HIV-associated Pulmonary Arterial Hypertension Research Articles

HIV-derived proteins contribute to the development of pulmonary arterial hypertension in mice

Pulmonary arterial hypertension (PAH) is a life-threatening lung disease caused by remodeling of pulmonary vascular walls which is associated with a sustained elevation in pulmonary arterial pressure leading to RV failure and ultimately death. HIV infection increases the risk of developing severe PAH and HIV-associated PAH has a poor prognosis with elevated mortality. Despite significant effort to understand its pathophysiology, the identification of signaling pathways involved in HIV-mediated onset and progression of PAH remains scarce. The aim of the present study is to unravel the mechanistic links between HIV and PAH and to investigate how HIV-derived proteins contribute to the pathological processes of pulmonary vascular remodeling (PVR) of PAH and right ventricle (RV) hypertrophy. Three different HIV mouse models have been used to answer these questions. Our results showed that transgenic HIV-1 Tg26 mice, which mimics people living with HIV (PLWH) with low viremia and without progression to AIDS, exhibit increased right ventricular systolic pressure (RVSP), Fulton-index and thickness of pulmonary arterial wall indicating PVR and RV hypertrophy in these mice. More importantly, transfer of bone marrow (BMT) from Tg26 to wild-type (WT) mice and chronic treatment with HIV-encoded Tat protein induce development of PAH and RV hypertrophy in WT mice indicating that HIV-derived proteins contribute to the pathogenesis of PAH in mouse models of HIV. In order to explore signaling pathways involved in the HIV-related PAH, RNA sequencing and qPCR were performed using lung samples from control/Tg26 mice and BMT mice. We found increased expression of the proliferative marker Ki67 in Tg26 lung endothelial cells (EC). In Tg26 lung vascular smooth muscle cells (VSMC), markers of contractile SMC phenotype (SM22, SM MHC) were decreased while markers for synthetic SMC phenotype (Vimentin, Rbp-1) were upregulated suggesting increased EC proliferation and SMC de-differentiation in Tg26 mice. Moreover, we identified ten genes which expression levels were up/ downregulated in the lungs of Tg26 mice which can potentially contribute to the development of HIV-associated PAH. In conclusion, we have established a novel model of HIV, the BMT Tg26 to WT mice, to study the contribution of immune cell derived viral proteins to PAH and demonstrated that at least one viral protein, the HIV-Tat, is involved in the development of PAH and RV hypertrophy associated with HIV. Additional studies are needed to further elucidate the role of these signaling mechanisms in HIV-induced PAH in order to develop effective therapy for the prevention and treatment of this lung disorder. Supported by NIH NHLBI 1R01HL147639 (EBdC) and Augusta University IGP IGPP00030 (LK). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Patient and disease characteristics of pulmonary arterial hypertension patients for prostacyclin receptor agonist selexipag treatment initiation

Aim: to evaluate demographic and disease characteristics in pulmonary arterial hypertension (PAH) patients, for which selexipag is prescribed as PAH-specific treatment.Materials and methods: the study enrolls 73 patients with PAH, where there were 49 patients with idiopathic PAH and 24 patients with associated conditions. These patients were diagnosed in department of pulmonary hypertension and heart disease of the National Medical Research Centre of cardiology named after academician E.I. Chazov of Ministry of Health. Clinical, functional and hemodynamic characteristics of PAH patients were examined. The diagnosis was confirmed according to Eurasian (2019) and Russian (2020) guidelines for the diagnosis and treatment of pulmonary hypertension.Results: At selexipag initiation, median of patient`s age was 43 years, 86,3% were female. Etiological analysis revealed idiopathic PAH in 49 (67,1%) patients, 24 (32,9%) had associated conditions: 14 (19,2%) had connective tissue disease‒associated PAH, 6 (8,2%) had PAH after correction of the initial heart defect, 4 (5,5%) had HIV-associated PAH. The median 6-minute walking distance (6MWD) was 370 (300,0-443,75) m, which was corresponding to WHO functional class III, the median Borg dyspnea index was 5 (3,0-6,0). 7 (9,6%) patients did not undergo 6MWD due to severity of their condition. According to right heart catheterization data the median mean pulmonary arterial pressure was 58,5 (48,25-65,0) mmHg, the median right atrium pressure was 7,5 (5,0-10,0) mmHg, the median venous oxygen saturation 58,5% (56,0-66,0), the median cardiac index was 2,0 (1,6-2,5) liter/min/ m2, the median pulmonary vascular resistance was 15,0 (10,3-19,1) Wood units. At selexipag initiation, according to Eurasian (2019) and Russian (2020) guidelines 1 (1,3%) was at low risk, 21 (28,8%) were at intermediate risk and 51 (69,9%) were at high risk of 1-year mortality. Due to risk status, selexipag was initiated in double (50,7%) and triple (49,3%) PAH-specific therapy.Conclusions: At selexipag initiation, PAH-patients typically have WHO FC III and are at high risk, despite receiving PAH-specific treatment. Selexipag was prescribed as part of a combination regimen in most patients.

