title: Adenovirus vectors block human immunodeficiency virus-1 replication in human alveolar macrophages by inhibition of the long terminal repeat.
abstract: Heterologous viruses may transactivate or suppress human immunodeficiency virus (HIV)-1 replication. An adenovirus type 5 gene transfer vector (Ad5) HIV-1 vaccine was recently evaluated in a clinical trial, without efficacy. In this context, it is relevant to ask what effect Ad vectors have on HIV-1 replication, particularly in cells that are part of the innate immune system. Infection of HIV-1-infected human alveolar macrophages (AMs) obtained from HIV-1(+) individuals with an Ad vector containing no transgene (AdNull) resulted in dose-responsive inhibition of endogenous HIV-1 replication. HIV-1 replication in normal AMs infected with HIV-1 in vitro was inhibited by AdNull with a similar dose response. Ad reduced AM HIV-1 replication up to 14 days after HIV-1 infection. Fully HIV-1-infected AMs were treated with 3'-azido-3'-deoxythymidine, after which Ad infection still inhibited HIV-1 replication, suggesting a postentry step was affected. Substantial HIV-1 DNA was still produced after Ad infection, as quantified by TaqMan real-time PCR, suggesting that the replication block occurred after reverse transcription. AdNull blocked HIV-1 long terminal repeat (LTR) transcription, as assessed by an vesicular stomatitis virus G protein pseudotyped HIV-1 LTR luciferase construct. The formation of HIV-1 DNA integrated into the host chromosome was not inhibited by Ad, as quantified by a two-step TaqMan real-time PCR assay, implying a postintegration block to HIV-1 replication. These data indicate that Ad vectors are inhibitory to HIV-1 replication in human AMs based, in part, on their ability to inhibit LTR-driven transcription.
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kaner
authors.forename: Francisco
authors.initials: F
authors.lastname: Santiago
authors.forename: Franck
authors.initials: F
authors.lastname: Rahaghi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Michaels
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D018893:Bronchoalveolar Lavage; D001999:Bronchoscopy / Q000379:methods; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D016676:Macrophages, Alveolar / Q000821:virology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D019076:Transgenes; D014779:Virus Replication