REGULATION OF M-CSF PRODUCTION IN HUMAN MONOCYTES

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We previously reported that monocyte-derived macrophages (MDM) infected with HIV-1 produce high levels of macrophage colony stimulating factor (M-CSF). M-CSF production parallels both the rate and amount of HIV-1 produced and is dependent on active replication of the virus (JI 1995). Others have found that the lymphokine, interleukin-2 (IL-2), upregulates M-CSF receptor expression and enhances M-CSF production by human monocytes, which facilitates differentiation and increases the susceptibility of MDM to HIV-1 infection. IL-2 is used for therapeutic restoration of CD4+ T cells in AIDS patients, but it causes a transient burst of HIV-1 RNA from unidentified cells shortly after administration. We investigated the in vitro ability of IL-2 to enhance HIV-1 expression in macrophages via upregulation of M-CSF production. We found that exposure of MDM to IL-2 prior to infection leads to a dramatic decrease in HIV-1 replication, which correlates with an IL-2-induced down-modulation of the HIV-1 receptor, CD4, and the chemokine co-receptor, CCR5. However, production of M-CSF is not modulated, suggesting that IL-2 may not only be of benefit in restoring immune function in AIDS patients, but may also help prevent infection of healthy macrophages by decreasing the expression of HIV-1 receptors and co-receptors (AIDS 1998). Although M-CSF can modulate the susceptibility and rate of infection of MDM with HIV-1 and its production is enhanced following infection, its role in the infection of MDM with other viruses has not been characterized. We infected MDM with a panel of single stranded RNA viruses including HIV-1, HIV-2, measles virus (MV) and respiratory syncitial virus (RSV). We found that infection of MDM with monocytropic strains of HIV-1 or HIV-2 led to enhanced production of M-CSF. However, infection of MDM with MV or RSV failed to induce production of M-CSF, but did result in production of select pro-inflammatory cytokines and beta chemokines. Treatment of HIV-infected MDM with AZT led to complete inhibition of HIV-1 replication, which prevented enhanced production of M-CSF mRNA and protein and confirmed the need for viral replication. The addition of M-CSF antagonists to cultures of HIV-infected MDM, including monoclonal and polyclonal antibodies to M-CSF and soluble M-CSF receptors, dramatically inhibited HIV-1 replication. Furthermore, production of MIP-1 alpha, a monocyte chemotactic factor secreted by HIV-1-infected MDM, was also significantly reduced when HIV-1 infected MDM were treated with M-CSF antagonists. Taken together, these results suggest that biologic antagonists to M-CSF may be useful therapies for inhibiting HIV-1 replication in MDM by blocking production of HIV-1, reducing chemokine (MIP-1 alpha) recruitment of HIV susceptible T cells and macrophages, and preventing the establishment and maintenance of infected MDM as a reservoir for HIV.