HIV- RELATED PULMONARY ARTERIAL HYPERTENSION: A CASE REPORT

The use of highly active antiretroviral therapy (HAART) has increased the life expectancy of HIV-infected patients. With prolonged survival and improved control of infectious susceptibility, vascular complications have emerged as a signicant source of morbidity and mortality in HIV-infected patients [1]. HIV-associated pulmonary arterial hypertension (HIV-PAH) is an important lung disease in HIV-infected persons who live longer with antiretrovirals. HIV-PAH may be detected via chest radiographs, CT scans, or electrocardiograms, but Doppler echocardiography is the most useful screening test to identify candidates for right heart catheterization. Because the survival for HIV-infected individuals with PAH with advanced symptoms (New York Heart Association, NYHA class III-IV) is worse compared with less symptomatic individuals (NYHA class I-II) (2), identication of asymptomatic individuals is of critical importance. Histologically, THE lesions in HIV-infected patients with PAH include concentric laminar intimal brosis, medial hypertrophy, recanalized thrombi, and plexiform lesions (3). According to a more recent study by Sitbon et al [4] in 2008, the prevalence has remained at 0.5% even in the modern era of HIV therapy, suggesting that HAART has not made a dramatic impact on the prevention of HIV-PAH. We present a case of HIVPAH to highlight the importance of the non-infectious pulmonary complications associated with HIV disease.

Does arterial oxygenation during exercise add prognostic value in pulmonary arterial hypertension?

BackgroundThe 6-min walking distance (6MWD) is often used to assess prognosis in pulmonary arterial hypertension (PAH) patients. Whether or not changes in arterial oxygen saturation (SpO2) during exercise add prognostic value to the 6MWD in these patients is unclear. The objective of this study was to investigate if SpO2 changes during exercise adds prognostic value to the 6MWD in PAH patients. MethodsAmbispective study that includes 137 patients with PAH: 38 idiopathic/heritable (i/h PAH), 42 with connective tissue disease (CTD-PAH), 34 with porto-pulmonary hypertension (PoPH), 21 with HIV-associated PAH and 2 with pulmonary venous occlusive disease (PVOD). Patients were characterized and, treated according to international recommendations, and were followed-up for 5 years. To integrate SpO2 changes during exercise, we calculated the desaturation distance ratio (DDR) either in its original form (from a maximal theoretical value of 100%) or the actual resting SpO2 value of the patient (new DDR) as well as the distance saturation product (DSP). Results(1) during follow-up, 40 patients died (29.2%); (2) results confirmed the prognostic value of the 6MWD (AUC 0.913 [IQR 0.868–0.958]; p < 0.0001), original DDR (AUC 0.923 [0.881–0.966]; p < 0.001), New DDR (AUC 0.917 [0.872–0.961], p < 0.001), and DSP (AUC 0.914 [0.869–0.959], p < 0.001); and, (3) neither the original or new DDR or DSP added significant prognostic value to 6MWD in these patients. ConclusionsConsideration of three different composite indices of arterial oxygenation changes during exercise does not add prognostic value to that of the 6MWD in patients with PAH.

