For decades, the HIV narrative centered on immune collapse. Today, thanks to antiretroviral therapy (ART), millions live with suppressed virus. Yet, a hidden battle rages within their bodies—a smoldering fire of chronic inflammation driving alarming rates of heart disease, diabetes, and neurocognitive decline. This insidious process, rooted in immunometabolic dysfunction, is the new frontier in HIV research.
Why Inflammation Persists When the Virus is Controlled
The immune system's victory over HIV comes at a cost. Even with undetectable viral loads, persistent immune activation lingers due to:
Gut Sabotage
HIV demolishes gut-associated lymphoid tissue (GALT), breaching the intestinal barrier. Bacterial toxins like LPS flood the bloodstream, triggering relentless immune alarms via Toll-like receptors (TLRs) 6 .
A 2025 analysis of Spain's CoRIS cohort revealed hopeful trends: serious non-AIDS events (e.g., heart attacks, strokes) dropped by 32% from 2006–2023. Researchers credit aggressive management of comorbidities—like statins for cholesterol—but warn disparities remain, especially in women underrepresented in studies 1 .
Spotlight Experiment: The REPRIEVE Trial Substudy Linking Inflammation to Heart Attacks
Background: The landmark REPRIEVE trial proved pitavastatin reduces cardiovascular risk in ART-treated HIV patients. But why were they vulnerable? A 2025 substudy answered this by dissecting the role of inflammation and plaque type.
Methodology:
- Participants: 804 ART-treated adults with low-moderate ASCVD risk.
- Imaging: Coronary CT angiography to classify plaque type (calcified vs. noncalcified).
- Biomarkers: Baseline IL-6, hs-cTnT (cardiac injury marker), and others.
- Follow-up: Tracked major adverse cardiovascular events (MACE: heart attack, stroke, CVD death) over 5 years 1 .
Results & Analysis:
| Risk Factor | MACE Hazard Ratio | High-Risk Threshold |
|---|---|---|
| IL-6 | 2.9× increase | ≥2.18 pg/mL |
| hs-cTnT | 5.5× increase | ≥9.64 ng/L |
| Noncalcified Plaque | 62% prevalence | Present vs. Absent |
- Noncalcified plaque—soft, unstable deposits prone to rupture—was 60% more common in MACE patients.
- Pitavastatin's benefit tripled in those with elevated hs-cTnT or noncalcified plaque, confirming inflammation drives statin-responsive heart disease 1 .
Takeaway
"HIV transforms arteries into tinderboxes," says Dr. Mark Mascolini, covering CROI 2025. "Inflammation lights the fuse; statins douse the flame."
[Interactive chart showing relationship between inflammation markers and cardiovascular events would appear here]
Metabolic Sabotage: How HIV Hijacks Cellular Power Plants
HIV rewires immune cell metabolism to fuel its replication and evade attack:
Monocytes/Macrophages
Inflamed "foam cells" gulp lipids but can't process them, spewing IL-1β and driving atherosclerosis 6 .
Mitochondrial Meltdown
Viral proteins (Vpr, Tat) damage mitochondria, flooding cells with reactive oxygen species (ROS) that accelerate aging 3 .
| Pathway | Role in Healthy Cells | Hijacked by HIV |
|---|---|---|
| Glycolysis | Quick energy burst | Provides nucleotides for viral DNA |
| Oxidative Phosphorylation | Efficient ATP production | Damaged; increases toxic ROS |
| Pentose Phosphate | Makes DNA precursors | Boosts dNTP pool for reverse transcription |
Children Born with HIV: A Legacy of Inflammation
Two 2025 IAS studies sounded alarms:
South African Cohort
- Early-treated, virally suppressed children showed elevated IL-6 (+15%), CRP (+76%), and VEGF (+37%)—markers linked to future heart disease.
- Teens had 87% higher gut-inflammation markers (S100 proteins) 4 .
Canadian Cohort
- Children starting ART after 6 months had larger viral reservoirs (56–79 vs. 12.6 copies/million CD4 cells) and higher IL-6/IL-18, tightly correlated to reservoir size 4 .
Urgent Insight: "The womb may be ground zero for lifelong inflammation," notes Dr. Fatima Kakkar. "Early ART shrinks reservoirs, but we need therapies targeting residual immune dysfunction."
The Researcher's Toolkit: Decoding Inflammation
| Reagent/Technology | Function | Key Insight |
|---|---|---|
| Olink Proteomics | Measures 100+ inflammation proteins in tiny samples | Identified IL-6, sCD14 as top risk biomarkers 9 |
| Flow Cytometry | Detects cell surface/inflammatory markers (CD14+CD16+ monocytes) | Links "inflammatary" monocytes to atherosclerosis 6 |
| 3D Brain Organoids | Models neuroinflammation using human stem cells | Revealed metabolic disruption alters neuronal synapses 9 |
| Coronary CTA | Visualizes noncalcified plaque in arteries | Noncalcified plaque predicts HIV-related heart attacks 1 |
| Reservoir Quantification (e.g., IPDA) | Measures intact HIV DNA in cells | Smaller reservoirs = lower inflammation in kids 4 |
| Pent-2-ene-1,5-diol | 27354-43-4 | C5H10O2 |
| Arimoclomol citrate | 368860-21-3 | C20H28ClN3O10 |
| Phenobarbital, C-13 | 52947-04-3 | C12H12N2O3 |
| (+)-alpha-Barbatene | 53060-59-6 | C15H24 |
| H-Lys(Fmoc)-OMe.HCl | C22H27ClN2O4 |
Extinguishing the Fire: The Future of HIV Care
Innovations aim to quell inflammation beyond ART:
Long-Acting Options
Injectable lenacapavir (new WHO-recommended PrEP) and cabotegravir reduce adherence burden, potentially curbing viral escape and inflammation 2 .
Immunometabolic Therapies
- GLP-1 agonists (e.g., semaglutide) for weight loss and cardiovascular protection.
- CMV suppression with valganciclovir reduced inflammation in a 2025 trial 1 .
Precision Medicine
Karolinska's multi-omics platform identifies "high-risk" inflammation profiles for targeted therapy 9 .
As Dr. Ujjwal Neogi summarizes: "Our goal isn't just undetectable virus—it's restoring metabolic harmony." With every stride in immunometabolism, we move closer to extinguishing HIV's silent fire for good.
Bottom Line
HIV inflammation is no longer an afterthought. It's the catalyst behind the defining health battles of the ART era—and the key to unlocking longer, healthier lives.