The role of cytotoxic CD8(+) T cells is well defined in retroviral immunity but the role of CD4(+) T helper (Th) cells is poorly understood. The Friend retrovirus (FV) murine infection model is a good model to study immune responses in retroviral infections and hence was used to characterize the role of Th cells during acute infection. In vivo depletion of Th cells in acutely infected mice demonstrated that Th cells were vital in controlling viral spread and onset of erythroleukaemia and for the maintenance of FV-specific CD8(+) T-cell and neutralizing antibody responses. Kinetic analysis of FV-specific Th-cell responses using class-II tetramers showed that the magnitude of the Th-cell response correlated with the level of resistance to FV-induced leukaemia in different mouse strains. FV-specific CD4(+) T-cell receptor beta-transgenic (TCRbeta-tg) T cells were adoptively transferred into mice infected for different time periods [1, 2 and 3 weeks post-infection (p.i.)] to investigate the direct antiviral effect of CD4(+) T cells in FV infection. Results indicated that FV-specific CD4(+) TCRbeta-tg T cells were functionally active until 2 weeks p.i., retaining their ability to produce gamma interferon (IFN-gamma) and reduce viral loads. However, the donor cells lost their antiviral activity starting from 3 weeks p.i. Interestingly, in vivo depletion of regulatory T cells (Tregs) at this time point restored IFN-gamma production by transferred CD4(+) T cells. The current study reveals that Th cells were critical for recovery from acute FV infection but were functionally impaired during the late phase of acute infection due to induced Tregs.