Thalidomide stimulates T cell responses and interleukin 12 production in HIV-infected patients

We performed a placebo-controlled study to evaluate the effects of immunomo dulatory treatment with thalidomide on HIV levels, TNF-alpha levels, and im mune status of 31 HIV-infected individuals, after temporary suppression of viral replication with antiretroviral drugs. Treatment with a combination o f zidovudine and lamivudine (ZDV/LMV) for 14 days resulted in a median decl ine in plasma viremia of 1.93 log(10) RNA equivalents/ml. After discontinua tion of ZDV/LMV, thalidomide therapy (200 mg/day for 4 weeks) did not retar d the prompt return of HIV titers to the pretreatment levels, and had no ef fect on plasma levels of TNF-alpha, In contrast, thalidomide treatment resu lted in significant immune stimulation. We observed increased levels of pla sma soluble IL-2 receptor, soluble CD8 antigen, and IL-12 (p < 0.01 for all parameters), as well as increased cutaneous delayed-type hypersensitivity reactions to recall antigens (p < 0.01) in thalidomide-treated patients. Th ese changes were associated with a median increase in HIV titer of 0.2 log( 10) RNA equivalents/ml in the thalidomide-treated group (p < 0.05), which r esolved after stopping the drug, Further studies mere performed in vitro to elucidate the mechanism of thalidomide-induced immune stimulation. When pu rified T cells from HIV-infected individuals were stimulated by immobilized anti-CD3 in the presence of thalidomide, a costimulatory effect of the dru g mas observed, resulting in increased production of IL-2 and IFN-gamma, an d increased T cell-proliferative responses. Further experiments showed that thalidomide increased IL-12 production by antigen-presenting cells in a T cell-dependent manner. Our findings suggest a potential application for tha lidomide as a novel immune adjuvant in HIV disease.