**5.5. Paraoxonases**

Changes in antioxidant enzymes, such as the family of paraoxonases (PONs), may partially explain some of the mechanisms involved in HAART-associated dyslipidemia and conse‐ quently characterize a higher risk for cardiovascular diseases and atherosclerosis [63]. The hypothesis that the PIs can promote reductions in the activity of PONs and an increased risk for atherosclerotic disease in HIV-1 patients has been shown through previous evidence. PON1 is an antioxidant enzyme present in serum is strongly associated with apolipoprotein-A1 (apoAl) from HDL and protects LDL against oxidative modifications [69, 70]. The action of serum PON1 most likely occurs through the involvement of the enzyme in reverse cholesterol transport, a well-established anti-atherogenic propriety of HDL [71]. PON1 has the ability to inhibit LDL oxidation (oxLDL) and significantly reduce the lipid peroxidase enzyme, which decreases the accumulation of cholesterol in peripheral tissues [72]. The oxidative modification of LDL in the arterial wall plays a central role in the pathogenesis of atherosclerosis, which is characterized by the deposition of lipids and the formation of atherosclerotic plaques that cause narrowing of the blood vessels [73]. The inhibition of oxLDL by HDL is attributed to the high antioxidant content of the lipoprotein possibly due to the antioxidant properties of apoA1 and by the presence of other different antioxidant enzymes, such as glutathione peroxidase and PON, which prevent the formation of or degrade bioactive products of oxLDL [68]. Some studies have shown that the activity of PON1 may be affected and/or inactivated by oxidative stress, which could explain its reduced activity during HIV-1 infection [69-71]. In HIV-1 patients and those who undergo HAART, there is a significant increase in oxidative stress. In asymptomatic HIV-1 patients, there is an increased oxidative stress characterized by elevated lipid peroxidation products and/or a quantitative decrease in antioxidants compared to seronegative controls that are considered to be in a healthy condition. Therefore, possible reductions in the activity of PON1 and HDL concentrations may characterize an increased cardiovascular risk in individuals infected with HIV-1 [70, 71, 75]. The PON1 activity that was reduced in ART-naïve patients, and restored in patients treated with HAART suggested that the activity of PON1 is associated with the immune status in HIV-1 patients. However, in individuals treated with lopinavir/ritonavir, even with low plasma viremia, PON1 activity was reduced and a higher atherogenic risk was shown by the high TC:HDL ratio, suggesting that a PI-based regimen affects the mechanisms involved in the oxidation of LDL, which promotes greater atherogenic risk [69-74].

## **5.6. LDL oxidation**

are essential for mitochondrial biogenesis and metabolic function. Furthermore, functional changes of mitochondria in skeletal tissue promote insulin resistance and consequent dysli‐

136 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

HAART-associated lipodystrophy and dyslipidemia may be related to genetic predisposition. Studies on HIV-1 patients with hypertriglyceridemia and low HDL were shown to be associ‐ ated with different polymorphisms in the *APOCIII* gene. Promoter polymorphisms -455T>C and -482C>T in the *APOCIII* gene are both associated with increased levels of TG containing lipoproteins (VLDL) and low HDL values. Carriers of the -455T>C genetic variant had 30% lower levels of HDL compared to those without this polymorphism and plasma lipid concen‐ trations increase according to the number of these variant alleles. Another variant nucleoside, the -1131T>C promoter polymorphism in the *APOA5* gene, was associated with hypertrigly‐

Changes in antioxidant enzymes, such as the family of paraoxonases (PONs), may partially explain some of the mechanisms involved in HAART-associated dyslipidemia and conse‐ quently characterize a higher risk for cardiovascular diseases and atherosclerosis [63]. The hypothesis that the PIs can promote reductions in the activity of PONs and an increased risk for atherosclerotic disease in HIV-1 patients has been shown through previous evidence. PON1 is an antioxidant enzyme present in serum is strongly associated with apolipoprotein-A1 (apoAl) from HDL and protects LDL against oxidative modifications [69, 70]. The action of serum PON1 most likely occurs through the involvement of the enzyme in reverse cholesterol transport, a well-established anti-atherogenic propriety of HDL [71]. PON1 has the ability to inhibit LDL oxidation (oxLDL) and significantly reduce the lipid peroxidase enzyme, which decreases the accumulation of cholesterol in peripheral tissues [72]. The oxidative modification of LDL in the arterial wall plays a central role in the pathogenesis of atherosclerosis, which is characterized by the deposition of lipids and the formation of atherosclerotic plaques that cause narrowing of the blood vessels [73]. The inhibition of oxLDL by HDL is attributed to the high antioxidant content of the lipoprotein possibly due to the antioxidant properties of apoA1 and by the presence of other different antioxidant enzymes, such as glutathione peroxidase and PON, which prevent the formation of or degrade bioactive products of oxLDL [68]. Some studies have shown that the activity of PON1 may be affected and/or inactivated by oxidative stress, which could explain its reduced activity during HIV-1 infection [69-71]. In HIV-1 patients and those who undergo HAART, there is a significant increase in oxidative stress. In asymptomatic HIV-1 patients, there is an increased oxidative stress characterized by elevated lipid peroxidation products and/or a quantitative decrease in antioxidants compared to seronegative controls that are considered to be in a healthy condition. Therefore, possible reductions in the activity of PON1 and HDL concentrations may characterize an increased cardiovascular risk in individuals infected with HIV-1 [70, 71, 75]. The PON1 activity that was reduced in ART-naïve patients, and restored in patients treated with HAART suggested that

pidemia [62-64].

**5.4. Genetic factors**

**5.5. Paraoxonases**

ceridemia in PI-based patients [65-68].

Oxidative modifications to LDL, which are considered the initial event in the pathogenesis of atherosclerosis, are attributed to oxidative stress mechanisms initiated by agents such as superoxide, nitric oxide and hydrogen peroxide (H2O2) that transform LDL into oxLDL [77, 77]. The deposition of oxLDL in the arterial intimal layer promotes a cytotoxic effect on the vascular endothelium, followed by inflammation and modification of monocytes into macro‐ phages that phagocytose oxLDL particles to form the foam cells which accumulate in the intima and lead to the development of atheromatous plaques [78]. The oxLDL particles are immuno‐ genic, and serum levels of anti-oxLDL antibodies (Abs) can be used as indicators of oxidative stress [76-78]. The immunoglobulin G (IgG) anti-oxLDL Abs are pro-atherogenic and can predict the progression of coronary and carotid atherosclerosis, whereas IgM anti-oxLDL Abs appear to be associated with a possible protective role against the development of atheroma‐ tous plaques [79]. During the process of infection by HIV-1, the increase in atherogenic risk results from changes in lipid metabolism associated with the severity, duration and stages of infection. Different degrees of lipodystrophy occur in patients along with a decrease in LDL receptor expression, which could lead to increased oxidation of LDL particles and the conse‐ quent development of atherosclerosis [80]. HIV-1 patients treated with lopinavir/ritonavir have shown higher levels of IgG anti-oxLDL Abs compared to patients treated with efavirenz or nevirapine regimens, and these levels were associated with an increase in the atherogenic indices [78-80].
