Host‐Pathogen Interactions in the Pulmonary Vasculature During Infection with Human Immunodeficiency Virus

Abstract

BackgroundAntiretroviral therapy has improved the life of individuals infected with Human Immunodeficiency Virus (HIV), however, they remain susceptible to deadly pulmonary complications as a result of dysfunctional pulmonary vascular Smooth Muscle Cells (SMC) and Endothelial Cells (EC). While modern vascular biology establishes that EC are resistant to HIV infection but susceptible to HIV cytopathic effects as bystander cells, virologists have shown that the endothelium helps in the spread of the virus on their roles as antigen‐presenting cells. Nevertheless, EC permissiveness to HIV infection may depend on tissue and functional status. Several in vitro studies disagree with findings in vivo, which complicates pulmonary vascular mechanistic studies. Cells in co‐culture may reproduce the scenario in vivo and facilitate reliable studies on host cell‐pathogen interactions in the lung during HIV infection. This study investigated the HIV infection status and inflammatory cytokine release patterns in the lung microenvironment using co‐cultures in vitro. Based on the literature, we hypothesize that EC are resistant to HIV infection but release inflammatory cytokines in the presence of HIV.MethodsWe cultured pulmonary vascular cells either individually, in co‐culture with T lymphocytes or in tri‐cultures including EC, SMC and T cells +/− HIV. Vascular cells were exposed to either cell‐free HIV or HIV‐infected lymphocytes. Cell cultures were imaged in real time using an IncuCyte ZOOM (Essen Biosciences). Cell supernatants were analyzed by electrochemiluminescence using the V‐PLEX Proinflammatory Panel 1 Human Kit (Meso Scale Discovery). Statistical analyses were done using GraphPad Prism 6.ResultsWe found that SMC are permissive to infection by either cell‐free HIV or HIV‐infected T cells. Pulmonary EC were also susceptible to infection by cell‐free HIV and HIV‐infected lymphocytes, but not when in tri‐culture with SMC. The SMC displayed marked cytoplasmic condensation when exposed to HIV, while the EC showed cytolysis but none of these effects where observed in the tri‐cultures. When cultured separately, SMC exhibited strong proinflammatory phenotypes compared to the EC. When combined, the tri‐cultures exhibited moderate inflammatory cytokine release, suggesting that the EC may restrict inflammation in the pulmonary microenvironment.ConclusionsPulmonary SMC may mediate EC restrictions to HIV infection. In addition, vascular cells may protect each other from acute cytopathic effects of HIV. While this study sheds new light onto the cell‐cell dynamics in the pulmonary microenvironment, future studies will address whether this apparent protection involves HIV‐mediated re‐programing of the vascular cells leading to chronic vascular cell dysfunction.Support or Funding InformationSponsored by NIH/NIGMS R25 GM096955 (ESM) and NHLBI R21 HL129852 (SA)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.