title: Exposure to apoptotic activated CD4+ T cells induces maturation and APOBEC3G-mediated inhibition of HIV-1 infection in dendritic cells.
abstract: Dendritic cells (DCs) are activated by signaling via pathogen-specific receptors or exposure to inflammatory mediators. Here we show that co-culturing DCs with apoptotic HIV-infected activated CD4(+) T cells (ApoInf) or apoptotic uninfected activated CD4(+) T cells (ApoAct) induced expression of co-stimulatory molecules and cytokine release. In addition, we measured a reduced HIV infection rate in DCs after co-culture with ApoAct. A prerequisite for reduced HIV infection in DCs was activation of CD4(+) T cells before apoptosis induction. DCs exposed to ApoAct or ApoInf secreted MIP-1α, MIP-1β, MCP-1, and TNF-α; this effect was retained in the presence of exogenous HIV. The ApoAct-mediated induction of co-stimulatory CD86 molecules and reduction of HIV infection in DCs were partially abrogated after blocking TNF-α using monoclonal antibodies. APOBEC3G expression in DCs was increased in co-cultures of DCs and ApoAct but not by apoptotic resting CD4(+) T cells (ApoRest). Silencing of APOBEC3G in DC abrogated the HIV inhibitory effect mediated by ApoAct. Sequence analyses of an env region revealed significant induction of G-to-A hypermutations in the context of GG or GA dinucleotides in DNA isolated from DCs exposed to HIV and ApoAct. Thus, ApoAct-mediated DC maturation resulted in induction of APOBEC3G that was important for inhibition of HIV-infection in DCs. These findings underscore the complexity of differential DC responses evoked upon interaction with resting as compared with activated dying cells during HIV infection.
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Venkatramanan
authors.initials: V
authors.lastname: Mohanram
authors.forename: Ulrika
authors.initials: U
authors.lastname: Johansson
authors.forename: Annette E
authors.initials: AE
authors.lastname: Sköld
authors.forename: Joshua
authors.initials: J
authors.lastname: Fink
authors.forename: Sushil
authors.initials: S
authors.lastname: Kumar Pathak
authors.forename: Barbro
authors.initials: B
authors.lastname: Mäkitalo
authors.forename: Lilian
authors.initials: L
authors.lastname: Walther-Jallow
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Spetz
mesh_terms: D000071480:APOBEC-3G Deaminase; D017209:Apoptosis; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D018925:Chemokines / Q000378:metabolism; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D003564:Cytidine Deaminase / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers; D003713:Dendritic Cells / Q000166:cytology / Q000821:virology*; D006801:Humans; D016133:Polymerase Chain Reaction
chemical_list: D018925:Chemokines; D017077:Culture Media, Conditioned; D016207:Cytokines; D017931:DNA Primers; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase