Antiretrovirals Induce Direct Endothelial Dysfunction In Vivo

Abstract

HIV-associated cardiovascular diseases have been widely described, but clinical studies aimed at establishing cause-effect relationships between HIV-associated cardiovascular disease and either the HIV infection or antiretroviral therapy have been problematic. Endothelial dysfunction is a sensitive marker and early event in atherosclerosis, and many have suggested that protease inhibitors promote endothelial dysfunction indirectly by inducing elevations in circulating lipids. To determine whether nucleoside reverse transcriptase inhibitors and/or protease inhibitors induce endothelial dysfunction, and to test whether this effect is dependent upon drug-mediated alteration in plasma lipid concentrations, we treated male Sprague-Dawley rats with pharmacological doses of azidothymidine (AZT), indinavir, or AZT plus indinavir through their drinking water for 1 month and assessed endothelial function in aortic rings using an isometric force measurement. Circulating levels of plasma lipids and endothelin-1, a marker for endothelial injury and/or dysfunction, were also determined. We found that AZT and AZT plus indinavir treatments dramatically reduced endothelium-dependent vessel relaxation. However, AZT treatment did not significantly alter plasma levels of cholesterol or triglyceride. In addition, plasma endothelin-1 levels were elevated in rats treated with AZT plus indinavir. Indinavir treatment alone increased plasma cholesterol levels but had no effect on endothelial function. These findings suggest that in addition to modulating plasma lipid levels, antiretrovirals, particularly AZT and perhaps other nucleoside reverse transcriptase inhibitors, may have direct effects on the vascular endothelium. Together with other increased risk factors for atherosclerosis in HIV patients, AZT-induced endothelial dysfunction may contribute to the cardiovascular diseases associated with HIV antiretroviral therapy.

Antiretroviral Treatment is Associated with Increased Attentional Load-Dependent Brain Activation in HIV Patients

“…As long-term HIV infection as well as ARVs are independent risk factors for atherosclerosis (Lorenz et al 2007), and as ARVs may lead to endothelial dysfunction (Jiang et al 2006), our HIV+ARV subjects might also have reduced vascular reactivity, which in turn could lead to abnormal BOLD responses on fMRI. While our HIV+ARV subjects did have slightly longer duration of HIV infection, it was not significantly different from the untreated HIV group.…”

“…Hence, HIV+ARV subjects may have had higher viral burden in the brain parenchyma, despite undetectable plasma viral load, and hence greater inflammatory responses in the brain and greater BOLD signals. Previous study has shown that higher levels of glial markers, myoinositol, and to a lesser degree, total creatine and choline compounds, predicted higher BOLD signals in the brain .Whether the ARVs cause direct neurotoxicity or increase inflammatory response in the brain remains unclear, but most of the NRTIs in our HIV patients' regimen were of the less neurotoxic type; only one patient was on ddI and one on d4T.As long-term HIV infection as well as ARVs are independent risk factors for atherosclerosis (Lorenz et al 2007), and as ARVs may lead to endothelial dysfunction (Jiang et al 2006), our HIV+ARV subjects might also have reduced vascular reactivity, which in turn could lead to abnormal BOLD responses on fMRI. While our HIV+ARV subjects did have slightly longer duration of HIV infection, it was not significantly different from the untreated HIV group.…”

“…As NRTIs inhibit gamma-DNA polymerase, which is responsible for replication of mitochondrial DNA (mtDNA), its long-term use may cause mtDNA dysfunction (Dalakas 2001). Recent studies further indicate that some antiretrovirals, particularly azidothymi-dine (AZT) and NRTIs, may induce direct endothelial dysfunction (Jiang et al 2006), which may ultimately lead to compromised blood-brain barrier (BBB) and further brain injury.…”

“…As NRTIs inhibit gamma-DNA polymerase, which is responsible for replication of mitochondrial DNA (mtDNA), its long-term use may cause mtDNA dysfunction (Dalakas 2001). Recent studies further indicate that some antiretrovirals, particularly azidothymi-dine (AZT) and NRTIs, may induce direct endothelial dysfunction (Jiang et al 2006), which may ultimately lead to compromised blood-brain barrier (BBB) and further brain injury.However, the few brain-imaging studies that evaluated the effects of ARVs showed varied results, from greater metabolite abnormalities in those treated with NRTIs (Schweinsburg et al 2005) to persistent brain abnormalities during early periods of treatment and improved or better brain function (e.g., metabolite levels or BBB integrity) after longer periods of treatment (Avison et al 2004;Chang et al 1999;Tarasow et al 2004). Therefore, whether ARVs exacerbate HIV-associated brain injury and contribute to the increased brain activation observed in prior fMRI studies remains controversial.…”

Relationship of Body Composition, Metabolic Status, Antiretroviral Use, and HIV Disease Factors to Endothelial Dysfunction in HIV-Infected Subjects

“…28 We were unable to confirm a role for the PI class in inducing endothelial dysfunction. Human data 8,[10][11][12] and experimental models [29][30][31][32][33] have implicated PIs as a cause of endothelial dysfunction. The mechanism appears to include impaired nitric oxide bioavailability.…”