Human immunodeficiency virus-2 (HIV-2) is less pathogenic than HIV-1, and the disease progression in HIV-2-infected individuals seems to be similar to that seen in HIV-1-infected long-term nonprogressors. Cell-mediated immune responses and the production of noncytotoxic CD8+ T-cell antiviral factors (CAF) and beta-chemokines have been correlated to protection against HIV-1 and associated with asymptomatic infection and slower disease progression. We investigated the antigen-induced beta-chemokine production in HIV-2-infected patients living in Sweden and in Guinea-Bissau. We also compared in vitro CD8+ T-cell-mediated noncytotoxic antiviral activity against beta-chemokine-sensitive R5 virus (HIV-1Bal) and beta-chemokine-insensitive X4 virus (HIV-1IIIB) in HIV-2-infected patients with that in HIV-1-infected patients. HIV-2-specific beta-chemokine production was demonstrated in a majority of the HIV-2-infected subjects. CD8+ T cells of both HIV-1 and HIV-2-infected individuals suppressed R5 virus replication in vitro in a similar manner, while the inhibition of X4 virus replication seemed to be more frequent and of a higher magnitude among HIV-2-infected patients compared to HIV-1-infected subjects. Taken together, our results indicate that the production of CD8+ T-cell noncytotoxic antiviral factors may contribute to the low transmission of the virus and slower disease progression in HIV-2-infected patients.