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Published ahead of print on October 5, 2009
Am. J. Respir. Cell Mol. Biol. 2009, doi:10.1165/rcmb.2008-0063OC
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Submitted on February 7, 2008
Accepted on October 5, 2009

Adenovirus Vectors Block HIV-1 Replication in Human Alveolar Macrophages by Inhibition of the LTR

Robert J Kaner1, Francisco Santiago2, Franck Rahaghi1, Elizabeth Michaels3, John P Moore3, and Ronald G Crystal4*

1 Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, United States, 2 Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States, 3 Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States, 4 Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, United States; Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States

* To whom correspondence should be addressed. E-mail: geneticmedicine{at}med.cornell.edu.

Heterologous viruses may transactivate or suppress HIV-1 replication. An Ad type 5 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 (AM) 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 AM 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 following HIV-1 infection. Fully HIV-1 infected AM were treated with AZT, after which Ad infection still inhibited HIV-1 replication, suggesting a post-entry step was affected. Substantial HIV-1 DNA was still produced after Ad infection as quantified by TaqMan real-time PCR, suggesting the replication block occurred after reverse transcription. AdNull blocked HIV-1 LTR transcription as assessed by a VSV-G 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 2 step TAQMAN real-time PCR assay, implying a post-integration block to HIV-1 replication. These data indicate that Ad vectors are inhibitory to HIV-1 replication in human AM based in part, on their ability to inhibit LTR-driven transcription.
Key words: human alveolar macrophages • HIV-1 • adenovirus






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