A
vaccine for the prevention of human immunodeficiency virus (
HIV) infection is desperately needed to control the
AIDS pandemic. To address this problem, we developed
vesicular stomatitis virus
glycoprotein-pseudotyped replication-defective simian immunodeficiency viruses (dSIVs) as an
AIDS vaccine strategy. The dSIVs retain characteristics of a live attenuated virus without the drawbacks of potential virulence caused by replicating virus. To improve vaccine immunogenicity, we incorporated
CD40 ligand (
CD40L) into the dSIV envelope.
CD40L is one of the most potent stimuli for dendritic cell (DC) maturation and activation. Binding of
CD40L to its receptor upregulates expression of major histocompatibility complex class I, class II, and costimulatory molecules on DCs and increases production of proinflammatory
cytokines and
chemokines, especially
interleukin 12 (IL-12). This
cytokine polarizes CD4(+) T cells to Th1-type immune responses. DC activation and mixed lymphocyte reaction (MLR) studies were performed to evaluate the immunogenicity of CD40L-dSIV in vitro. Expression levels of CD80, CD86,
HLA-DR, and CD54 on DCs transduced with the dSIV incorporating
CD40L (CD40L-dSIV) were significantly higher than on those transduced with dSIV. Moreover, CD40L-dSIV-transduced DCs expressed up to 10-fold more
IL-12 than dSIV-transduced DCs. CD40L-dSIV-transduced DCs enhanced proliferation and
gamma interferon secretion by naive T cells in an MLR. In addition, CD40L-dSIV-immunized mice exhibited stronger humoral and cell-mediated immune responses than dSIV-vaccinated animals. The results show that incorporating
CD40L into the dSIV envelope significantly enhances immunogenicity. As a result, CD40L-dSIVs can be strong candidates for development of a safe and highly immunogenic
AIDS vaccine.