An Effective Vaccination Approach Augments Anti-HIV Systemic and Vaginal Immunity in Mice with Decreased HIV-1 Susceptible alpha 4 beta 7(high) CD4(+) T Cells

作者：Zhu Wei; Shi Guoping; Tang Haijun; Lewis Dorothy E; Song Xiao Tong^*

来源：Current HIV Research, 2013, 11(1): 56-66.

• ALDH1a2
• alpha 4 beta 7
• CCR9
• CD4+T cell
• dendritic cell
• HIV-1 Vaccine
• shRNA

HIV-1 preferentially infects activated CD4(+) T cells expressing alpha 4 beta 7 integrin and conventional vaccination approaches non-selectively induce immune responses including alpha 4 beta 7(high) CD4(+) T cells, suggesting that current candidate AIDS vaccines may produce more target cells for HIV-1 and paradoxically enhance HIV-1 infection. Thus it remains a challenge to selectively induce robust anti-HIV immunity without the unwanted HIV-1 susceptible alpha 4 beta 7(high) CD4(+) T cells. Here we describe a vaccination strategy that targets ALDH1a2, a retinoic acid producing enzyme in dendritic cells (DCs). Silencing ALDH1a2 in DCs enhanced the maturation and production of proinflammatory cytokines of DCs and promoted Th1/Th2 differentiation while suppressing Treg. ALDH1a2-silenced DCs effectively downregulated the expression of guthoming receptors alpha 4 beta 7 and CCR9 on activated T and B lymphocytes. Consequently, intranasal immunization of a lentiviral vaccine encoding ALDH1a2 shRNA and HIV-1 gp140 redirected gp140-specific mucosal T cell and antibody responses from the gut to the vaginal tract, while dramatically enhancing systemic gp140-specific immune responses. We further demonstrated that silencing ALDH1a2 in human DCs resulted in downregulation of beta 7 expression on activated autologous CD4(+) T cells. Hence this study provides a unique and effective strategy to induce alpha 4 beta 7(low) anti-HIV immune responses.

• 出版日期2013-1