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Pathogenesis of SIV pneumonia: selective replication of viral genotypes in the lung
1Division of Comparative Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA.
Abstract:
Lymphocytic interstitial pneumonia of HIV-infected individuals and SIV pneumonia of macaques are both characterized by diffuse infiltration of the lungs with lymphocytes, plasma cells, and macrophages. This study was undertaken to determine whether there are specific, macrophage-tropic genotypes that selectively replicate in the lung of macaques with SIV pneumonia, as in SIV encephalitis. Using a rapid, reproducible SIV/macaque model of AIDS, 11 pig-tailed macaques were intravenously inoculated with an immunosuppressive viral strain, SIV/DeltaB670, and a macrophage-tropic molecule clone, SIV/17E-Fr, and euthanized at 3 months postinoculation. All 11 macaques had severe (6 macaques) or moderate (5 macaques) pneumonia. To identify the viral genotypes that were replicating in the lung parenchyma, bronchoalveolar lavage (BAL) cells, and peripheral blood mononuclear cells (PBMC) of each macaque, RNA was isolated and the SIV env V1 region was amplified, cloned, and sequenced. Lung homogenates and BAL cells contained a more limited repertoire of viral genotypes than PBMC. SIV/17E-Fr was the major genotype in the lungs of 5 macaques and in BAL cells of 6 macaques. The remainder of the macaques had SIV/17E-Fr and the macrophage-tropic strains of SIV/DeltaB670 clones 2 and 12. In contrast, SIV/17E-Fr was the predominant strain in the PBMC of only 3 of 11 macaques. The viral strain that predominated in PBMC was rarely the strain that predominated in the lungs (only 3 of 11 macaques). The severity of pulmonary lesions did not correlate with the levels of viral RNA in lung homogenates or in plasma. However, when only SIV/17E-Fr was expressed in the lung, the viral load in the lung was significantly higher (P = 0.016) than when SIV/DeltaB670 was present alone or in combination with SIV/17E-Fr. These data suggest that SIV pneumonia is associated with selective replication of specific macrophage-tropic genotypes in the lung and that SIV/17E-Fr has a selective advantage for replication in the lung.
Insights
Specific simian immunodeficiency virus (SIV) genotypes, particularly SIV/17E-Fr, selectively replicate in macaque lungs, causing SIV pneumonia. This macaque model informs understanding of HIV-associated lung disease.
Area of Science:
- Virology
- Immunology
- Pathology
Background:
- Lymphocytic interstitial pneumonia in HIV-infected humans and SIV pneumonia in macaques share pathological features, including diffuse lung infiltration by immune cells.
- Previous research suggests specific macrophage-tropic simian immunodeficiency virus (SIV) genotypes may selectively replicate in the brain during SIV encephalitis.
Purpose of the Study:
- To investigate whether specific, macrophage-tropic SIV genotypes selectively replicate in the lungs of macaques with SIV pneumonia.
- To identify viral genotypes present in lung parenchyma, bronchoalveolar lavage (BAL) cells, and peripheral blood mononuclear cells (PBMC) of SIV-infected macaques.
Main Methods:
- Eleven pig-tailed macaques were intravenously inoculated with SIV/DeltaB670 and SIV/17E-Fr, an immunosuppressive and a macrophage-tropic strain, respectively.
- Macaques were euthanized at 3 months post-inoculation, and lung homogenates, BAL cells, and PBMC were collected.
- RNA was isolated, and the SIV env V1 region was amplified, cloned, and sequenced to identify replicating viral genotypes.
Main Results:
- All macaques developed moderate to severe pneumonia.
- Lung homogenates and BAL cells showed a more restricted viral genotype repertoire compared to PBMC.
- SIV/17E-Fr was the dominant genotype in the lungs of 5 macaques and BAL cells of 6 macaques. When SIV/17E-Fr replicated alone in the lung, viral load was significantly higher (P = 0.016).
Conclusions:
- SIV pneumonia in macaques is associated with the selective replication of specific macrophage-tropic SIV genotypes within the lung parenchyma.
- The SIV/17E-Fr strain demonstrates a selective advantage for replication in the macaque lung.
- These findings provide insights into the pathogenesis of SIV pneumonia and may have implications for understanding HIV-related lung complications.