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Evaluation of Platelet Activation by HIV Protease Inhibitors - The HIV-PLA II Study
Gerrit Kann1, Junaid Owasil1, Karina Kuczka2
1HIVCENTER, Medical HIV Treatment and Research Unit, Johann Wolfgang Goethe University Frankfurt, Frankfurt am Main, Germany.
Insights
HIV protease inhibitors increase thrombocyte activation and aggregation, raising cardiovascular event risks. This study identifies a novel platelet activation pathway linked to protease inhibitor-based combination antiretroviral therapy.
Area of Science:
- Cardiovascular Medicine
- Hematology
- Infectious Diseases
Background:
- Previous studies linked protease inhibitors (PIs) and abacavir to increased cardiovascular event (CVE) risk in HIV patients on combination antiretroviral therapy (cART).
- Platelet activation is hypothesized to play a significant role in the elevated CVE risk associated with cART.
Purpose of the Study:
- To investigate the impact of different cART regimens on platelet activation markers in HIV-1-infected, therapy-naïve adults.
- To explore potential mechanisms linking specific cART components to thrombotic complications.
Main Methods:
- The HIV-PLA II study analyzed 45 HIV-1-infected adults initiating cART (PI, NNRTI, or integrase inhibitor based).
- Ex vivo assessment of platelet markers (CD62P, PAC-1 binding), monocyte activation (CD11b), and endogenous thrombin potential (ETP) at baseline and weeks 4, 12, 24.
- Therapy regimens were blinded to laboratory investigators.
Main Results:
- No significant changes in CD11b or ETP were observed across study groups.
- Significant increases in CD62P expression and PAC-1 binding were found in patients receiving PI-based cART.
- These findings indicate enhanced platelet activation and aggregation potential in patients on PIs.
Conclusions:
- HIV protease inhibitors significantly increase CD62P expression and PAC-1 binding, indicating heightened platelet degranulation and aggregation.
- A novel pathway of platelet activation associated with PI-containing cART may contribute to the increased CVE risk.
- These findings highlight the importance of monitoring platelet activation in HIV patients on specific cART regimens.
Background:
In the past, protease inhibitors (PIs) and the reverse transcriptase inhibitor abacavir were identified increasing the risk for thromboembolic complications and cardiovascular events (CVE) of HIV infected patients taking a combination antiretroviral therapy (cART). Results of the previous HIV-PLA I-study lead to the assumption that platelet activation could play a substantial role in increasing CVE risks.
Methods:
The open label, monocentric HIV-PLA II-study investigated HIV-1-infected, therapy-naïve adults (n=45) starting with cART, consisting either of boosted PI (atazanavir, n= 6, darunavir, n=11), NNRTI (efavirenz, n=14) or integrase inhibitor (raltegravir, n=14), each plus tenofovir/emtricitabine co-medication. Main exclusion criteria were tobacco smoking, the intake of NSAIDs or abacavir or past CVE. Platelet adhesive molecule p-selectin (CD62P) and FITC anti-human Integrin α-IIb/Integrin β-3 (CD41/CD61) antibody (PAC-1) binding, monocyte CD11b/monocyte-associated CD41 expression and the endogenous thrombin potential (ETP) were assessed ex vivo-in vitro at baseline, weeks 4, 12 and 24. Therapy regimens were blinded to the investigators for laboratory and statistical analyses.
Results:
CD11b and ETP showed no significant changes or differences between all study groups. In contrast, the mean + SD mean fluorescence units (MFI) of CD62P and PAC-1 increased significantly in patients taking PI, indicating an enhanced potential for thrombocyte activation and aggregation.
Conclusion:
CD62P expression, detecting the ɑ-platelet degranulation of pro-inflammatory and pro-thrombotic factors and adhesive proteins, and PAC-1 expression, representing a marker for conformation changes of the GIIb/IIIa receptor, increased significantly in patients taking HIV protease inhibitors. The findings of this study revealed a yet unknown pathway of platelet activation, possibly contributing to the increased risk for CVE under HIV protease inhibitor containing cART.
Clinical Trial Registration No:
DRKS00000288.
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