Guest Editors’ Memo

This issue of Advances in Pulmonary Hypertension highlights several associated conditions causing pulmonary arterial hypertension (PAH) that are of particular relevance globally and deserve to be on our radar: schistosomiasis, Human immunodeficiency virus (HIV), and liver disease. These well-known conditions provide unique challenges to our understanding and treatment of PAH.Schistosomiasis affects a shocking 200 million or more throughout the world, with 5–10% developing PAH. Yet it can be easy to forget that schistosomiasis is cause of Group I PAH. Brian Graham reviews the background, mechanisms, diagnosis, and treatment schistosomiasis-associated pulmonary arterial hypertension. Graham leaves us with several cutting-edge questions yet to be answered regarding this disease.Nicholas Kolaitis and Christopher Barnett provide us with an updated review on HIV-associated PAH. They take us through epidemiology, pathogenesis, and the impact of antiretroviral therapy. The approach to treatment includes a critical review of drug-drug interactions between HIV and PAH medications.Rosechelle Ruggiero and Sonja Bartolome deliver a focused review of portopulmonary hypertension for the treating provider. They take us through current definitions, clinical features, and management with a crucial focus on special considerations for liver transplantation.We gratefully thank all of our contributing authors for sharing their knowledge and insights. As the world shrinks, and our knowledge of mechanisms of disease and treatment grow, these articles are timely and well worth the read.

Human Immunodeficiency Virus–Associated Pulmonary Arterial Hypertension

Human immunodeficiency virus (HIV) attacks the immune system and can cause acquired immunodeficiency syndrome. Thankfully, antiretroviral therapy is highly effective, and people infected with HIV can live long lives with proper adherence to therapy. One of the important noninfectious complications of HIV is the development of pulmonary arterial hypertension (PAH). This review will cover the epidemiology, pathogenesis, and clinical characteristics of HIV-associated PAH. It will also cover the current knowledge on use of vasodilator therapy in this population.

An Outlook on the Etiopathogenesis of Pulmonary Hypertension in HIV.

Although overall survival rates of patients infected with human immunodeficiency virus (HIV) have been significantly improved by antiretroviral therapy (ART), chronic comorbidities associated with HIV result in a worsening quality of life. Pulmonary arterial hypertension (PAH) is the most prevalent comorbidity associated with HIV infection. Despite low viremia and a non-replicative state maintained by ART, few people develop PAH. Previous data from animal models and human pulmonary microvascular endothelial cells (HPMVECs) suggests a constellation of events occurring during the propagation of HIV-associated PAH (HIV-PAH). However, these studies have not successfully isolated HIV virions, HIV-DNA, protein 24 antigen (p24), or HIV-RNA from the pulmonary endothelial cells (ECs). It provides an insight into an ongoing inflammatory process that could be attributed to viral proteins. Several studies have demonstrated the role of viral proteins on vascular remodeling. A composite of chronic inflammatory changes mediated by cytokines and growth factors along with several inciting risk factors such as Hepatitis C virus (HCV) co-infection, genetic factors, male predominance, illegal drug usage, and duration of HIV infection have led to molecular changes that result in an initial phase of apoptosis followed by the formation of apoptotic resistant hyperproliferative ECs with altered phenotype. This study aims to identify the risk factors and mechanisms behind HIV-PAH pathobiology at the host-pathogen interface at the intracellular level.

Management and prognosis of HIV-associated pulmonary arterial hypertension: 20 Years of evidence from the REHAP registry.

Pulmonary arterial hypertension (PAH) is an independent predictor of death in patients with human immunodeficiency virus (HIV) infection. HIV is the leading cause of PAH (HIV-PAH) worldwide. We described the characteristics, treatment patterns, and prognosis of a cohort of HIV-PAH patients and compared them with those of an equivalent cohort of patients with idiopathic/familial PAH (IPAH/FPAH). We retrospectively analysed and compared the demographic, clinical, and treatment data from patients with HIV-PAH and those with IPAH/FPAH in the Spanish PAH registry (REHAP) from 1998 to 2018. The HIV-PAH overall survival (OS) rate up to 5 years was compared to the age- and sex-matched IPAH/FPAH population. Changes in treatment patterns in patients with HIV-PAH after 2010 and their effects on OS were also analysed. Compared to those with IPAH/FPAH (n = 739), patients with HIV-PAH (n = 132) were younger, mainly men, and had a better functional status. The clinical presentation, haemodynamics, and respiratory function were similar between the groups. Parenteral drug use was the most common mode of HIV transmission. Approximately 11% of patients with HIV-PAH did not receive PAH-targeted therapy. The age- and sex-adjusted 5-year OS rate from diagnosis was 74.0% for patients with HIV-PAH and 68.7% for those with IPAH (p < 0.159). During/after 2010, 23% of patients with IPAH/FPAH received upfront dual oral combination, while oral monotherapy remained the main first-line treatment in patients with HIV-PAH. The overall OS rate remained stable. Patients with HIV-PAH were predominantly young men. The short-term prognosis is similar to that of age- and sex-matched patients with IPAH/FPAH, despite a better functional status. Oral monotherapy remains the preferred first-line treatment in the current cohorts.

