title: An effective vaccination approach augments anti-HIV systemic and vaginal immunity in mice with decreased HIV-1 susceptible α4β7high CD4+ T cells.
abstract: HIV-1 preferentially infects activated CD4(+) T cells expressing α4β7 integrin and conventional vaccination approaches non-selectively induce immune responses including α4β7(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 α4β77(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 α4β77 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 β7 expression on activated autologous CD4(+) T cells. Hence this study provides a unique and effective strategy to induce α4β7(low) anti-HIV immune responses.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, The Methodist Hospital, Houston, TX, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Guoping
authors.initials: G
authors.lastname: Shi
authors.forename: Haijun
authors.initials: H
authors.lastname: Tang
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Lewis
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Song
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D020868:Gene Silencing; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D015497:HIV-1 / Q000276:immunology*; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D050697:Retinal Dehydrogenase / Q000502:physiology*; D014611:Vaccination / Q000379:methods*; D014621:Vagina / Q000276:immunology*
chemical_list: D016207:Cytokines; D016023:Integrins; C071777:integrin alpha4beta7; D000080924:Aldehyde Dehydrogenase 1 Family; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase