Two different populations of infected T cells are present in human immunodeficiency virus (HIV)-infected individuals: activated cells that produce virions and quiescent cells that harbor the viral genome but are unable to produce virus unless they are activated. Using an in vitro model of acute HIV infection, we have evaluated the effect of depleting activated T cells with an immunotoxin and subsequently inhibiting activation of quiescent T cells with an immunosuppressive agent. CD25 (Tac, p55), the alpha chain of the interleukin 2 receptor, is expressed on activated, but not quiescent, T cells. An anti-CD25-ricin A chain immunotoxin eliminated activated, CD25+ HIV-infected cells and, thereby, inhibited viral production by these cells. Subsequent addition of cyclosporine to the residual CD25- cells prevented their activation and thereby suppressed their ability to produce virus and to propagate the infection to uninfected T cells.