HIV and pulmonary hypertension: CD4 and viral load matter

The use of combination antiretroviral therapy (ART) has transformed HIV infection from a fatal illness into a chronic disease. As a consequence, the long-term cardiopulmonary complications, including HIV-associated pulmonary arterial hypertension, have emerged as the primary source of morbidity and mortality, representing an important health-care concern.1 HIV-associated pulmonary arterial hypertension is a life-threatening condition characterised by pulmonary vascular remodelling, elevated pulmonary arterial pressure, and right heart failure.

Treatment of HIV-associated pulmonary arterial hypertension: single-center experience

Abstract Introduction Currently there is no evidence-based strategy for PAH drug application adjusted for patients with HIV-associated PAH. Data regarding the use of sildenafil and endothelin receptors antagonists (ERA) are limited case series. Purpose To present the long-term data on treatment with sildenafil, macitentan and ambrisentan in pts with HIV-PAH. Material and methods In prospective study were consecutively enrolled 18 treatment-naïve pts with HIV-PAH (7 males, 34.5 yrs; 29; 53 yrs), mean follow-up was 1.64yrs; 0,16–59–9.28 yrs. 4 pts were in IV FC, 5-III FC and 9 in II FC PAH (WHO). RHC, ECHO, 6MWT, ergospirometry and NTproBNP level were evaluated at a baseline. Intravenous drug abuse reported in 72% pts, all of them were co-infected with hepatitis. Nine pts (50%) treated with HAART therapy at a baseline. Five pts did not have PAH-specific therapy, 11 pts received sildenafil, 1 IV FC PAH pt with HAART – sildenafil+macitentan and 1 III FC PAH pt with HAART-sildenafil+ambrisentan. Follow-up data (FC, 6MWT, ECHO, ergospirometry, NT-proBNP) were available for 8 PAH-treated pts. Results Pts on PAH therapy had achieved improvement in 6 MWT with mean distance increase 69.3±52 m (p=0.01); NTproBNP level decrease (p=0.018) and FC PAH improvement in 7 pts. In pts with PAH therapy the size of right atrium decreased (56.4±7.8 vs 47.8±6.7 mm, p=0.027). The combinations of sildenafil and macitentan and sildenafil with ambrisentan were well tolerated and resulted 6MWT increase, low NTproBNP and FC improvement. Nevertheless there was no significant changes in peak VO2 consumption. Two pts with sildenafil therapy lost for follow up. Three pts with sildenafil but without HAART therapy dead: in one case due to pneumonia, other 2 cases due to pulmonary embolism. Four pts without HAART and PAH therapy dead. In our population strong association between survival and HAART therapy presence was revealed (p=0.01). Conclusion No adverse reactions of PAH-specific therapy were reported in pts on HAART. PAH therapy had a positive influence on FC, exercise capacity, heart remodeling and NT-proBNP level. There were no deaths in pts who receive HAART and PAH therapy. Nevertheless in our population strong association between survival and HAART therapy presence was revealed. Funding Acknowledgement Type of funding source: None

Echocardiographic Findings and Follow-Up in Two HIVAssociated Pulmonary Arterial Hypertension Cases

Pulmonary arterial hypertension associated with HIV infection is a separate entity. The prevalence is up to one thousand times higher than in general population. The mechanisms are multifactorial and incompletely elucidated. Echocardiography can suggest the diagnosis, but the gold standard method of diagnosing pulmonary arterial hypertension is right heart catheterization. We present clinical and paraclinical findings (NYHA, 6MWD, sPAP, RVGLS) and follow-up in two patients living with HIV, who are included in the Romanian National Program of Pulmonary Arterial Hypertension. In patients, the possible thromboembolism or left heart dysfunction were excluded. Each case has its own particularities, but both of them responded to treatment with sildenafil and improved clinical and paraclinical parameters. Mortality is high, usually due to right heart failure and pulmonary arterial hypertension is considered an independent predictor of death in HIV-infected patients. Co-management with both a Pulmonary Hypertension (PH) expert and a HIV expert is recommended.

