Macrophages as susceptible targets for HIV infection, persistent viral reservoirs in tissue, and key immunoregulatory cells that control levels of virus replication and extent of disease. Although macrophages are major targets for human immunodeficiency virus (HIV) infection in vivo, study of HIV-macrophage interactions in vitro was hindered because many laboratory strains of HIV would not replicate in macrophages, and because survival of macrophages in culture was poor. Addition of purified macrophage colony-stimulating factor (M-CSF) to cultured macrophages markedly improves their survival, but does not induce proliferation. HIV isolates that replicate in macrophages will also replicate in lymphocytes; however, isolates adapted to lymphoid cells (such as HIV-HTLVIIIB) will not replicate in macrophages. The envelope gene appears to be a major determinant of the cell tropism of viral isolates. T-cell grown virus stocks synthesize abundant gp120, while virus grown in macrophages contains relatively much less gp120. Electron microscopy of virions from macrophages shows them to be depleted of gp120 surface "spikes." Recombination studies show that the portion of the genome coding for the envelope glycoprotein appears to determine cell tropism. Lastly, rsCD4 neutralized macrophage-tropic isolates less efficiently than T-cell tropic isolates. HIV replication in macrophages is partially under the control of cellular factors, although these have been less well characterized than they have in lymphocytes. 