The macrophage response to HIV-1: Intracellular control of X4 virus replication accompanied by activation of chemokine and cytokine synthesis

During human immunodeficiency virus (HIV)-1 infection, T lymphocytes and macrophages play dual roles. They are the primary targets for virus replication, but they are also primary effector cells in acquired and innate immunity, respectively. The authors are now investigating how these roles come together in the response of human monocyte-derived macrophages (MDM) to certain HIV-1. The authors and others have previously shown that MDM permit entry of some X4 virus strains, but control viral replication intracellularly. In the present study, viral DNA synthesis, entry into the nucleus, and transcription to RNA were all observed in X4 virus-infected MDM. MDM arrested HIV-1 replication prior to expression of mature capsid antigen p24 and production of cell-free infectious viral particles. Cell-associated transmissible HIV-1 was detected by cocultivation of infected MDM and susceptible T lymphocytes. A second protective response of MDM to specific R5 as well as X4 HIV-1 was identified in rapid and extensive secretion of tumor necrosis factor-alpha, macrophage inflammatory protein-1alpha, and RANTES. These findings support the view that MDM act aggressively to control HIV-1 replication: X4 strains by severely limiting the progeny virus production and R5 strains by producing beta-chemokines competent to block virus entry into target cells. Optimizing these innate immune responses offers another means to control HIV-1 infection in the human host.