HIV-associated Pulmonary Hypertension Research Articles

Abstract 15659: Development of Novel EMAP-II Neutralizing Antibody Therapy for HIV-Associated Pulmonary Hypertension via Abrogation of HIV-Nef Induced Pulmonary Endothelial Damage

Rationale: People living with HIV experience increased rates of cardiovascular co-morbidities including pulmonary hypertension (600-fold higher prevalence) despite immediate prescription of combined antiviral therapy (ART) upon HIV diagnosis. Previously, we reported that the virally encoded HIV-Nef protein persists in extracellular vesicles (EV) isolated from bronchoalveolar lavage fluid of aviremic HIV patients on ART. Interestingly, Nef-positivity correlated with increased EMAPII levels, a cellular protein which when released extracellularly specifically amplifies endothelial apoptosis. We hypothesize that Nef-EMAPII signaling axis induces endothelial apoptosis and senescence, which could give rise to apoptosis-senescence-resistant, plexiform lesion-forming endothelial cells. Methods and Results: Co-culture with Nef EV producing SupT1 T-cells induces endothelial senescence quantified using senescence associated marker-p16INK4a (p<0.001) which corresponds to increased EMAPII surface expression. Nef induced endothelial senescence as quantified by β-Galactosidase activity was blocked with EMAPII neutralizing antibody (Fig). Transgenic mice with endothelium specific Nef expression had elevated EMAP II surface expression. Two-dose injection of EMAPII neutralizing antibodies (1 mg/mouse, sc) abrogates apoptosis induction as determined by cleaved caspase 3+ pulmonary endothelial cells (p<0.001). Furthermore, Nef Tg mice derived pulmonary endothelial cells had reduced colony formation (p<0.001) which is being tested with EMAPII neutralization as a therapeutic agent. Conclusion: Nef induced apoptosis and cellular senescence can be targeted with EMAP II neutralizing antibodies both in vitro and in vivo . These data suggest that A) Nef can give rise to apoptosis-senescence-resistant plexiform lesion forming endothelial cells and B) neutralizing EMAPII antibodies can be employed to block progression of PAH.

Mice with humanized immune system as novel models to study HIV-associated pulmonary hypertension.

People living with HIV and who receive antiretroviral therapy have a significantly improved lifespan, compared to the early days without therapy. Unfortunately, persisting viral replication in the lungs sustains chronic inflammation, which may cause pulmonary vascular dysfunction and ultimate life-threatening Pulmonary Hypertension (PH). The mechanisms involved in the progression of HIV and PH remain unclear. The study of HIV-PH is limited due to the lack of tractable animal models that recapitulate infection and pathobiological aspects of PH. On one hand, mice with humanized immune systems (hu-mice) are highly relevant to HIV research but their suitability for HIV-PH research deserves investigation. On another hand, the Hypoxia-Sugen is a well-established model for experimental PH that combines hypoxia with the VEGF antagonist SU5416. To test the suitability of hu-mice, we combined HIV with either SU5416 or hypoxia. Using right heart catheterization, we found that combining HIV+SU5416 exacerbated PH. HIV infection increases human pro-inflammatory cytokines in the lungs, compared to uninfected mice. Histopathological examinations showed pulmonary vascular inflammation with arterial muscularization in HIV-PH. We also found an increase in endothelial-monocyte activating polypeptide II (EMAP II) when combining HIV+SU5416. Therefore, combinations of HIV with SU5416 or hypoxia recapitulate PH in hu-mice, creating well-suited models for infectious mechanistic pulmonary vascular research in small animals.

Assessment of probability of pulmonary arterial hypertension among HIV-1 infected patients on haart and its relationship with Cd4 cells Count and viral load.

