Human immunodeficiency (HIV) infection is a leading global health problem that causes approximately one million deaths each year. Although antiretroviral therapy can slow down the disease progression and improve the quality of life of infected individuals, it cannot eradicate the virus. A successful vaccine is one of the most cost-effective alternatives to control the incidence and mortality of HIV infection. CD4+ T cells play a key role in orchestrating other forms of human immune responses, therefore, an HIV vaccine that includes a component capable of eliciting CD4+ T cell responses is highly desirable. To this end, we have previously designed a polypeptide vaccine comprised of multiple CD4+ T cell epitopes. In the current study, we tested the immunogenicity of this vaccine in mouse models by using IFN-γELISPOT and intracellular cytokine staining assays. We found that several epitopes in this vaccine elicited CD4+ T cell immune responses in both congenic mice and human HLA-A2/DRB1 transgenic mice. These new epitopes may be further tested for their ability to augment immune responses elicited by other forms of HIV vaccines.