HDL: an ally going off track?

By Ana Espino | Published on December 2nd, 2025 | 3 min read


Chronic HIV infection, even when well controlled by antiretroviral therapy, is associated with an increased cardiometabolic risk, including higher rates of cardiovascular events, hypertension, insulin resistance, and dyslipidemia. This elevated risk cannot be explained solely by traditional factors, but also by persistent immunometabolic disturbances linked to the chronic low-grade inflammation characteristic of HIV.  

More recently, the role of HDL lipoproteins in this pathology has come under consideration. Normally cardioprotective, their function may become altered in the context of HIV infection. In this setting, the study was conducted to identify the functional impairments of HDL in people living with HIV. It also aims to shed light on the mechanisms responsible for these dysfunctions and to understand how these lipoproteins contribute to the pathophysiology of cardiometabolic syndrome. Finally, the objective is to determine whether these abnormalities may represent a relevant therapeutic target.  

What if HDL were doing more harm than good?  

In this study, the composition, function, and biological role of HDL were examined in the context of chronic HIV infection, with or without antiretroviral therapy. The findings show that in people living with HIV, HDL particles display alterations in both structure and function: reduced cholesterol efflux capacity, loss of anti-inflammatory and antioxidant properties, and changes in their protein and lipid composition. These abnormalities can be observed even when HDL-cholesterol levels remain normal, indicating that the quality of HDL is more important than their quantity.  

An increase in pro-inflammatory proteins (such as serum amyloid A) within HDL was also observed, along with the loss of proteins like apolipoprotein A-I. These dysfunctional HDL particles contribute to endothelial cell activation, progression of atherosclerosis, and disruption of glucose metabolism, thereby playing a central role in HIV-associated cardiometabolic syndrome.  

When “good cholesterol” loses its way  

Chronic HIV exposes patients to an increased risk of cardiometabolic complications, even under effective treatment. Among the contributing mechanisms, HDL dysfunction emerges as a key player, transforming a normally protective lipoprotein into a potential driver of disease.  

The objective of this review was to better understand this qualitative transformation of HDL and its involvement in cardiometabolic syndrome. The data suggest that in HIV, it is not only HDL levels that matter, but also the loss of their protective function, linked to altered composition and prolonged exposure to inflammation.  

Despite these significant insights, the study has several limitations — including a lack of longitudinal studies, difficulty in standardizing methods for assessing HDL function, and the absence of validated clinical criteria to characterize dysfunctional HDL — which highlight the need for further research. Such research should include:

• development of reliable biomarkers reflecting HDL functionality; 
• exploration of therapeutic strategies aimed at restoring HDL activity, for example through LXR receptor agonists or CETP inhibitors; 
• integration of these advances into personalized management of cardiometabolic risk in people living with HIV.

Read next: HIV and Dual Therapy: a promising step towards maintaining viral suppression