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In vitro Uncoating of HIV-1 Cores
Published on: November 8, 2011
HIV-1 penetrates coronary artery endothelial cells by transcytosis
C Gujuluva1, A R Burns, T Pushkarsky
1Department of Medicine, UCLA School of Medicine, Los Angeles, CA, USA.
Insights
Human Immunodeficiency Virus type 1 (HIV-1) can cross the endothelium, not through cell junctions, but by forming vacuoles within endothelial cells. This transcellular pathway allows HIV-1 to penetrate the heart and brain barriers.
Area of Science:
- Cardiovascular Science
- Virology
- Cell Biology
Background:
- The mechanism of HIV-1 cardiomyopathy pathogenesis remains unclear, despite HIV-1 detection in heart muscle cells.
- It is unknown if HIV-1 infects coronary artery endothelial cells (CAEC) or uses transcellular/paracellular routes to cross the endothelium.
Purpose of the Study:
- To investigate the mechanism of HIV-1 penetration across the coronary artery endothelial cell (CAEC) barrier.
- To determine if HIV-1 infection of CAEC is productive or abortive.
Main Methods:
- Constructed a CAEC barrier model using primary human CAEC.
- Utilized PCR, infectious assays, immunofluorescence, and transmission electron microscopy to study HIV-1 infection and barrier integrity.
- Measured HIV-1 invasion, paracellular permeability, and changes in tight junction proteins.
Main Results:
- HIV-1 infection of CAEC was abortive, with no productive replication observed.
- HIV-1 significantly penetrated the CAEC barrier within 24 hours post-infection.
- HIV-1 induced cytoplasmic vacuolization in CAEC and brain microvascular endothelial cells (BMVEC), facilitating virus passage.
Conclusions:
- The endothelium is permeable to HIV-1.
- HIV-1 utilizes a transcellular route, forming vacuoles within endothelial cells, to cross the coronary and brain barriers.
Background:
The pathogenesis of HIV-1-related cardiomyopathy is poorly understood, but HIV-1 has been detected in cardiomyocytes. Whether HIV-1 penetrates into the myocardium by infection of coronary artery endothelial cells (CAEC) or using transcellular or paracellular routes across CAEC has not been resolved.
Materials And Methods:
A model of the CAEC barrier was constructed with primary CAEC (derived from human coronary vessels). Polymerase chain reaction (PCR) assay, infectious assay, and immunofluorescence were employed to show abortive nature of HIV-1 infection of CAEC. Tight junction (TJ) and cell adhesion proteins were visualized by immunofluorescence. The time course of HIV-1 invasion was measured by HIV-1 RNA assay. Inulin permeability assay determined paracellular leakage. Transmission electron microscopy demonstrated virus-induced endothelial vacuolization.
Results:
Despite a strong display on CAEC of CXCR4 and a lesser expression of CCR3 and CCR5, HIV-1 did not productively replicate in CAEC, as shown by infectious assay, immunofluorescence, and electron microscopy. HIV-1 infection of CAEC was abortive with minimal reverse transcription of strong stop DNA and pol but not full-length or two LTR DNA circles. Upon infection of the model with 1 million RNA copies of HIV-1JR-FL, virus penetration 2 hr postinfection (PI) was negligible but increased by 1,750% 24 hr PI. The paracellular permeability increased during this period by only 25%. Neither AOP-RANTES nor v-MIPII significantly reduced HIV-1JR-FL invasion. Virus infection did not alter the integral TJ protein occludin and the TJ-associated protein ZO-1. HIV-1 exposed CAEC and brain microvascular endothelial cells (BMVEC) developed extensive cytoplasmic vacuolization with retroviral-like particles in the vacuoles.
Conclusions:
The endothelium is not an impenetrable barrier to HIV-1. The virus opens a transcellular route across coronary and brain endothelia in cytoplasmic vacuoles.
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