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HIV-1 Nef is associated with complex pulmonary vascular lesions in SHIV-nef-infected macaques
John C Marecki1, Carlyne D Cool, Jane E Parr
1Department of Medicine, University of Colorado at Denver and Health Sciences Center, 4200 East Ninth Avenue, Box C272, Denver, CO 80262, USA. John.Marecki@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.
Insights
The HIV nef gene, when present in Simian-Human Immunodeficiency Virus (SHIV-nef), causes pulmonary arterial lesions in macaques. These lesions, similar to those in HIV-related pulmonary hypertension (HRPH), suggest Nef’s role in disease development.
Area of Science:
- Virology
- Pathology
- Immunology
Background:
- HIV-related pulmonary hypertension (HRPH) shares histologic features with idiopathic pulmonary arterial hypertension.
- The role of viral proteins in HRPH plexiform lesion development is unknown.
- Simian immunodeficiency virus (SIV) macaque models mimic HIV infection, making them suitable for studying pulmonary arterial hypertension.
Purpose of the Study:
- To investigate the presence of pulmonary arterial lesions in archived SIV-infected macaque lung tissues.
- To explore the potential role of viral proteins, specifically HIV nef, in the pathogenesis of pulmonary arterial hypertension.
Main Methods:
- Archived macaque and human lung sections were analyzed using immunohistochemistry.
- Vascular lesions were examined for specific cellular markers and viral protein presence.
Main Results:
- Complex plexiform-like lesions were observed exclusively in macaques infected with SHIV-nef, not SIV.
- Lesion cells stained positive for Factor VIII, muscle-specific actin, and smooth muscle actin.
- HIV Nef was detected in lung mononuclear cells of SHIV-nef macaques and vascular cells of HRPH patients.
Conclusions:
- The presence of vascular lesions in SHIV-nef infected animals suggests a role for the HIV nef gene.
- Nef's presence in vascular cells of HRPH patients further implicates it in severe pulmonary arterial disease development.
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