Pulmonary infections are a major cause of the morbidity and mortality associated with infection by human immunodeficiency virus-1 (HIV-1). Based on the knowledge that alveolar macrophages (AM) play a central role in pulmonary host defenses, and that HIV-1 can infect AM, the underlying thesis of this proposal is that inherited and acquired host factors that influence the manner in which AM interact with HIV-1 are major determinants, directly and/or indirectly, of the dysfunction of pulmonary host defenses that is associated with HIV-1 infection. In this context, our goals are to understand the inherited and acquired host factors that modify the biology of HIV-1 interaction with human AM, to study mechanisms by which HIV-1 infection of AM lead to T-cell depletion in the lung, and to examine how the interaction of HIV-l and AM may be interrupted by modifying the intracellular and/or extracellular environment of the AM. Capitalizing on the recent discovery that chemokine receptors serve as co- receptors for HIV-1, and strategies to efficiently modify the genetic repertoire of human AM using replication deficient, recombinant adenovirus (Ad) vectors, we propose to use a panel of primary HIV-1 isolates for phenotype and co-receptor usage, and a characterized cohort of normal donors to serve as a source of AM, to evaluate: (1) co-receptor usage on AM from different individuals by HIV-1 isolates with different phenotypes; (2) the association of HIV-1 infection of AM with AM-induced apoptosis of T-cells via the fas ligand-fas pathway; and (3) modulation of the genetic repertoire of AM relevant to.co-receptor expression and HIV-l infection. This proposal represents a unique collaboration of two groups with diverse skills: the expertise of the Cornell University Medical College group regarding AM biology and Ad vector-mediated gene transfer; the expertise of the Aaron Diamond AIDS Research Center regarding HIV-1 biology; and the combined access of our two groups to the relevant biologic reagents and study populations.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
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