TNF-alpha has been implicated in the pathogenesis of, and the immune response against, HIV-1 infection. To clarify the roles of TNF-alpha against HIV-1-related virus infection in an SHIV-macaque model, we genetically engineered an SHIV to express the TNF-alpha gene (SHIV-TNF) and characterized the virus's properties in vivo. After the acute viremic stage, the plasma viral loads declined earlier in the SHIV-TNF-inoculated monkeys than in the parental SHIV (SHIV-NI)-inoculated monkeys. SHIV-TNF induced cell death in the lymph nodes without depletion of circulating CD4(+) T cells. SHIV-TNF provided some immunity in monkeys by increasing the production of the chemokine RANTES and by inducing an antigen-specific proliferation of lymphocytes. The monkeys immunized with SHIV-TNF were partly protected against a pathogenic SHIV (SHIV-C2/1) challenge. These findings suggest that TNF-alpha contributes to the induction of an effective immune response against HIV-1 rather than to the progression of disease at the early stage of infection.