A state of T-cell activation, reflected by a marked degree of spontaneous proliferation in vitro, exists among patients with human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) but not in those with retroviral-induced adult T-cell leukemia (ATL). We wished to define the mechanism by which the immune activation of circulating cells from HAM/TSP is driven, thus gaining insight into the pathogenesis of this HTLV-I-associated disease. By using a modification of the polymerase chain reaction, we compared the levels of interleukin 2 (IL-2) and IL-2 receptor alpha chain (IL-2R alpha) mRNA expression to the transcription of the HTLV-I transactivator gene, pX, in peripheral blood mononuclear cells of HAM/TSP and ATL patients as well as seropositive carriers. Up-regulation of IL-2 and IL-2R alpha transcripts was detected in HAM/TSP and seropositive carriers that paralleled the coordinate mRNA expression of the pX transactivator. In addition, IL-2 and soluble IL-2R alpha serum levels in HAM/TSP and seropositive carriers were elevated. Despite markedly elevated levels of soluble IL-2R alpha in ATL, transcripts for IL-2 and pX were not demonstrable in the circulating cells. Finally, the marked degree of in vitro spontaneous proliferation present in HAM/TSP was profoundly inhibited by specific anti-IL-2R or anti-IL-2 blocking antibodies. Collectively, these results suggest that immune activation in HAM/TSP, in contrast to ATL, is virally driven by the transactivation and coordinate expression of IL-2 and IL-2R alpha. This deregulated autocrine process may contribute to the evolution of inflammatory nervous system damage in HAM/TSP.