Inflammation is a crucial component of the immune response essential for host defense and tissue repair. However, when the immune response becomes dysregulated, it can contribute to the pathogenesis of chronic diseases. While acute inflammation is a short-lived, protective response, chronic inflammation is sustained over time and can lead to immune dysfunction, tissue damage, and disease progression. The chronic inflammation theory of disease suggests that persistent immune activation/inflammation underlies both infectious and non-infectious conditions and serves as a unifying mechanism across distinct pathological states. In this review article, we argue that human immunodeficiency virus (HIV) infection represents a prime model for studying chronic inflammation, and that despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) exhibit persistent immune activation, systemic inflammation, and an increased risk of cardiovascular, metabolic, and neurodegenerative diseases. Here, the interplay between microbial translocation, immune dysregulation, and metabolic reprogramming fuels a state of chronic inflammation that accelerates disease progression beyond HIV itself. Key factors such as T-cell exhaustion, persistent monocyte/macrophage activation, and immunometabolic dysfunction contribute to such a sustained inflammatory state. This review explores the molecular and cellular mechanisms driving chronic inflammation in HIV infection with a focus on immunometabolism and its implications for broader inflammatory diseases. By understanding such pathways, we can identify novel therapeutic targets to mitigate inflammation-driven disease progression not only in HIV but across a spectrum of chronic inflammatory conditions.

Although the underlying mechanisms driving human immunodeficiency virus (HIV)-mediated cardiovascular diseases (CVD) onset and progression remain unclear, the role of chronic immune activation as a significant mediator is increasingly being highlighted. Chronic inflammation is a characteristic feature of CVD and considered a contributor to diastolic dysfunction, heart failure, and sudden cardiac death. This can trigger downstream effects that result in the increased release of pro-coagulant, pro-fibrotic, and pro-inflammatory cytokines. Subsequently, this can lead to an enhanced thrombotic state (by platelet activation), endothelial dysfunction, and myocardial fibrosis. Of note, recent studies have revealed that myocardial fibrosis is emerging as a mediator of HIV-related CVD. Together, such factors can eventually result in systolic and diastolic dysfunction, and an increased risk for CVD. In light of this, the current review article will focus on (a) the contributions of a chronic inflammatory state and persistent immune activation, and (b) the role of immune cells (mainly platelets) and cardiac fibrosis in terms of HIV-related CVD onset/progression. It is our opinion that such a focus may lead to the development of promising therapeutic targets for the treatment and management of CVD in HIV-positive patients.

Human immunodeficiency virus (HIV) infection induces chronic immune activation by stimulating both the innate and adaptive immune systems, resulting in persistent inflammation and immune cell exhaustion. Of note, the modulation of cytokine production and its release can significantly influence the immune response. Type I interferons (IFN-Is) are cytokines that play a crucial role in innate immunity due to their potent antiviral effects, regulation of IFN-stimulated genes essential for viral clearance, and the initiation of both innate and adaptive immune responses. Thus, an understanding of the dual role of IFN-I (protective versus harmful) during HIV-1 infections and elucidating its contributions to HIV pathogenesis is crucial for advancing HIV therapeutic interventions. This review therefore delves into the intricate involvement of IFN-I in both the acute and chronic phases of HIV infection and emphasizes its impact on viral persistence, immune activation, and immunometabolism in treated HIV-infected individuals.

With the successful roll-out of combination antiretroviral treatment, HIV is currently managed as a chronic illness. Of note, immune activation and chronic inflammation are hallmarks of HIV-1 infection that persists even though patients are receiving treatments. Despite strong evidence linking immune activation and low-grade inflammation to HIV-1 pathogenesis, the underlying mechanisms remain less well-understood. As intracellular metabolism is emerging as a crucial factor determining the fate and activity of immune cells, this review article focuses on how links between early immune responses and metabolic reprograming may contribute to HIV pathogenicity. Here, the collective data reveal that immunometabolism plays a key role in HIV-1 pathogenesis. For example, the shift from quiescent immune cells to its activation leads to perturbed metabolic circuits that are major drivers of immune cell dysfunction and an altered phenotype. These findings suggest that immunometabolic perturbations play a key role in the onset of non-AIDS-associated comorbidities and that they represent an attractive target to develop improved diagnostic tools and novel therapeutic strategies to help blunt HIV-1 pathogenesis.