Endothelial Cells: Gatekeepers in HIV Disease Progression

Written by Bryant Avalos, PhD, Postdoctoral Researcher at University of California, San Diego


Endothelial Cells: Gatekeepers in HIV Disease Progression 

Endothelial cells are emerging as key regulators of immune dynamics in HIV infection. Traditionally viewed as passive linings of the vascular system, these cells actively participate in sensing and responding to systemic inflammation, especially under chronic viral stress. In people living with HIV (PWH), sustained immune activation and exposure to viral proteins such as gp120 and Tat disrupt endothelial integrity, triggering a cascade of vascular dysfunction. This dysfunction is compounded by elevated oxidative stress, cytokine exposure, and increased trafficking of immune cells across the endothelium — processes that ultimately compromise barrier function and promote inflammation in multiple organ systems. Even under effective antiretroviral therapy (ART), markers of endothelial activation remain elevated, linking these vascular changes to long-term comorbidities such as cardiovascular disease, neurocognitive decline, and kidney injury. As such, endothelial cells are not only collateral targets of HIV pathology but also active players in disease progression, making them a compelling focus for adjunctive therapeutic strategies. 

What Are Endothelial Cells? 

Endothelial cells form a thin, monolayer lining inside all blood vessels, from the largest arteries to the smallest capillaries. Despite their seemingly passive location, endothelial cells are incredibly dynamic. They regulate: 

  • Vascular tone and blood flow by releasing nitric oxide (NO) and other vasoactive substances. 

  • Barrier function to control the movement of cells and molecules between the bloodstream and surrounding tissues. 

  • Hemostasis by balancing pro- and anti-coagulant factors. 

  • Inflammation by expressing adhesion molecules and cytokines that recruit immune cells to sites of injury or infection. 

  • Angiogenesis by sprouting new vessels in response to tissue demands. 

In short, endothelial cells act as gatekeepers between the blood and tissues — a function that becomes critically important during infections. 

How HIV Impacts Endothelial Cells 

While HIV does not directly infect endothelial cells under normal conditions (since they lack the CD4 receptor), the virus and its proteins can still profoundly alter endothelial cell function through indirect mechanisms. 

Key mechanisms include: 

  • Viral proteins like gp120 and Tat: These proteins can interact with endothelial cell surface molecules, disrupting barrier integrity and promoting inflammation. 

  • Chronic immune activation: HIV infection induces sustained immune activation, leading to high circulating levels of inflammatory cytokines (e.g., TNF-α, IL-6) that damage endothelial cells. 

  • Monocyte and T-cell trafficking: HIV infection increases the adhesion of infected and activated monocytes and T cells to the endothelium, promoting vascular inflammation. 

  • Oxidative stress: HIV-associated oxidative stress impairs nitric oxide production, leading to endothelial dysfunction. 

  • Microparticle shedding: Endothelial cells release procoagulant microparticles during HIV infection, contributing to thrombosis and vascular injury. 

Thus, endothelial cells become both targets and amplifiers of HIV-associated inflammation. 

Endothelial Dysfunction and HIV-Associated Comorbidities 

As antiretroviral therapy (ART) has dramatically extended life expectancy for people with HIV, non-AIDS comorbidities have emerged as major health threats. Many of these — such as cardiovascular disease, stroke, kidney disease, and neurocognitive impairment — share a common pathogenic feature: endothelial dysfunction. 

HIV-related endothelial dysfunction contributes to: 

  • Atherosclerosis: Damaged endothelial cells promote the formation of plaques by recruiting monocytes and altering lipid handling. 

  • Thrombosis: Disruption of the endothelium’s anticoagulant properties increases clot formation, leading to stroke or heart attacks. 

  • Neurocognitive disorders: Dysfunctional brain endothelial cells (blood-brain barrier) allow infiltration of inflammatory cells and viral proteins, contributing to neuroinflammation. 

  • Pulmonary hypertension: HIV infection can cause pulmonary vascular endothelial remodeling, leading to high blood pressure in the lungs. 

