PPAR agonists inhibit HIV replication and TNF-alpha production

In HIV-infected patients, stimulation of peroxizome proliferator-activated receptors (PPAR) may not only improve the metabolic alterations associated with highly active antiretroviral therapy (HAART) but may also decrease viral replication and TNF-alpha production, according to a report in the 1 September issue of the Journal of Acquired Immune Deficiency Syndromes.

Because of speculation that insulin resistance is involved in HIV-related lipodystrophy, PPAR-gamma agonists (e.g., glitazones) and PPAR-alpha agonists (e.g., fenofibrate) are being used to treat the condition, the authors explain. However, other drugs such as metformin that have been tried have increased HIV replication and decreased CD4 cell counts.

Dr. Paul Skolnik from Boston University Medical Center, Massachusetts, and colleagues investigated the effects of PPAR agonists on HIV replication and TNF-alpha production (which increases HIV replication) in acutely infected human peripheral blood mononuclear cells (PBMCs), alveolar macrophages (AMs), and a monoblastoid cell line chronically infected with HIV-1 (U1 cells).

PPAR agonists inhibited HIV-1 replication up to 65%, depending on drug concentrations and the presence or absence of lipopolysaccharide (LPS), in PBMCs and U1 cells, the authors report, without affecting cell viability except at the highest drug concentrations.

PPAR agonists also significantly inhibited TNF-alpha production in the absence and presence of LPS in PBMCs, U1 cells, and AMs at very low concentrations, the report indicates, with AMs showing greater resistance to the effects of PPAR agonists than the other two cell types.

“We hypothesize that alterations in mitogen-activated protein kinase signaling pathways have contemporaneous and interrelated effects on HIV replication, cytokine production, and lipid metabolism,” the investigators write. “Modulation of these pathways using PPAR agonists may improve the metabolic alterations during HAART in conjunction with desirable decreases in HIV replication and TNF-alpha production.

“More detailed studies of the mechanism of action of these agents on lipid metabolism and HIV replication may allow for the discovery of more selective agents or the establishment of more focused treatment protocols to help HIV-infected persons experiencing adverse metabolic effects from HAART,” the researchers conclude.