Background: HIV patients are more likely to develop cardiovascular disease than the general population and have a 2500-fold increased risk of developing pulmonary artery hypertension (PAH). HIV associated pulmonary hypertension was said to be more severe and is associated with higher mortality. Methodology: Across-sectional conducted among consecutive HIV patients age greater than 18 years receiving treatment at the antiretroviral therapy (ART) clinic of the Federal Medical Centre Nguru Yobe State Northeastern Nigeria. Results: One hundred and twenty (120) subjects were recruited into the study, thirteen had incomplete data and were excluded from the analysis. There was a significant negative correlation between CD4 cells count with tricuspid regurgitant flow velocity (TRv), pulmonary regurgitant flow velocity (PRv), pulmonary artery trunk diameter (PATd), right ventricular to left ventricular internal diameter (RV/LV) ratio, left ventricular eccentricity index (LVEI), and right atrial area (RAA), while the correlation between CD4 cells count and right ventricular acceleration time (RVAT) was positive and significant. On the other hand, the correlations between viral load and TRv, PRv, PATd, RV/LV ratio, and RAA were positive and significant while that between viral load and RVAT was negative and significant. Conclusions: This study revealed that HIV patients with low CD4 cell count and high viral load had a high probability of developing PAH ( significant negative relationship between variables associated with the probability of PAH with CD4 cell count and significant positive relationship with viral load), In HIV patients the probability of developing PAH decreases with adequate treatment (that suppress viral replication and increases CD4 count). We, therefore, recommend routine assessment of the probability of PAH in patients with HIV infection particularly those with low CD4 cell count and high viral load and encourage early commencement of HAART to prevent the development of pulmonary arterial hypertension.

Right ventricular load and contractility in HIV-associated pulmonary hypertension.

BackgroundPeople living with human immunodeficiency virus (PLWH) are at risk of developing pulmonary hypertension (PH) and right ventricular (RV) dysfunction, but understanding of the relationship of RV function to afterload (RV-PA coupling) is limited. We evaluated the clinical and hemodynamic characteristics of human immunodeficiency virus (HIV)-associated PH.MethodsWe performed a retrospective review of patients with a diagnosis of HIV undergoing right heart catheterization (RHC) from 2000–2016 in a tertiary care center. Inclusion criteria were diagnosis of HIV, age ≥ 18 years and availability of RHC data. PH was classified as either pulmonary arterial hypertension (PAH; mean pulmonary arterial pressure [mPAP] ≥ 25mmHg with pulmonary artery wedge pressure [PAWP] ≤ 15mmHg) or pulmonary venous hypertension (PVH; mPAP ≥ 25mmHg with PAWP > 15). We collected demographics, CD4 cell count, HIV viral load, RHC and echocardiographic data. The single beat method was used to calculate RV-PA coupling from RHC.ResultsSixty-two PLWH with a clinical likelihood for PH underwent RHC. Thirty-two (52%) met PH criteria (15 with PAH, 17 with PVH). Average time from diagnosis of HIV to diagnosis of PH was 11 years. Eleven of 15 individuals with PAH were on antiretroviral therapy (ART) while all 17 patients with PVH were on ART. Compared to PLWH without PH, those with PH had an increased likelihood of having a detectable HIV viral load and lower CD4 cell counts. PLWH with PAH or PVH had increased RV afterload with normal RV contractility, and preserved RV-PA coupling.ConclusionPLWH with PH (PAH or PVH) were more likely to have a detectable HIV viral load and lower CD4 count at the time of RHC. PLWH with PAH or PVH had increased RV afterload, normal RV contractility, with preserved RV-PA coupling suggestive of an early onset, mild, and compensated form of PH. These results should be confirmed in larger studies.

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.

HIV-Associated Pulmonary Hypertension: A Global Perspective

Human immunodeficiency virus (HIV) infection is a well-recognized cause of pulmonary arterial hypertension (PAH). Worldwide, an estimated 37 million individuals are infected with HIV, and the availability of effective HIV therapy means that more of these patients are living longer and developing cardiovascular complications, including PAH. In European populations, it is estimated that 0.5% of patients with HIV infection develop moderate to severe PAH, so that HIV infection may be one of the most common causes of PAH worldwide. Untreated, the prognosis of HIV-associated PAH is particularly poor, and a large proportion of patients with HIV infection live in resource-poor regions of the world where PAH therapy is not available. In this review, the available data on epidemiology, hemodynamics, mechanisms, and therapeutic strategies for HIV-associated PAH are summarized.

