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Cellular injury associated with renal thrombotic microangiopathy in human immunodeficiency virus-infected macaques
Stephan Segerer1, Frank Eitner1, Yan Cui1
1*Department of Pathology, University of Washington, Seattle, Washington; and Division of Nephrology, University of Aachen, Aachen, Germany.
Abstract:
Pigtailed macaques infected with a virulent human immunodeficiency virus-2 (HIV-2) strain develop renal thrombotic microangiopathy (TMA), which morphologically resembles aspects of human HIV-associated TMA. Apoptotic cell death of microvascular endothelial cells might be a pathogenetic clue to this disease. For defining further the pattern of cellular injury in this model, serial kidney sections of 58 macaques infected with HIV-2 and 7 uninfected controls were studied by routine microscopy, terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling (TUNEL), 4',6-diamidino-2-phenylindole staining, and immunohistochemistry for single-stranded DNA, p53, the Wilms' tumor suppressor gene-1 peptide product, caspase-3, and the proliferation marker Ki67. Selected cases were further evaluated by in situ end labeling and transmission electron microscopy. Kidneys of 13 HIV-2-infected animals contained a pattern of cellular injury, which was characterized by (1) nuclear swelling with an ultrastructural morphology different from apoptotic nuclei, (2) sharply demarcated areas of renal cells with chromatin nicks (TUNEL positive) and single-stranded DNA, (3) absence of an inflammatory or proliferative response, (4) upregulation of p53 and loss of at least one cellular differentiation marker (Wilms' tumor suppressor gene-1), (5) a tight correlation with the diagnosis of renal TMA, and (6) a contrast between profound changes in the renal cellular morphology and the apparently unaffected clinical condition of the host. This pattern of injury, which shares some features of both apoptotic and oncotic necrosis, might be involved in the pathogenesis of HIV-associated renal TMA in this model.
Insights
Pigtailed macaques infected with human immunodeficiency virus-2 (HIV-2) developed renal thrombotic microangiopathy (TMA). This study identified a unique cellular injury pattern in HIV-2 infected macaques, potentially explaining HIV-associated TMA.
Area of Science:
- Nephrology
- Virology
- Pathology
Background:
- Pigtailed macaques infected with human immunodeficiency virus-2 (HIV-2) exhibit renal thrombotic microangiopathy (TMA).
- This condition shares morphological similarities with human HIV-associated TMA.
- Apoptotic cell death of microvascular endothelial cells is a potential pathogenetic factor.
Purpose of the Study:
- To define the pattern of cellular injury in the HIV-2 macaque model of renal TMA.
- To investigate the pathogenetic mechanisms underlying HIV-2-associated renal TMA.
Main Methods:
- Analysis of kidney sections from 58 HIV-2 infected and 7 control macaques.
- Utilized routine microscopy, TUNEL assay, DAPI staining, and immunohistochemistry for DNA damage markers (p53, single-stranded DNA), apoptosis (caspase-3), differentiation (Wilms' tumor suppressor gene-1), and proliferation (Ki67).
- In situ end labeling and transmission electron microscopy were employed for selected cases.
Main Results:
- A distinct pattern of renal cellular injury was observed in 13 HIV-2 infected animals.
- This injury pattern included nuclear swelling, TUNEL-positive chromatin nicks, single-stranded DNA, absence of inflammation/proliferation, p53 upregulation, loss of differentiation markers, and correlation with TMA.
- Profound cellular changes occurred despite an apparently unaffected clinical state.
Conclusions:
- The identified cellular injury pattern in HIV-2 macaques shares features of both apoptosis and oncotic necrosis.
- This pattern may contribute to the pathogenesis of HIV-associated renal TMA in this animal model.
- Further research is warranted to elucidate the precise mechanisms of HIV-2-associated renal pathology.