Importantly, even in patients on effective ART with suppressed viral loads, markers of endothelial dysfunction — such as elevated soluble ICAM-1, VCAM-1, and E-selectin — often remain high. 

HIV, Endothelial Cells, and Immune Cell Trafficking 

One of the underappreciated roles of endothelial cells during HIV infection is their regulation of immune cell trafficking. 

  • Increased permeability: HIV-induced inflammation loosens tight junctions between endothelial cells, allowing immune cells (and sometimes the virus) to migrate into tissues. 

  • Enhanced adhesion molecule expression: Endothelial cells upregulate molecules like ICAM-1 and VCAM-1, which bind to integrins on immune cells, facilitating their migration across the vascular wall. 

  • Reservoir formation: The trafficking of infected monocytes across the endothelium into tissues such as the brain, gut, and lymph nodes contributes to the formation of viral reservoirs — major obstacles to HIV cure. 

Thus, endothelial cells not only respond to infection but also actively shape HIV pathogenesis by controlling immune cell movement. 

Blood-Brain Barrier Disruption in HIV  

The schematic below illustrates the impact of HIV on the integrity of the blood-brain barrier (BBB), highlighting how compromised endothelial cells facilitate viral infiltration into the central nervous system (CNS). In healthy conditions, endothelial cells form tight junctions (TJs) that restrict immune and pathogen entry into the brain. HIV infection disrupts this barrier in several ways: 

  1. Trojan Horse Mechanism: Infected CD4+ T cells or monocytes cross the endothelium and carry HIV into the CNS, bypassing the restrictive nature of the BBB. 

  2. Transcellular Migration: HIV can induce changes in endothelial cells that allow viral particles to be transported across the endothelial cytoplasm. 

  3. Free Virus Entry: Loss of TJ integrity and increased endothelial permeability enable direct passage of free HIV virions into brain tissue. 

These disruptions are driven by inflammatory cytokines, viral proteins, and reduced pericyte coverage, all of which destabilize endothelial cell junctions. The breakdown of this neurovascular barrier contributes to HIV-associated neurocognitive disorders (HAND), even in patients with systemically suppressed viral loads. 

Figure 1: Mechanisms for BBB Infiltration of HIV. Image adapted from Rudd, H., Toborek, M. "Pitfalls of Antiretroviral Therapy: Current Status and Long-Term CNS Toxicity." Biomolecules 2022, 12, 894. https://doi.org/10.3390/biom12070894

Tools for Studying Endothelial Cell Function and Identity 

Investigating endothelial dysfunction in the context of HIV requires precise molecular tools to track changes in endothelial activation, barrier integrity, and immune interaction. Researchers commonly rely on a suite of well-characterized endothelial-specific markers to distinguish endothelial cells from other vascular and immune cell types, especially in mixed cultures or tissue sections. 

Common Endothelial Cell Markers 

Several markers are widely used to confirm endothelial cell identity or monitor activation: 

  • CD31 (PECAM-1): A classic pan-endothelial marker involved in leukocyte transmigration and maintaining intercellular junctions. 

  • VE-Cadherin (CD144): A critical adherens junction protein essential for vascular integrity. 

  • von Willebrand Factor (vWF): A marker of endothelial origin, particularly used in immunohistochemistry to identify endothelial-lined vessels. 

  • ICAM-1 and VCAM-1: Cell adhesion molecules upregulated in response to inflammatory stimuli, commonly used as markers of endothelial activation. 

  • E-Selectin: Another inducible adhesion molecule reflective of endothelial response to TNF-α and IL-1β. 

  • Endoglin (CD105): Expressed in angiogenic endothelial cells, especially in pathological vascular remodeling contexts. 

