HIV RCTS: HIV Reverse Cholesterol Transport Study
Study Details
Study Description
Brief Summary
Primary Objective:
To examine changes in expression of genes [particularly ABCA1 and SREBP2] involved in reverse cholesterol transport (RCT) in monocytes from HIV-infected subjects starting antiretroviral therapy and the different effect of NNRTI and PI based regimens
Secondary Objective:
To examine changes in monocyte intracellular cholesterol content in HIV-infected subjects starting antiretroviral therapy and the different effect of NNRTI and PI based regimens
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Detailed Description
HIV infection is associated with low HDL-cholesterol, an independent risk-factor for cardiovascular disease (CVD). NNRTI-based HAART increases HDL-c, with nevirapine shown to increase production of its major apolipoprotein ApoA-I. In contrast, initiation of PI-based HAART leads to persistently low HDL-c despite a reduction in HIV RNA and immunologic recovery.
HDL-c is formed through reverse cholesterol transport (RCT), the process where cholesterol is transferred from intracellular pools to circulating lipoproteins which are then eliminated by the liver. Accumulation of intracellular cholesterol in cells such as macrophages and their precursor (circulating monocytes) has been implicated in atherogenesis.
In vitro data suggests the HIV protein Nef directly interferes with cellular proteins involved in RCT such as ATP-binding cassette transporter A1 (ABCA1) in monocyte-derived macrophages. ABCA1 expression is controlled by peroxisome proliferator-activated receptor gamma (PPARG) and the intracellular cholesterol sensor sterol regulatory element binding protein 2 (SREBP2). In adipose tissue it is known that PI treatment downregulates SREBP and PPARG expression.
Preliminary work in the investigators lab has reproduced these findings in monocytes in untreated HIV infection in vivo and demonstrated relationships between gene expression for ABCA1, SREBP2, monocyte intracellular cholesterol and circulating lipoproteins. These early data suggest that defects in RCT determine intracellular cholesterol levels in HIV-infected subjects whereas increased LDL-c is a greater determinant of intracellular cholesterol in HIV negative subjects. This suggests a potentially pivotal role for RCT abnormalities in low HDL-c, increased intracellular cholesterol and atherogenesis in HIV infection.
The investigator's aim to examine the impact of initiation of ART with either PI or NNRTI on RCT in circulating monocytes in vivo and how this impact correlates with changes in amount and size of circulating HDL-c.
Study Design
Outcome Measures
Primary Outcome Measures
- Change in ABCA1 mRNA expression in monocytes [June 2013]
Eligibility Criteria
Criteria
Inclusion Criteria:
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18 years old
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HIV-infected
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Not currently on antiretroviral therapy (>6/12), but about to start
Exclusion Criteria:
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On lipid lowering medication (statin / fibrate / niacin)
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HCV Ab+
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Chelsea & Westminster Hospital | London | United Kingdom | SW10 9NH |
Sponsors and Collaborators
- University College Dublin
- Chelsea and Westminster NHS Foundation Trust
Investigators
- Principal Investigator: Patrick WG Mallon, FRACP FRCPI PhD, HIV Molecular Research Group, UCD School of Medicine and Medical Sciences. Department of Infectious Diseases, Mater Misericordiae University Hospital and Mater Private Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- HIV RCTS