal T cell expressed and secreted (RANTES), macrophage inf lammatory protein-1 alpha (MLP-1 alpha), monocyte chemotactic protein-1 (MC P-1), and MCP-3 on virus replication in cultures established from CD8(+) T cell-depleted peripheral blood mononuclear cells (PBMC) of HIV-infected ind ividuals that were either cocultivated with allogeneic T cell blasts (ATCB) of uninfected individuals or directly stimulated by mitogen plus interleuk in-2. RANTES was the only chemokine that showed a clear-cut suppressive eff ect on HIV replication in both culture systems, although inhibitory effects were frequently also observed with MIP-1 alpha, MCP-3, and, occasionally, with MCP-1, In contrast, MCP-1 frequently enhanced HIV production in most p atients' cultures or cocultures that were characterized by secreting relati vely low levels (<20 ng/mL) of MCP-1. When CD8-depleted PBMC of HIV+ indivi duals were cocultivated with ATCB of uninfected healthy donors, a positive correlation was observed between MCP-1 concentrations and the enhancement o f HIV-1 replication occurring after depletion of CD8(+) cells from donors' cells. Depletion of CD14(+) cells (monocytes) from ATCB resulted in the dow n-regulation of virus replication during cocultivation with CD8-depleted PB MC of infected individuals. Of interest, MCP-1 zip-regulated HIV production in these CD14-depleted ATCB cocultures, Altogether these observations sugg est that MCP-1 may represent an important factor enhancing HIV spreading, p articularly in anatomical sites, such as the brain, where infection of macr ophages and microglial cells plays a dominant role.