Myocardial and microvascular inflammation/infection in patients with HIV-associated pulmonary artery hypertension.

Right ventricle compromise affects survival of patients with HIV-associated pulmonary artery hypertension (PAH). Myocardial histology with viral assessment may clarify the mechanism of right ventricular deterioration and provide clues on PAH origin. Fifteen patients with HIV infection, PAH and right ventricular dysfunction underwent cardiac magnetic resonance, catheterization, coronary with ventricular angiography and biventricular endomyocardial biopsy. Endothelial expression of HLA-DR, ICAM-1, E-selectin and VCAM-1 was semi-quantitatively evaluated. PCR for HIV, hepatitis C virus, human herpes virus-6, human herpes virus-8, Epstein-Barr virus, adenovirus, cytomegalovirus, enterovirus, influenza A/B and parvovirus B19 was performed. In PCR-positive hearts, viral protein adenovirus-1 and TORDJI-22 were assessed by immunohistology. New York Heart Association class was 2.4 ± 0.5, mean pulmonary artery pressure 49.93 ± 10.15 mmHg and wedge pressure 9.5 ± 2.19 mmHg. Coronaries were normal with slow flow. Left ventricular and/or right ventricular micro-aneurysms were seen in eight patients. Cardiac magnetic resonance documented increased right ventricular end-diastolic volume with reduced ejection fraction, normal left ventricular end-diastolic volume and left ventricular ejection fraction. Subepicardial/mesocardial oedema and delayed enhancement in the inter-ventricular junction and/or left ventricular inferolateral wall was detected in eight patients. Histology showed active lymphocytic myocarditis in 12 patients, with microvasculitis in three. Endothelial adhesion molecules were over-expressed in all patients. PCR was positive in four patients for hepatitis C virus and in two for adenovirus, and viruses localized both in cardiomyocytes and endothelial cells. Inflammation/infection of myocardium and intramural vessels is detectable in patients with HIV-associated PAH. It may adversely affect right ventricular function and have a role in the compromised pulmonary circulation.

HIV and the heart: the impact of antiretroviral therapy: a global perspective

From a global perspective, cardiovascular disease (CVD) in human immunodeficiency virus (HIV) may result from cardiac involvement upon presentation of opportunistic infections in the presence of advanced immunosuppression, be a consequence of HIV-induced immune activation or derive from antiretroviral therapy-associated dyslipidaemia and insulin resistance. Indeed, in developed countries with unlimited access to antiretroviral therapy CVD has become one of the major causes of death in HIV. Therefore, cardiovascular risk reduction and lifestyle modifications are essential and careful selection of the antiretroviral drugs according to underlying cardiovascular risk factors of great importance. In developing countries with delayed roll-out of antiretroviral therapy pericardial disease (often related to TB), HIV-associated cardiomyopathy, and HIV-associated pulmonary hypertension are the most common cardiac manifestations in HIV. In Africa, the epicentre of the HIV epidemic, dynamic socio-economic and lifestyle factors characteristic of epidemiological transition appear to have positioned the urban African community at the cross-roads between historically prevalent and 'new' forms of CVD, such as coronary artery disease. In this context, cardiovascular risk assessment of HIV-infected patients will become a critical element of care in developing countries similar to the developed world, and access to antiretroviral therapy with little or no impact on lipid and glucose metabolism of importance to reduce CVD in HIV.

Injection Drug Use as a “Second Hit” in the Pathogenesis of HIV-associated Pulmonary Hypertension

Injection Drug Use as a “Second Hit” in the Pathogenesis of HIV-associated Pulmonary Hypertension

Bosentan and Sildenafil in the Treatment of HIV-Associated Pulmonary Hypertension

We present the case of an HIV/HCV-coinfected patient with HIV-related pulmonary hypertension (HRPH) who experienced a good clinical and functional response to bosentan, with a subsequent switch to oral sildenafil due to increased transaminase levels. Bosentan resulted less handy in this case, probably due to both side effects and co-morbidities.

