TY - JOUR
T1 - Lung Vascular Remodeling, Cardiac Hypertrophy, and Inflammatory Cytokines in SHIVnef-Infected Macaques
AU - Almodovar, Sharilyn
AU - Swanson, Jessica
AU - Giavedoni, Luis D.
AU - Kanthaswamy, Sreetharan
AU - Long, Carlin S.
AU - Voelkel, Norbert F.
AU - Edwards, Michael G.
AU - Folkvord, Joy M.
AU - Connick, Elizabeth
AU - Westmoreland, Susan V.
AU - Luciw, Paul A.
AU - Flores, Sonia C.
N1 - Funding Information:
This study was supported by the NIH/NHLBI grants R01 HL083491, its supplement under the American Recovery and Reinvestment Act, R01 HL059785 (to SCF), T32-HL007171 (UC-Denver Cardiovascular Physiology Laboratory), and NIH/NCATS UL1 TR001082 (Colorado CTSA), R01 AI096966, and R56 AI080418 (to EC). The CNPRC is supported by the NIH Base Operating Grant OD011107. The NEPRC was supported by NIH/NCRR P51 RR000168, and RR000169. Texas Biomedical Research Institute is supported by OD011133. Content is the authors’ sole responsibility and does not necessarily represent official NIH views.
Publisher Copyright:
© 2018 Mary Ann Liebert, Inc.
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
KW - SHIVnef
KW - inflammation
KW - pathogenesis
KW - pulmonary vascular remodeling
UR - http://www.scopus.com/inward/record.url?scp=85045514456&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045514456&partnerID=8YFLogxK
U2 - 10.1089/vim.2017.0051
DO - 10.1089/vim.2017.0051
M3 - Article
C2 - 29256819
AN - SCOPUS:85045514456
VL - 31
SP - 206
EP - 222
JO - Viral Immunology
JF - Viral Immunology
SN - 0882-8245
IS - 3
ER -