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

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

Correspondence and requests for reprints should be addressed to John C. Marecki, Ph.D., Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado at Denver and Health Sciences Center, 4200 East Ninth Avenue, Box C272, Denver, CO 80262. E-mail: John.Marecki{at}UCHSC.edu

Rationale: HIV-infected patients with pulmonary arterial hypertension have histologic manifestations that are indistinguishable from those found in patients with idiopathic pulmonary arterial hypertension. In addition, the role of pleiotropic viral proteins in the development of plexiform lesions in HIV-related pulmonary hypertension (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, and thus hallmarks of pulmonary arterial hypertension 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 lumenal obliteration, intimal disruption, medial hypertrophy, thrombosis, and recanalized lumena were found exclusively in animals infected with SHIV-nef (a chimeric viral construct containing the HIV nef gene in an SIV backbone), but not in animals infected with SIV. The mass of cells in the lesions were factor VIII positive, 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 patients with HRPH, but not in patients with idiopathic pulmonary arterial hypertension, 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 patients with HRPH, suggest that Nef plays a key role in the development of severe pulmonary arterial disease.

Key Words: idiopathic pulmonary arterial hypertension • HIV-1 • Nef • pulmonary hypertension • SHIV-nef

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