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Pulmonary disease remains a primary source of morbidity and mortality in persons living with HIV (PLWH), although the advent of potent combination antiretroviral therapy has resulted in a shift from predominantly infectious to noninfectious pulmonary complications. PLWH are at high risk for COPD, pulmonary hypertension, and lung cancer even in the era of combination antiretroviral therapy. The underlying mechanisms of this are incompletely understood, but recent research in both human and animal models suggests that oxidative stress, expression of matrix metalloproteinases, and genetic instability may result in lung damage, which predisposes PLWH to these conditions. Some of the factors that drive these processes include tobacco and other substance use, direct HIV infection and expression of specific HIV proteins, inflammation, and shifts in the microbiome toward pathogenic and opportunistic organisms. Further studies are needed to understand the relative importance of these factors to the development of lung disease in PLWH., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

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.

IntroductionThe disease spectrum for HIV-infected individuals has shifted toward comorbid non-AIDS conditions including chronic lung disease, but quantitative image analysis of lung disease has not been performed.ObjectivesTo quantify the prevalence of structural changes of the lung indicating emphysema or fibrosis on radiographic examination.MethodsA cross-sectional analysis of 510 HIV-infected participants in the multicenter Lung-HIV study was performed. Data collected included demographics, biological markers of HIV, pulmonary function testing, and chest computed tomographic examinations. Emphysema and fibrosis-like changes were quantified on computed tomographic images based on threshold approaches.ResultsIn our cohort, 69% was on antiretroviral therapy, 13% had a current CD4 cell count less than 200 cells per microliter, 39% had an HIV viral load greater than 500 copies per milliliter, and 25% had at least a trace level of emphysema (defined as >2.5% of voxels

With effective antiretroviral therapy (ART), cardiovascular diseases (CVD) are emerging as a major cause of morbidity and death in the aging HIV-infected population. To address whether HIV-Nef, a viral protein produced in infected cells even when virus production is halted by ART, can lead to endothelial activation and dysfunction, we tested Nef protein transfer to and activity in endothelial cells. We demonstrated that Nef is essential for major endothelial cell activating effects of HIV-infected Jurkat cells when in direct contact with the endothelium. In addition, we found that Nef protein in endothelial cells is sufficient to cause apoptosis, ROS generation and release of monocyte attractant protein-1 (MCP-1). The Nef protein-dependent endothelial activating effects can be best explained by our observation that Nef protein rapidly transfers from either HIV-infected or Nef-transfected Jurkat cells to endothelial cells between these two cell types. These results are of in vivo relevance as we demonstrated that Nef protein induces GFP transfer from T cells to endothelium in CD4.Nef.GFP transgenic mice and Nef is present in chimeric SIV-infected macaques. Analyzing the signal transduction effects of Nef in endothelial cells, we found that Nef-induced apoptosis is mediated through ROS-dependent mechanisms, while MCP-1 production is NF-kB dependent. Together, these data indicate that inhibition of Nef-associated pathways may be promising new therapeutic targets for reducing the risk for cardiovascular disease in the HIV-infected population. [ABSTRACT FROM AUTHOR]

Although reduced bioavailability of nitric oxide (NO) has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH), its consequences on organellar structure and function within vascular cells is largely unexplored. We investigated the effect of reduced NO on the structure of the Golgi apparatus as assayed by giantin or GM130 immunofluorescence in human pulmonary arterial endothelial (HPAECs) and smooth muscle (HPASMCs) cells, bovine PAECs, and human EA.hy926 endothelial cells. Golgi structure was also investigated in cells in tissue sections of pulmonary vascular lesions in idiopathic PAH (IPAH) and in macaques infected with a chimeric simian immunodeficiency virus containing the human immunodeficiency virus (HIV)-nef gene (SHIV-nef) with subcellular three-dimensional (3D) immunoimaging. Compounds with NO scavenging activity including 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), methylene blue, N-acetylcysteine, and hemoglobin markedly fragmented the Golgi in all cell types evaluated as did monocrotaline pyrrole, while LY-83583, sildenafil, fasudil, Y-27632, Tiron, Tempol, or H2O2 did not. Golgi fragmentation by NO scavengers was inhibited by diethylamine NONOate, was evident in HPAECs after selective knockdown of endothelial nitric oxide synthase using small interfering RNA (siRNA), was independent of microtubule organization, required the GTPase dynamin 2, and was accompanied by depletion of a-soluble N-ethylmaleimide-sensitive factor (NSF) acceptor protein (a-SNAP) from Golgi membranes and codispersal of the SNAP receptor (SNARE) Vti1a with giantin. Golgi fragmentation was confirmed in endothelial and smooth muscle cells in pulmonary arterial lesions in IPAH and the SHIV-nef-infected macaque with subcellular 3D immunoimaging. In SHIV-nef-infected macaques Golgi fragmentation was observed in cells containing HIV-nef-bearing endosomes. The observed Golgi fragmentation suggests that NO plays a significant role in modulating global protein trafficking patterns that contribute to changes in the cell surface landscape and functional signaling in vascular cells. [ABSTRACT FROM AUTHOR]

