## 7. Pulmonary Hypertension  
Pulmonary arterial hypertension (PAH) is a rare but serious HIV complication, affecting \(\sim\)0.5% of patients [57, 58]. It causes vascular remodeling similar to idiopathic PAH, including endothelial and smooth muscle hyperplasia, intimal fibrosis, thrombi, and plexiform lesions. Inflammatory infiltrates (lymphocytes, histiocytes) are common, while alveolar septal thickening and interstitial fibrosis may also occur [57].  
Various imaging techniques (electron microscopy, immunohistochemistry, in situ hybridization, PCR) have not detected HIV in vascular wall cells. However, viral proteins are present in lung tissue and likely contribute to PAH development [57].  
The viral proteins incriminated are glycoprotein 120 (gp 120), trans-activator of transcription (Tat) and negative factor (Nef) proteins, each having an important role in infection.  
Gp 120 is found in viral membranes and mediates the attachment to the host cell. It stimulates cytokine release from macrophages, increases endothelin-1 synthesis, and triggers endothelial cell apoptosis [59].  
Trans-activator of transcription protein causes injury to the endothelial cells. Tat attaches to the endothelial cells through integrins and the type 2 receptor for VEGF. Tat and gp120 stimulate the production of hypoxia-inducible factor 1-alpha (HIF-1\(\alpha\)) and platelet-derived growth factor-\(\beta\) (PDGF-\(\beta\)), both of which promote cell proliferation.  
Nef protein is synthesized early in viral infection and mediates disease progression. It downregulates major histocompatibility complex 1 (MHC-I) and CD4 receptors, weakening the immune response. Instead of recycling, CD4 receptors are broken down inside lysosomes. Nef also inhibits cell mobility, stimulates CD4+ T-cell apoptosis, and has been linked to the structural changes observed in PAH. Specific Nef mutations have been identified in HIV patients who develop PAH [59].  
Other factors incriminated in PAH pathogeny are drugs (heroin, morphine, cocaine) that cause injury of the endothelial cells and co-infections with microorganisms like _Mycobacterium tuberculosis_, _Pneumocystis cariniini_, _Schistosoma mansoni_, which all cause lesions of the lung parenchyma and lead to persistent lung inflammation [57].  
In Sitbon et al.'s study, PAH prevalence in HIV patients was 0.46% (35/7648 cases). Mean pulmonary artery pressure (PAP) was 46 \(\pm\) 13 mmHg in existing PAH and 30 \(\pm\) 9 mmHg in new cases. Better outcomes were seen in patients with CD4 > 200 cells/mL and cardiac index \(\geq\) 2.8 L/min/m\({}^{2}\)[60].  
Recent advancements in the treatment of pulmonary arterial hypertension (PAH) in individuals with HIV have focused on integrating novel therapeutic agents and optimizing existing treatment strategies to improve patient outcomes. HIV patients do not respond to the vasodilating test, so calcium channel blockers are not useful. Traditional PAH treatments, such as endothelin receptor antagonists (e.g., bosentan, ambrisentan) and phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil), continue to be integral in managing HIV-associated PAH. These therapies have demonstrated efficacy in improving hemodynamics and exercise capacity. However, clinicians must remain vigilant regarding potential drug-drug interactions between PAH-specific medications and antiretroviral therapies, as well as the unique side effect profiles in HIV-infected individuals. Anticoagulation therapy is generally avoided because of the increased risk of bleeding and interactions with antiretroviral medications [60]. Ongoing research is essential to further understand the pathophysiology of HIV-associated PAH and to develop targeted therapies. Future studies should focus on the long-term efficacy and safety of emerging treatments like sotatercept in the HIV-positive population, as well as the potential benefits of combination therapies.