Abstract
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.
Highlights
More than twenty-five years into the AIDS pandemic, a safe and effective vaccine has not been developed to prevent human immunodeficiency virus (HIV) infection [19]
In a rat study conducted by our laboratory, animals vaccinated with defective simian immunodeficiency viruses (dSIVs) expressing gamma interferon (IFN-␥) had humoral and cell-mediated immune responses to Gag but only partially controlled replication of a recombinant vaccinia virus expressing simian immunodeficiency virus (SIV) Gag-Pol used as a surrogate challenge (55a)
The results of the Western blot show that the vesicular stomatitis virus glycoprotein (VSV-G), Gag, and CD40 ligand (CD40L) proteins were present in CD40LdSIV particles (Fig. 2A)
Summary
More than twenty-five years into the AIDS pandemic, a safe and effective vaccine has not been developed to prevent human immunodeficiency virus (HIV) infection [19]. In a rat study conducted by our laboratory, animals vaccinated with dSIV expressing gamma interferon (IFN-␥) had humoral and cell-mediated immune responses to Gag but only partially controlled replication of a recombinant vaccinia virus expressing SIV Gag-Pol used as a surrogate challenge (55a). We took advantage of the immunoregulatory characteristics of CD40L and the wide cell tropism of VSV-G by incorporating both into the envelope of pseudotyped viral particles to enhance the immunogenicity of dSIVs. We evaluated the immunogenicity of CD40L-dSIV in vitro using monocyte-derived DCs with a phenotype comparable to that of interstitial DCs [5]. The results suggested that CD40L, as a vaccine adjuvant, significantly enhanced the ability of dSIV to activate DCs and prime naive T cells in vitro. CD40L-dSIV-immunized mice had higher antibody and cell-mediated immune (CMI) responses than dSIV-immunized animals, suggesting that this strategy could increase the immune responses required for controlling HIV infection
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
