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Published ahead of print on May 25, 2006, doi:10.1164/rccm.200601-005OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 4, August 2006, 437-445

A more recent version of this article appeared on August 15, 2006
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Submitted on January 3, 2006
Accepted on May 25, 2006

HIV-1 Nef is Associated with Complex Pulmonary Vascular Lesions in SHIV-nef-infected Macaques

John C Marecki1*, Carlyne D Cool2, Jane E Parr2, Virginia E Beckey1, Paul A Luciw3, Alice F Tarantal3, Angela Carville4, Richard P Shannon5, Adela Cota-Gomez1, Rubin M Tuder6, Norbert F Voelkel7, and Sonia C Flores1

1 Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA, 2 Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA, 3 California National Primate Research Center, University of California, Davis, Davis, California, USA, 4 New England National Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA, 5 Allegheny General Hospital, Pittsburgh, Pennsylvania, USA, 6 Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, 7 Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA; Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA

* To whom correspondence should be addressed. E-mail: John.Marecki{at}UCHSC.edu.

Rationale: HIV-infected patients with pulmonary arterial hypertension have histological manifestations that are indistinguishable from those found in patients with idiopathic pulmonary arterial hypertension (IPAH). In addition, the role of pleiotropic viral proteins in the development of plexiform lesions in HIV-related PH (HRPH) has not been explored. Simian immunodeficiency virus (SIV) infection of macaques has been found to closely recapitulate many of the characteristic features of HIV infection, thus hallmarks of PAH should also be found in this nonhuman primate model of HIV. Objectives: To determine whether pulmonary arterial lesions were present in archived SIV-infected macaque lung tissues from Johns Hopkins University and two National Primate Research Centers. Methods: Archived macaque and human lung sections were examined via immunohistochemistry for evidence of complex vascular lesions. Results: Complex plexiform-like lesions characterized by luminal obliteration, intimal disruption, medial hypertrophy, thrombosis and recanalized lumina were found exclusively in animals infected with SHIV-nef, but not in animals infected with SIV. The mass of cells in the lesions were Factor VIII+, and contained cells positive for muscle-specific and smooth muscle actins. Lung mononuclear cells were positive for HIV Nef, suggesting viral replication. Endothelial cells in both the SHIV-nef macaques and HRPH, but not in IPAH patients, were also Nef-positive. Conclusions: The discovery of complex vascular lesions in SHIV-nef- but not SIV-infected animals and the presence of Nef in the vascular cells of HRPH patients suggest that Nef plays a key role in the development of severe pulmonary arterial disease.
Key words: Pulmonary hypertension, HIV-1, SHIV-nef, rhesus macaque,idiopathic pulmonary arterial hypertension




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