Inhibitory and enhancing effects of IFN-γ and IL-4 on SHIV_KU replication in rhesus macaque macrophages: Correlation between TH₂ cytokines and productive infection in tissue macrophages during late-stage infection

HIV-1 is dual-tropic for CD4⁺ T lymphocytes and macrophages, but virus production in the macrophages becomes manifest only during late-stage infection, after CD4⁺ T cell functions are lost, and when opportunistic pathogens begin to flourish. In this study, the SHIV/macaque model of HIV pathogenesis was used to assess the role of cytokines in regulating virus replication in the two cell types. We injected complete Freund's adjuvant (CFA) intradermally into SHIV_KU-infected macaques, and infused Schistosoma mansoni eggs into the liver and lungs of others. Tissues examined from these animals demonstrated that macrophages induced by CFA did not support viral replication while those induced by S. mansoni eggs had evidence of productive infection. RT-PCR analysis showed that both Th₁ (IL-2 and IFN-γ) and Th₂ cytokines (IL-4 and IL-10) were present in the CFA lesions but only the Th₂ cytokines were found in the S. mansoni lesions. Follow-up studies in macaque cell cultures showed that whereas IFN-γ caused enhancement of virus replication in CD4⁺ T cells, it curtailed viral replication in infected macrophages. In contrast, IL-4 enhanced viral replication in infected macrophages. These studies strongly suggest that cytokines regulate the sequential phases of HIV replication in CD4 T cells and macrophages.