Alveolar macrophages (AM) are a key reservoir of human immunodeficiency virus-1 (HIV-1) infection in the lung. In the course of studies attempting to alter the genetic repertoire of human AM in order to understand HIV-1 interaction with these cells, we made the novel observation that treatment of human AM with modified adenovirus gene transfer vectors (Ad) prior to HIV- 1 infection blocks subsequent HIV- 1 replication, even in the absence of an Ad transgene, The purpose of this proposal is to understand the mechanism of Ad inhibition of HIV-1 replication in human AM at the molecular level.
The specific aims of the proposal are to understand: 1. The step(s) in the HIV-1 lifecycle that are being inhibited by Ad; 2. The Ad component(s) that are responsible for causing the inhibition; and 3. The intracellular pathway(s) in AM that are being modulated to mediate this effect of Ad on HIV-1 replication. To accomplish these goals, experiments will be performed to assess the effect of timing of Ad treatment of AM relative to HIV-1 infection on the inhibitory effect in comparison with specific inhibitors of various steps in the HIV-1 life cycle. Transcription from the HIV-1 LTR will be compared with the results of p24 ELISA under conditions of the various inhibitors. A TAQMAN PCR assay will be used to quantify the synthesis of HIV-1 specific DNA. To ascertain the Ad components responsible, Ad variants such as empty capsids and vectors deficient in specific Ad genes such as E4 will be used. The intracellular pathways responsible for mediating the inhibitory effect of Ad on HIV-1 replication will be modeled in cell lines deficient in relevant signal transduction molecules such as STAT-1. Correlation will be made with changes in AM gene expression detected by gene chip technology and confirmed with Northern and Western analysis. Taken together, these studies will provide insight into the mechanism of Ad inhibition of HIV-1 replication in human AM.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Colombini-Hatch, Sandra
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Kaner, Robert J; Santiago, Francisco; Rahaghi, Franck et al. (2010) Adenovirus vectors block human immunodeficiency virus-1 replication in human alveolar macrophages by inhibition of the long terminal repeat. Am J Respir Cell Mol Biol 43:234-42
Worgall, Stefan; Martushova, Katherine; Busch, Annette et al. (2002) Apoptosis induced by Pseudomonas aeruginosa in antigen presenting cells is diminished by genetic modification with CD40 ligand. Pediatr Res 52:636-44
Darteil, Raphael; Wang, Manping; Latta-Mahieu, Martine et al. (2002) Efficient gene regulation by PPAR gamma and thiazolidinediones in skeletal muscle and heart. Mol Ther 6:265-71
Ailawadi, Maneesh; Lee, Jay M; Lee, Sang et al. (2002) Adenovirus vector-mediated transfer of the vascular endothelial growth factor cDNA to healing abdominal fascia enhances vascularity and bursting strength in mice with normal and impaired wound healing. Surgery 131:219-27
Rice, Joshua; Connor, Ruth; Worgall, Stefan et al. (2002) Inhibition of HIV-1 replication in alveolar macrophages by adenovirus gene transfer vectors. Am J Respir Cell Mol Biol 27:214-9
Ben-Gary, Harvey; McKinney, Robin L; Rosengart, Todd et al. (2002) Systemic interleukin-6 responses following administration of adenovirus gene transfer vectors to humans by different routes. Mol Ther 6:287-97
Kikuchi, T; Crystal, R G (2001) Antigen-pulsed dendritic cells expressing macrophage-derived chemokine elicit Th2 responses and promote specific humoral immunity. J Clin Invest 108:917-27
Kaner, R J; Worgall, S; Leopold, P L et al. (1999) Modification of the genetic program of human alveolar macrophages by adenovirus vectors in vitro is feasible but inefficient, limited in part by the low level of expression of the coxsackie/adenovirus receptor. Am J Respir Cell Mol Biol 20:361-70
Worgall, S; Connor, R; Kaner, R J et al. (1999) Expression and use of human immunodeficiency virus type 1 coreceptors by human alveolar macrophages. J Virol 73:5865-74