The DNA Damage Response and HIV-Associated Pulmonary Arterial Hypertension

The HIV-infected population is at a dramatically increased risk of developing pulmonary arterial hypertension (PAH), a devastating and fatal cardiopulmonary disease that is rare amongst the general population. It is increasingly apparent that PAH is a disease with complex and heterogeneous cellular and molecular pathologies, and options for therapeutic intervention are limited, resulting in poor clinical outcomes for affected patients. A number of soluble HIV factors have been implicated in driving the cellular pathologies associated with PAH through perturbations of various signaling and regulatory networks of uninfected bystander cells in the pulmonary vasculature. While these mechanisms are likely numerous and multifaceted, the overlapping features of PAH cellular pathologies and the effects of viral factors on related cell types provide clues as to the potential mechanisms driving HIV-PAH etiology and progression. In this review, we discuss the link between the DNA damage response (DDR) signaling network, chronic HIV infection, and potential contributions to the development of pulmonary arterial hypertension in chronically HIV-infected individuals.

Culture of pulmonary artery endothelial cells from pulmonary artery catheter balloon tips: considerations for use in pulmonary vascular disease.

Endothelial dysfunction is a hallmark of pulmonary arterial hypertension (PAH) but there are no established methods to study pulmonary artery endothelial cells (PAECs) from living patients. We sought to culture PAECs from pulmonary artery catheter (PAC) balloons used during right-heart catheterisation (RHC) to characterise successful culture attempts and to describe PAEC behaviour.PAECs were grown in primary culture to confluence and endothelial cell phenotype was confirmed. Standard assays for apoptosis, migration and tube formation were performed between passages three to eight. We collected 49 PAC tips from 45 subjects with successful PAEC culture from 19 balloons (39%).There were no differences in subject demographic details or RHC procedural details in successful versus unsuccessful attempts. However, for subjects who met haemodynamic criteria for PAH, there was a higher but nonsignificant (p=0.10) proportion amongst successful attempts (10 out of 19, 53%) versus unsuccessful attempts (nine out of 30, 30%). A successful culture was more likely in subjects with a lower cardiac index (p=0.03) and higher pulmonary vascular resistance (p=0.04). PAECs from a subject with idiopathic PAH were apoptosis resistant compared to commercial PAECs (p=0.04) and had reduced migration compared to PAECs from a subject with portopulmonary hypertension with high cardiac output (p=0.01). PAECs from a subject with HIV-associated PAH formed fewer (p=0.01) and shorter (p=0.02) vessel networks compared to commercial PAECs.Sustained culture and characterisation of PAECs from RHC balloons is feasible, especially in PAH with high haemodynamic burden. This technique may provide insight into endothelial dysfunction during PAH pathogenesis.

Statin treatment prevents the development of pulmonary arterial hypertension in a nonhuman primate model of HIV-associated PAH

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by pulmonary vascular remodeling, elevated pulmonary arterial pressure, and right heart failure. Human immunodeficiency virus (HIV)-infected individuals have a higher incidence of PAH than the non-HIV infected population and evidence suggests a role for systemic and pulmonary inflammation in the pathogenesis of HIV-associated PAH. Due to their pleiotropic effects, including immune-modulatory and anti-inflammatory effects, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been considered for the treatment of PAH, with conflicting results. The effects of statins on HIV-associated PAH have not been specifically evaluated. We have developed a non-human primate (NHP) model of HIV-associated PAH that closely mimics HIV-PAH using simian immunodeficiency virus (SIV)-infected rhesus macaques (Macaca mulatta). We determined that treatment of healthy macaques with atorvastatin prior to and throughout SIV infection prevented the development of SIV-associated PAH. Additionally, SIV-infected macaques that initiated atorvastatin treatment during the early chronic disease stage had reduced incidence of PAH compared to untreated animals. Statin treatment reduced inflammatory mediators TGF-β, MIP-1α, and TNF-α and the numbers of CD14dimCD16+ non-classical monocytes, and CD14+CCR7−CD163−CD206+ alveolar macrophages previously shown to be associated with SIV-PAH. These results support the concept that statins reduce inflammatory processes that contribute to PAH and may provide a safe and effective prophylactic strategy for the prevention of PAH in HIV-infected individuals.

