Both neutralizing antibodies and cytotoxic T cells are necessary to control a viral infection. However, vigorous T helper responses are essential for their elicitation and maintenance. These findings have critical implications in the design of vaccination strategies aimed at triggering and sustaining antigen specific CD4+ in addition to CD8+ effector immune responses. Here we show that a recombinant replication-deficient HSV-1 vector encoding the HIV-1 matrix protein p17 (T0-p17) is capable to infect professional APCs in vitro and in vivo without interfering with the endogenous MHC class II processing of the transgene encoded antigen. Moreover, we show that injection of T0-p17 in the mouse dermis generates a strong p17-specific CD4+ T helper response preceding both cytotoxic and humoral responses. Importantly, T0-p17 infected peritoneal macrophages were capable to trigger a long-lasting expansion of p17-specific CD4+ T cells in vitro. Because of their capability to infect professional APCs without interfering with their biological functions, replication-deficient HSV vectors are appealing candidates for the development of vaccines able to trigger strong T helper responses.