Pathogenesis of HIV-Associated Pulmonary Hypertension: Potential Role of HIV-1 nef

Infection with HIV increases the risk for lung diseases, including noninfectious pulmonary hypertension (PH). HIV-associated PH (HIV-PH) is an important lung disease in HIV-infected persons who live longer with antiretrovirals. The early stages of HIV-PH may be overlooked by healthcare providers due to nonspecific symptoms, including progressive dyspnea and nonproductive cough. HIV-PH 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. HIV-PH has a poor prognosis with high mortality; improved biomarkers to identify earlier stages of PH would benefit clinical care. The HIV-PH mechanism remains unknown, but HIV proteins such as Tat and Nef may play a role. HIV-1 Nef is a broad-spectrum adaptor protein that may affect HIV-infected and uninfected pulmonary vascular cells. Studies in macaques suggest that Nef is important in HIV-PH pathogenesis because monkeys infected with a chimeric simian immunodeficiency virus (SIV) expressing HIV-nef (SHIVnef) alleles, but not monkeys infected with the native SIV, develop pulmonary vascular remodeling. Four consistent amino acid mutations arose spontaneously in Nef passaged in the monkeys. To translate these findings to humans, one research endeavor of the Lung HIV Study focuses on the identification of HIV nef mutations in HIV-infected individuals with PH compared with HIV-infected normotensive patients. We present some of the preliminary evidence. Ongoing longitudinal studies will establish the connection between Nef mutations and the propensity for HIV-PH.

Inflammation in HIV-Associated Pulmonary Hypertension: Cause or Effect?

Inflammation in HIV-Associated Pulmonary Hypertension: Cause or Effect?

HIV-associated pulmonary hypertension: A South African perspective

HIV-associated pulmonary hypertension: A South African perspective

Roles and Mechanisms of Human Immunodeficiency Virus Protease Inhibitor Ritonavir and Other Anti-Human Immunodeficiency Virus Drugs in Endothelial Dysfunction of Porcine Pulmonary Arteries and Human Pulmonary Artery Endothelial Cells

The objective of this study was to determine the effects of highly active antiretroviral therapy (HAART) drugs on pulmonary endothelial function. Porcine pulmonary arteries or human pulmonary arterial endothelial cells (HPAECs) were incubated with eight HAART drugs [ritonavir, indinavir, lopinavir, zidovudine (AZT), abacavir, stavudine, didanosine (ddI), and lamivudine] individually or in combination [three HAART drugs (3-plex; indinavir, stavudine, and ddI)] at their clinical plasma concentrations for 24 hours. Endothelium-dependent vasorelaxation in response to bradykinin was reduced significantly by the ritonavir in a concentration-dependent manner. Five other HAART drugs (indinavir, lamivudine, abacavir, AZT, and ddI) and the 3-plex significantly also impaired endothelium-dependent vasorelaxation in response to bradykinin. Five HAART drugs (ritonavir, indinavir, lamivudine, abacavir, and AZT) significantly decreased endothelial nitric oxide synthase (eNOS) expression and increased superoxide anion levels in both vessels and HPAECs. Furthermore, both ritonavir and AZT substantially activated ERK2 in HPAECs. Additionally, the antioxidants ginsenoside Rb1 and ginkgolide A effectively reversed HAART drug-induced vasomotor dysfunction and eNOS down-regulation. Inhibition of ERK1/2 also partially blocked ritonavir- and AZT-induced down-regulation of eNOS and vasomotor dysfunction. Thus, HAART drugs significantly impair endothelial functions of porcine pulmonary arteries and HPAECs, which may be mediated by eNOS down-regulation, oxidative stress, and ERK1/2 activation. These findings suggest that HAART drugs may contribute to the high incidence of pulmonary artery hypertension in human immunodeficiency virus-infected patients.