Golgi dysfunction has been previously investigated as a mechanism involved in monocrotaline-induced pulmonary hypertension (PAll). In the present study, we addressed whether Golgi dysfunction might occur in pulmonary vascular cells in idiopathic PAH (IPAH) and whether there might be a causal relationship between trafficking dysfunction and vasculopathies of PAH. Quantitative immunostaining for the Golgi tethers giantin and p115 on human lung tissue from patients with IPAH (n = 6) compared with controls demonstrated a marked cytoplasmic dispersal of giantinand p11 5-bearing vesicular elements in vascular cells in the proliferative, obliterative, and plexiform lesions in IPAH and an increase in the amounts of these Golgi tethers/matrix proteins per cell. The causality question was approached by genetic means using human immunodeficiency virus (HIV)-Nef, a protein that disrupts endocytic and transGolgi trafficking. Macaques infected with a chimeric simian immunodeficiency virus (SIV) containing the HIV-nef gene (SHIV-nef), but not the nonchimenc Sly virus containing the endogenous SIV-nef gene, displayed pulmonary arterial vasculopathies similar to those in human IPAH. Giantin and p1 15 levels and their subcellular distribution `in pulmonary vascular cells in lungs of SHIV-nef infected macaques (n = 4) were compared with SIV-infected (n = 3) and an uninfected macaque control. Only macaques infected with chimeric SHIV-nef showed pulmonary vascular lesions containing cells with dramatic cytoplasmic dispersal and an increase in giantin and p115. Specifically, the HIV-Nef-positive cells showed increased giantin, p115, and the activated transcription factor PY-STAT3. These data represent the first test of the Golgi dysfunction hypothesis in IPAH and place trafficking and Golgi disruption in the chain of causality of pulmonary vasculopathies in the macaque model. [ABSTRACT FROM AUTHOR]

The expression of manganese superoxide dismutase (MnSOD) is regulated by agents associated with cancer development. It has been shown that infection with the human immunodeficiency virus type 1 (HIV-1) is associated with the development of liver cancer and that the transactivating transcriptional factor (Tat) of human HIV-1 reduces the expression of MnSOD in several cell types. However, the role of Tat in the expression of MnSOD in hepatocellular carcinoma is unknown. Furthermore, the precise mechanisms whereby Tat suppresses MnSOD expression in hepatocellular carcinoma cells remain unclear. In this report, we build on our original observations that Tat changes the distribution of Sp family members on the MnSOD promoter, which accounts for Tat-dependent changes in basal expression. In hepatic cells, Tat expression upregulates Sp1/Sp3, which play different roles in regulating MnSOD transcription. While overexpression of Sp1 stimulates, overexpression of Sp3 represses transcriptional activity. The transcription repression effect of Sp3 is not due to Sp3 competing for the binding site with Sp1 because only the full-length Sp3 but not the truncated Sp3 suppresses MnSOD promoter activity. These findings suggest a novel mechanism by which Tat modulates the repression of the MnSOD gene and establish a link between HIV infection and liver cancer. [ABSTRACT FROM AUTHOR]

Abstract: Chronic human immunodeficiency virus infection is associated with higher incidence of pulmonary complications including hypertension, vasculopathy, lymphocytic alveolitis, and interstitial pneumonitis not attributed to either opportunistic infections or presence of the virus. The Tat (transactivator of transcription) protein, a required transactivator for expression of full-length viral genes, is pleiotropic and influences expression of cellular inflammatory genes. Tat-dependent transactivation of cellular genes requires specific mediators, including NF-κB, widely recognized as sensitive to changes in cellular oxidant burden. We hypothesized that overproduction of Tat leads to increased oxidant burden and to alterations in basal inflammatory status as measured by NF-κB activation. We engineered transgenic mouse lines that express Tat (86-amino-acid isoform) in the lung under the control of the surfactant protein C promoter. Tat-transgenic mice exhibit increased pulmonary cellular infiltration, increased nitrotyrosine and carbonyl protein modifications, and increased levels of NF-κB, MnSOD, and thioredoxin-interacting protein. These data indicate that Tat increases oxidant burden and resets the threshold for inflammation, which may increase susceptibility to secondary injuries. [Copyright &y& Elsevier]