Lung Vascular Remodeling, Cardiac Hypertrophy, and Inflammatory Cytokines in SHIVnef-Infected Macaques

Sharilyn Almodovar, Jessica Swanson, Luis D. Giavedoni, Sreetharan Kanthaswamy, Carlin S. Long, Norbert F. Voelkel, Michael G. Edwards, Joy M. Folkvord, Elizabeth Connick, Susan V. Westmoreland, Paul A. Luciw, Sonia C. Flores

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Fatal pulmonary arterial hypertension (PAH) affects HIV-infected individuals at significantly higher frequencies. We previously showed plexiform-like lesions characterized by recanalized lumenal obliteration, intimal disruption, medial hypertrophy, and thrombosis consistent with PAH in rhesus macaques infected with chimeric SHIVnef but not with the parental SIVmac239, suggesting that Nef is implicated in the pathophysiology of HIV-PAH. However, the current literature on non-human primates as animal models for SIV(HIV)-associated pulmonary disease reports the ultimate pathogenic pulmonary outcomes of the research efforts; however, the variability and features in the actual disease progression remain poorly described, particularly when using different viral sources for infection. We analyzed lung histopathology, performed immunophenotyping of cells in plexogenic lesions pathognomonic of PAH, and measured cardiac hypertrophy biomarkers and cytokine expression in plasma and lung of juvenile SHIVnef-infected macaques. Here, we report significant hematopathologies, changes in cardiac biomarkers consistent with ventricular hypertrophy, significantly increased levels of interleukin-12 and GM-CSF and significantly decreased sCD40 L, CCL-2, and CXCL-1 in plasma of the SHIVnef group. Pathway analysis of inflammatory gene expression predicted activation of NF-κB transcription factor RelB and inhibition of bone morphogenetic protein type-2 in the setting of SHIVnef infection. Our findings highlight the utility of SHIVnef-infected macaques as suitable models of HIV-associated pulmonary vascular remodeling as pathogenetic changes are concordant with features of idiopathic, familial, scleroderma, and HIV-PAH.

Original languageEnglish (US)
Pages (from-to)206-222
Number of pages17
JournalViral Immunology
Volume31
Issue number3
DOIs
StatePublished - Apr 2018

Keywords

  • SHIVnef
  • inflammation
  • pathogenesis
  • pulmonary vascular remodeling

ASJC Scopus subject areas

  • Immunology
  • Molecular Medicine
  • Virology

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    Almodovar, S., Swanson, J., Giavedoni, L. D., Kanthaswamy, S., Long, C. S., Voelkel, N. F., Edwards, M. G., Folkvord, J. M., Connick, E., Westmoreland, S. V., Luciw, P. A., & Flores, S. C. (2018). Lung Vascular Remodeling, Cardiac Hypertrophy, and Inflammatory Cytokines in SHIVnef-Infected Macaques. Viral Immunology, 31(3), 206-222. https://doi.org/10.1089/vim.2017.0051