ACUTE RIGHT VENTRICULAR FAILURE FOLLOWING ATTEMPTED PATENT FORAMEN OVALE CLOSURE IN A PATIENT WITH REFRACTORY HYPOXEMIA ON VENOVENOUS EXTRACORPOREAL MEMBRANE OXYGENATION

Patent foramen ovale (PFO) is prevalent and can have hemodynamic consequences in respiratory failure requiring venovenous extracorporeal membrane oxygenation (VV ECMO). A 42 year old male with HIV-associated pulmonary arterial hypertension was admitted for Acute Respiratory Distress Syndrome

The aetiology, clinical presentation and treatment of patients with pulmonary hypertension in Cape Town: A preliminary report from the Groote Schuur Hospital Pulmonary Hypertension Registry

Background There is a paucity of knowledge about pulmonary hypertension (PH) in sub-Saharan Africa and an urgent need for its investigation in this context. The impact of HIV infection in PH is also unknown. Objectives To determine the aetiology, clinical presentation, severity and current management of PH at a tertiary-level hospital in Cape Town, South Africa (SA). Methods Demographic and clinical data, including from special investigations, were captured retrospectively for all patients referred to the Groote Schuur Hospital Pulmonary Hypertension Clinic between October 2015 and November 2017 (n=58) and entered into an online registry. Descriptive statistics were used to present the baseline data at enrolment. Results Patients were mainly young and female and almost half (48.3%) had severe symptoms according to World Health Organization classification. The main aetiologies were pulmonary arterial hypertension (PAH) and chronic thromboembolic PH. More than a fifth of the patients were HIV-positive, with nine patients presenting with HIV-associated PAH. The median time from initial presentation to referral to a specialist centre was 227 days (interquartile range: 72 - 625 days). Only a small number of patients were on PH-specific treatment at enrolment and a notable number never underwent right-heart catheterisation. Conclusion PH diagnosis is often delayed and even at a tertiary institution with a dedicated clinic and access to special investigations, PH is suboptimally investigated and managed. Expansion of this registry to better understand the phenotype of this disease in SA can improve outcomes for these patients through awareness, early identification and effective management.

Abstract 17308: Effect of HIV Protein-Tat &amp; Cocaine on Hippo-YAP Signaling Axis in Pulmonary Arterial Smooth Muscle Cells

Introduction and hypothesis: Intravenous drug use (IVDU) is considered to be one of the important risk factors in the development of HIV-associated pulmonary arterial hypertension (HPAH). Our previous findings demonstrate that the exposure of cocaine to HIV infected individuals has an additive effect in enhancing the proliferation of pulmonary smooth muscle cells, thus further amplifying the development of pulmonary arteriopathy. Furthermore, various studies suggest the failure of Hippo pathway and increased YAP/TAZ activity in pulmonary hypertension (PH). Based on this, we hypothesized that YAP axis might be having a role in HIV and cocaine mediated smooth muscle hyperplasia. Methods: Primary human pulmonary arterial smooth muscle cells (HPASMCs) were grown and treated with cocaine hydrochloride (1μM) and/or HIV-Tat protein (25ng/mL) for 6h. In addition, primary HPASMC were treated for 24h with extracellular vesicles (EVs) transfected with miR-130a antagomir or scrambled miR followed by treatment of EVs isolated from supernatants of monocyte derived macrophage infected with HIV-Bal (5ng/ml) in the presence or absence of cocaine for 4 days. The expression of Hippo proteins was determined using western blot. Results: Combined treatment of HPASMCs with HIV-Tat and cocaine for 6h showed no change in the expression of MST proteins, however reduced expression of phosphorylated LATS1 relative to total LATS1 was observed. This correlated with the decline in the phosphorylated YAP to total YAP ratio. Pre-treatment of HPASMCs with YAP/TAZ inhibitor attenuated the HIV-Tat and cocaine mediated augmentation of cell proliferation. Furthermore, our recent findings demonstrate that EVs derived from HIV infected and cocaine treated MDMs (H+C EVs) when added to HPASMC result in increased proliferation on transfer of miR-130a. We now found that this H+C EVs mediated hyper-proliferation of smooth muscle cells is associated with the increased levels of total YAP protein. In addition, H+C EVs mediated increase in total YAP was prevented on the pretreatment of HPASMCs with EVs carrying anti-miR-130a. Conclusion: In conclusion, our preliminary findings suggest increased activation of Hippo-YAP signaling in pulmonary smooth muscle cells on the direct treatment with HIV protein and cocaine and also on exposure to EVs derived from HIV infected and cocaine treated macrophages.

HIV transgene expression impairs K+ channel function in the pulmonary vasculature.

