Neurological disease associated with HIV infection results from either primary replication of the virus or a combination of virus infection and replication of opportunistic pathogens in the CNS. Recent studies indicate that the primary infection is mediated mainly by viruses that utilize CCR5 as the coreceptor; it is not known whether the syndrome can be mediated by viruses that use the CXCR4 coreceptor. The macaque model of the disease using simian immunodeficiency virus (SIV) has confirmed that CCR5-using viruses such as SIV(mac)251 can cause primary disease in the CNS. In this report we have examined the role of simian-human immunodeficiency virus (SHIV)(KU-2), a CXCR4 virus which replicates productively in rhesus macrophages, in causing CNS disease. A survey of archival brain tissues from SHIV(KU-2)-infected rhesus and pig-tailed macaques that succumbed to AIDS showed productive viral replication in the CNS of 10 of 14 rhesus animals. Eight of these 10 had additional infections with opportunistic pathogens. In contrast, 21 of 22 pig-tailed macaques had no evidence of productive viral infection in the brain. In an earlier study we had shown that inoculation of SHIV-infected rhesus macaques with eggs of Schistosoma mansoni, a potent inducer of IL-4, resulted in enhanced replication of the virus in tissue macrophages. In the present study, we compared the replication of the virus in macrophages from normal rhesus and pig-tailed macaques and determined further whether exogenous IL-4 could cause enhancement of virus replication in these cells. These studies showed that the virus replicated productively in rhesus macrophages, and this was enhanced significantly after recombinant macaque IL-4 was added to the medium. IL-4 also caused enhancement of virus production in macrophages isolated from virus-infected animals. In contrast, the virus replicated only minimally in pig-tailed macaque macrophages and supplemental IL-4 had negligible effects. The data thus suggested that failure of pig-tailed macaques to develop encephalitis was due to the innate resistance of macrophages from this species of macaque to support replication of SHIV(KU-2). The ability of the virus to replicate in the brains of rhesus macaques was dependent on coinfection in the brain with opportunistic pathogens which presumably induced both macrophages and IL-4 in the CNS microenvironment. A supportive role for IL-4 in the CNS disease was suggested by the presence of IL-4 RNA in the encephalitic brains of rhesus macaques and reduced levels of this cytokine in the brains from pig-tailed macaques.