Nonproliferating bystander CD4(+) T cells lacking activation markers support HIV replication during immune activation

HIV replicates primarily in lymphoid tissue and immune activation is a majo r stimulus in vivo. To determine the cells responsible for HIV replication during Ag-driven T cell activation, we used a novel in vitro model employin g dendritic cell presentation of superantigen to CD4(+) T cells. Dendritic cells and CD4(+) T cells are the major constituents of the paracortical reg ion of lymphoid organs, the train site of Ag-specific activation and HIV re plication. Unexpectedly, replication occurred in nonproliferating bystander CD4(+) T cells that lacked activation markers. In contrast, activated Ag-s pecific cells were relatively protected from infection, which was associate d with CCR5 and CXC chemokine receptor 4 down-regulation. The finding that HIV replication is not restricted to highly activated Ag-specific CD4(+) T cells has implications for therapy, efforts to eradicate viral reservoirs, immune control of HIV, and Ag-specific immune defects.