title: Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1.
abstract: In the recently halted HIV type 1 (HIV-1) vaccine STEP trial, individuals that were seropositive for adenovirus serotype 5 (Ad5) showed increased rates of HIV-1 infection on vaccination with an Ad5 vaccine. We propose that this was due to activation and expansion of Ad5-specific mucosal-homing memory CD4 T cells. To test this hypothesis, Ad5 and Ad11 antibody titers were measured in 20 healthy volunteers. Dendritic cells (DCs) from these individuals were pulsed with replication defective Ad5 or Ad11 and co-cultured with autologous lymphocytes. Cytokine profiles, proliferative capacity, mucosal migration potential, and susceptibility to HIV infection of the adenovirus-stimulated memory CD4 T cells were measured. Stimulation of T cells from healthy Ad5-seropositive but Ad11-seronegative individuals with Ad5, or serologically distinct Ad11 vectors induced preferential expansion of adenovirus memory CD4 T cells expressing alpha(4)beta(7) integrins and CCR9, indicating a mucosal-homing phenotype. CD4 T-cell proliferation and IFN-gamma production in response to Ad stimulation correlated with Ad5 antibody titers. However, Ad5 serostatus did not correlate with total cytokine production upon challenge with Ad5 or Ad11. Expanded Ad5 and Ad11 memory CD4 T cells showed an increase in CCR5 expression and higher susceptibility to infection by R5 tropic HIV-1. This suggests that adenoviral-based vaccination against HIV-1 in individuals with preexisting immunity against Ad5 results in preferential expansion of HIV-susceptible activated CD4 T cells that home to mucosal tissues, increases the number of virus targets, and leads to a higher susceptibility to HIV acquisition.
authors.affiliation: Department of Immunology, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom.
authors.forename: Adel
authors.initials: A
authors.lastname: Benlahrech
authors.forename: Julian
authors.initials: J
authors.lastname: Harris
authors.forename: Andrea
authors.initials: A
authors.lastname: Meiser
authors.forename: Timos
authors.initials: T
authors.lastname: Papagatsias
authors.forename: Julia
authors.initials: J
authors.lastname: Hornig
authors.forename: Peter
authors.initials: P
authors.lastname: Hayes
authors.forename: Andre
authors.initials: A
authors.lastname: Lieber
authors.forename: Takis
authors.initials: T
authors.lastname: Athanasopoulos
authors.forename: Veronique
authors.initials: V
authors.lastname: Bachy
authors.forename: Eszter
authors.initials: E
authors.lastname: Csomor
authors.forename: Rod
authors.initials: R
authors.lastname: Daniels
authors.forename: Kerry
authors.initials: K
authors.lastname: Fisher
authors.forename: Frances
authors.initials: F
authors.lastname: Gotch
authors.forename: Len
authors.initials: L
authors.lastname: Seymour
authors.forename: Karen
authors.initials: K
authors.lastname: Logan
authors.forename: Romina
authors.initials: R
authors.lastname: Barbagallo
authors.forename: Linda
authors.initials: L
authors.lastname: Klavinskis
authors.forename: George
authors.initials: G
authors.lastname: Dickson
authors.forename: Steven
authors.initials: S
authors.lastname: Patterson
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology*; D039441:Integrin alpha4 / Q000276:immunology; D039641:Integrin beta Chains / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D009092:Mucous Membrane / Q000276:immunology; D010641:Phenotype; D054388:Receptors, CCR / Q000276:immunology; D054398:Receptors, CCR4 / Q000276:immunology; D014611:Vaccination
chemical_list: D016915:AIDS Vaccines; D000914:Antibodies, Viral; C119309:CC chemokine receptor 9; C515354:CCR4 protein, human; D039641:Integrin beta Chains; D054388:Receptors, CCR; D054398:Receptors, CCR4; C091368:integrin beta7; D039441:Integrin alpha4