Hiv-Associated Pulmonary Hypertension: Case Report

With the advent of highly active antiretroviral therapy, there has been a significant change in the epidemiology of pulmonary disease in HIV/AIDS. The relative prevalence of non-infectious manifestations is likely to rise. HIV associated pulmonary hypertension (HIV-PH), albeit low prevalence, is associated with significant morbidity and mortality. Presently, despite having scanty evidence on the management modalities of HIV-PH, evidence extrapolated from idiopathic pulmonary hypertension is being utilised to effectively manage some of these patients. Efforts should therefore be made to screen, diagnose and treat these patients. A case of a thirty year old female with HIV disease and severe pulmonary hypertension is presented.

Pulmonalarterielle Hypertonie bei HIV-Patienten

Symptomatic HIV-associated pulmonary artery hypertension (PHT) is a thousand times more frequent than idiopathic PHT and has a clearly worse prognosis. Using echocardiographic criteria the prevalence of PHT in HIV-positive patients, including all degrees of clinical severity, is about 7.5 %, half of those affected being asymptomatic (NYHA class I). The only available data are from just one controlled trial of drug treatment of HIV-associated PHT (BREATH-4-Trial), in which the endothelin-receptor antagonist bosentan was found to bring significant improvement in clinical parameters (NYHA functional class, walking distance). Further trials are required to test other therapeutic options such as prostanoids and phosphodiesterase-5-inhibitors.

Noninfectious Pulmonary Complications of HIV

Pulmonary complications of HIV infection increase as the disease progresses. Although the most common cause of pulmonary disease continues to be infection, a number of noninfectious entities should be considered when evaluating the HIV-infected individual with pulmonary symptoms. With the advent of highly active antiretroviral therapy, there have been significant changes in the epidemiology of these diseases. Improved understanding of pathogenesis has led to new therapies, especially for HIV-associated pulmonary hypertension. In those patients in whom a thorough microbiologic survey reveals no infection, one should consider noninfectious entities; these can be broadly categorized into 3 groups: malignant, inflammatory, or pulmonary vascular disease. Clinical history is critical in providing clues, but bronchoscopic visualization and tissue sampling are often required to confirm many of these diagnoses. As successful antiretroviral therapy continues to extend the lives of HIV-infected patients, the medical community should be able to recognize and diagnose these noninfectious pulmonary diseases.

Ortner syndrome and haemophilia

Compression and paralysis of the left recurrent laryngeal nerve by a dilated pulmonary artery is a rare complication of pulmonary hypertension. We here report the case of a patient with severe haemophilia A and HIV infection who presented with a persistent hoarseness of voice and a left vocal cord palsy caused by HIV-associated pulmonary hypertension. This case suggests that HIV-associated pulmonary hypertension should be suspected in any HIV patient presenting with unexplained left vocal cord palsy.

Induction of apoptosis and endothelin-1 secretion in primary human lung endothelial cells by HIV-1 gp120 proteins

Pulmonary hypertension associated with human immunodeficiency virus (HIV) infection also involves injury to the lung endothelium. However, the pathogenesis of HIV-induced pulmonary hypertension is not known; we hypothesized that HIV or secreted viral proteins could play a role in vascular injury and the increased frequency of pulmonary hypertension observed in HIV-infected patients. Here, we report that exposure of HIV-1 gp120 proteins to primary human lung microvascular endothelial cells causes apoptosis, as assessed by TUNEL assay, Annexin-V staining, and DNA laddering. Using ribonuclease protection assay and Western blotting we find that gp120-induced apoptosis of lung endothelial cells involves a down-regulation in Bcl-xl mRNA and proteins. In addition, gp120 significantly increases secretion of the potent vasoconstrictor endothelin-1 by human lung endothelial cells. These data suggest that secreted HIV gp120 proteins induce lung endothelial cell injury and could contribute to the development of HIV-associated pulmonary hypertension.

Antiretrovirals for HIV-Associated Pulmonary Hypertension

Pulmonary artery hypertension related to HIV (PAHRH) is a rare and poorly understood complication of the infection. The virus does not appear to infect