It has been demonstrated that human monocytes cultured in macrophage colony stimulating factor (M-CSF/ CSF-1) are 100 to 1,000 fold more susceptible to HIV-1 infection than cells cultured in medium alone. The frequency of HIV-infected cells, the level of HIV mRNA per infected cell, and the level of proviral DNA per infected culture were all reported to be greater when monocytes were cultured with M-CSF. Inasmuch as the effects of M-CSF on HIV infection are so great, and this factor is produced and functions in an autocrine and paracrine manner to facilitate both the differentiation and survival of mature monocytes and macrophages, we investigated the role of endogenous M-CSF production during HIV-1 infection of these cells. We found that human monocytes infected with HIV-1 and maintained in the absence of exogenous cytokine produced their own M-CSF at levels substantially higher than uninfected cells. The kinetics and level of M-CSF production paralleled both the rate and amount of HIV-1 produced. Furthermore, enhanced production of this cytokine was dependent on active replication of HIV-1 within the culture system. In contrast, production of the cytokines TNF-alpha, IL-1-beta, IL-6 and GM-CSF was not observed during in vitro infection of the monocyte-derived macrophages. This suggests that endogenous M-CSF production contributes to the survival of HIV-infected monocyte-derived macrophages, enables them to function as a reservoir for the virus, and facilitates the spread of virus in vivo. These results have recently been published (J. Immunol., 1995, 154:5528). Current research efforts concerning the role of endogenous M-CSF production by HIV-infected macrophages will evaluate potential cellular and molecular mechanisms that could be responsible for this phenomenon. In particular, we wish to determine whether specific HIV proteins regulate this effect. We hope to determine whether cells infected with HIV-1 produce this cytokine directly in response to a particular protein, or whether HIV proteins released from infected cells stimulate M-CSF production from uninfected cells in close proximity. To study the molecular regulation of M-CSF gene expression by HIV, we have subcloned the M-CSF promotor into the bluescript vector for use in transfection experiments. Our results could ultimately lead to new therapeutic approaches directed at eliminating or controlling the expression of HIV in human monocytes/macrophages, thereby reducing the possibility of transmission of virus to the more susceptible CD4+ T lymphocytes.