Experimental Approaches 

To evaluate endothelial responses in HIV research, investigators use a variety of methodologies: 

  • Immunocytochemistry (ICC) and Immunohistochemistry (IHC) 

  • Flow Cytometry 

  • Western Blot and ELISA 

Proteintech offers validated antibodies for many of these targets, which can be used in a range of applications including ICC, IHC, flow cytometry, and Western blotting. These reagents help researchers track endothelial activation across HIV disease stages, assess the impact of viral proteins, and evaluate responses to anti-inflammatory interventions. Check out a few of our highlighted products below or search for your target on the search bar above! 

Anti-Mouse CD31 Rabbit Recombinant Antibody (98258-1-RR) 

Figure 2: Mouse splenocytes were surface stained with Anti-Mouse CD31 Rabbit Recombinant Antibody (98258-1-RR, Clone: 242041B5) or Rabbit IgG Isotype Control Recombinant Antibody (98136-1-RR, Clone: 240953C9), and PE-Conjugated Goat Anti-Rabbit IgG(H+L). Cells were co-stained with APC Anti-Mouse CD45R (B220) (RA3-6B2) (APC-65139, Clone: RA3-6B2). Cells were not fixed. 

 

FcZero-rAb APC Anti-Human VE-cadherin/CD144 Rabbit Recombinant Antibody (APC-FcA98071) 

Figure 3: HUVEC cells were surface stained with APC Anti-Human VE-cadherin/CD144 Rabbit RecAb (APC-FcA98071, Clone: 240755B2) (red) or APC Rabbit IgG Isotype Control RecAb (APC-FcA98136, Clone: 240953C9) (blue). Cells were not fixed. 

VWF Recombinant Antibody (83854-2-RR) 

Figure 4: Immunofluorescent analysis of (4% PFA) fixed paraffin-embedded human tonsillitis tissue using VWF antibody (83854-2-RR, Clone: 240867D10 ) at dilution of 1:1000 and CoraLite®488-Conjugated Goat Anti-Rabbit IgG(H+L) (SA00013-2). Heat mediated antigen retrieval with Tris-EDTA buffer (pH 9.0). 

Protecting Endothelial Health: A Target for HIV Therapy? 

Given their central role in comorbidity development and viral persistence, strategies to protect endothelial cells are emerging as an important adjunct to HIV care. 

Potential strategies include: 

  • Statins: Improve endothelial function and reduce inflammation. 

  • Antioxidants: Target oxidative stress to preserve nitric oxide signaling. 

  • Anti-inflammatory therapies: Drugs like IL-1 blockers aim to reduce systemic inflammation and its impact on the endothelium. 

  • CCR5 antagonists: Inhibit immune cell trafficking to reduce endothelial activation and reservoir formation. 

  • Lifestyle interventions: Smoking cessation, exercise, and blood pressure control all help preserve endothelial health. 

Further research is needed to develop therapies that directly target endothelial dysfunction in the context of HIV infection, especially as the population of aging PWH grows. 

Conclusion 

Endothelial cells are much more than passive bystanders in HIV infection. They are actively involved in shaping immune responses, promoting inflammation, and contributing to the comorbidities that affect people living with HIV. By recognizing the central role of endothelial dysfunction, researchers and clinicians can better understand the full impact of HIV disease and work toward more comprehensive treatments that extend beyond controlling viral replication. 

As we continue to learn more about the interplay between HIV and the vascular system, preserving endothelial health may become just as important as preserving immune function in achieving true long-term wellness for people living with HIV. 

References 

  1. Deeks, S.G., et al. (2013). "The End of AIDS: HIV Infection as a Chronic Disease." The Lancet, 382(9903):1525–1533. 

  2. Hsue, P.Y., et al. (2012). "Inflammation and the Cardiovascular Complications of HIV Infection." Current Cardiology Reports, 14(1): 61–67. 

  3. Zidar, D.A., et al. (2015). "Inflammatory and Coagulation Biomarkers and Mortality in HIV-Infected Individuals." AIDS, 29(13): 1599–1603. 

  4. Hatano, H., et al. (2013). "Persistence of Endothelial Activation and Inflammation in Treated HIV Infection." Current HIV/AIDS Reports, 10(1): 22–30.