Human immunodeficiency virus (HIV) infection is an established risk factor for pulmonary arterial hypertension (PAH); however, the pathogenesis of HIV-related PAH remains unclear. Since K+ channel dysfunction is a common marker in most forms of PAH, our aim was to analyze whether the expression of HIV proteins is associated with impairment of K+ channel function in the pulmonary vascular bed. HIV transgenic mice (Tg26) expressing seven of the nine HIV viral proteins and wild-type (WT) mice were used. Hemodynamic assessment was performed by echocardiography and catheterization. Vascular reactivity was studied in endothelium-intact pulmonary arteries. K+ currents were recorded in freshly isolated pulmonary artery smooth muscle cells (PASMC) using the patch-clamp technique. Gene expression was assessed using quantitative RT-PCR. PASMC from Tg26 mice had reduced K+ currents and were more depolarized than those from WT. Whereas voltage-gated K+ channel 1.5 (Kv1.5) currents were preserved, pH-sensitive noninactivating background currents ( IKN) were nearly abolished in PASMC from Tg26 mice. Tg26 mice had reduced lung expression of Kv7.1 and Kv7.4 channels and decreased responses to the Kv7.1 channel activator L-364,373 assessed by vascular reactivity and patch-clamp experimental approaches. Although we found pulmonary vascular remodeling and endothelial dysfunction in Tg26 mice, this was not accompanied by changes in hemodynamic parameters. In conclusion, the expression of HIV proteins in vivo impairs pH-sensitive IKN and Kv7 currents. This negative impact of HIV proteins in K+ channels was not sufficient to induce PAH, at least in mice, but may play a permissive or accessory role in the pathophysiology of HIV-associated PAH.

Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH

The incidence of pulmonary arterial hypertension (PAH) is a significant co-morbidity observed in HIV (+) individuals. Pulmonary artery smooth muscle cells (PASMCs)—key components of the arterial vessel wall that regulate vessel diameter, demonstrate increased proliferation and hypertrophy in the lungs of HIV infected individuals, underscoring the role of these cells in the pathogenesis of HIV-associated PAH. While several pathways have been implicated in enhanced proliferation of PASMCs, detailed molecular mechanism(s) underlying HIV-associated PASMC proliferation still remain elusive. In the current study, we sought to investigate the effects HIV protein transactivator of transcription (TAT)-mediated proliferation on PASMCs. In agreement with earlier findings, our results also demonstrated TAT-mediated proliferation of human PASMCs. We identified activation of a novel Notch3 signaling pathway in TAT-mediated proliferation of PASMCs. Further validation of the Notch 3 pathway was demonstrated using both pharmacological (γ-secretase inhibitor, DAPT), as well as genetic approaches (Notch3 siRNA). Vascular endothelial growth factor A (VEGF-A) was identified as a novel downstream molecule that was induced following Notch activation. Findings from in vitro studies were further validated in archived simian immunodeficiency virus (SIV)-infected monkey lung tissues. There was increased activation of Notch3 signaling as well as enhanced expression of VEGF-A in the lungs of SIV-infected macaques compared with the lungs of SIV(−) controls. Taken together, we demonstrated that HIV-TAT increased the proliferation of PASMCs via the Notch3/VEGF-A axis. Targeting the Notch3/VEGF-A axis could thus be considered a potential therapeutic approach for the treatment of HIV-associated PAH.

HIV-associated pulmonary hypertension.

HIV-associated pulmonary arterial hypertension (HIV-PAH) is a well-recognized severe cardiovascular complication of HIV infection that confers an adverse prognosis irrespective of the stage of disease. This review will summarize the available data on HIV-PAH epidemiology and provide insights into the pathophysiology and therapeutic strategies currently available. Patients with HIV are several thousand times more likely to develop HIV-PAH compared to the incidence of idiopathic PAH. Several HIV viral proteins are implicated in the pathogenesis although the exact mechanism remains unknown. In the past two decades, there have been several new treatment strategies that appear effective in treating HIV-PAH. Novel pathophysiologic mechanisms implicating the transforming growth factor β receptor family may offer novel therapeutic targets in the future. As antiretroviral therapy continues to improve health outcomes for patients with HIV, there needs to be a shift in focus of care toward chronic noncommunicable diseases. Among cardiovascular disease-complicating chronic HIV infection, HIV-PAH is a severe progressive disease that leads to right heart failure and death. Currently available treatment strategies are effective, however, furthering our understanding of HIV-PAH will be critical as it is likely to become the commonest cause of PAH worldwide.