Human immunodeficiency virus (HIV) occurs as a number of genetic and biological variants. Of these, transmission of macrophage-tropic HIV variants appears to be favored, although most infected individuals also harbor T-cell-tropic cytopathic viruses and macrophage-tropic non-cytopathic viruses. Recent evidence regarding CD4+ T-cell depletion in vivo suggests that macrophage-tropic HIV isolates may be necessary and sufficient for the development of AIDS. This review summarizes the recent findings on macrophage-tropic viruses, and compares matched sets of experiments in HIV-infected humanized severe combined immunodeficiency (SCID) mice with a computer simulation of the lymph node microenvironment. This may help to understand why HIV infection of macrophages may have profound effects on the immune system.