**5.1. CRABP-1**

ranging from the regulation of local and systemic inflammation to cellular proliferation, metabolism, chemotaxis, and tissue repair. Different cytokines produced by these cells mediate the transition from innate to adaptive immunity response [39]. This process promotes an imbalance in the antioxidant system, a decrease in the production of anti-inflammatory cytokines and an elevation of pro-inflammatory cytokines, which increases the chances of developing atherosclerotic diseases [33-40]. The inflammatory process initiated by viral infection, a stimulus of endothelial lipase and phospholipase A2 occurs, which in turn can reduce HDL concentration [41-43]. The inflammatory process may also be characterized by an elevation of interferon-γ levels (IFNγ) originating from lymphocytes and macrophages. IFNγ levels are elevated at early stages of infection and are also correlated with the presence of hypertriglyceridemia [44, 45]. Tumor necrosis factor-α (TNFα) is another potent proinflammatory mediator whose concentrations increase in HIV-1 infected ART-naïve patients. TNFα promotes lipid peroxidation and disturbances in the metabolism of free fatty acids and

HAART-associated dyslipidemia is complex and involves immunological, hormonal, genetic predisposition aspects and the effects induced by different antiretroviral drugs [13, 47]. The observed dyslipidemia is characterized by hypertriglyceridemia, hypercholesterolemia, and decreased serum levels of HDL, either accompanied or unaccompanied by increased levels of LDL (Table 2) [47, 48]. Other metabolic and/or clinical common disorders include insulin resistance with hyperinsulinemia, increased C-peptide levels, diabetes mellitus and lipodys‐ trophy syndrome [44-48]. Diabetes mellitus is a group of metabolic disorders in which the blood glucose is higher than normal levels due to insufficiency of insulin release or improper response of cells to insulin. The resultant hyperglycemia produces sever complications [49]. The production and secretion of insulin is realized by pancreatic β-cells, and occurs in response to concentrations of amino acids, fatty acid and glucose. However, glucose is considered the first stimulus to the beta cells which secrete insulin. Regulated insulin release requires tight coupling in the β-cell between glucose metabolism and insulin secretory response [50]. HAART also affects the hydrolysis of TG-rich lipoproteins and tissue lipase, disrupts normal postprandial FFA and lipoprotein catabolism and interferes with peripheral fatty acid trapping. These effects could be due to the interaction of fatty acids with the master transcrip‐ tional regulator sterol regulatory element binding protein 1 (SREBP1) [51-56]. Nevertheless, the presence of dyslipidemia in individuals who use HAART is not necessarily accompanied by lipodystrophy and/or an evident insulin resistance, which suggests that the mechanism(s) involved in these disorders maybe independent [47, 51, 56, 57]. The NNRTI-based HAART, zidovudine, stavudine or lamivudine, has eventually become associated with the occurrence of dyslipidemia; however, lipid metabolism disorders are mainly evident in individuals who make use of the PI-based therapy [47, 48, 57, 58]. In as much as the mechanisms involved in PI-associated dyslipidemia are not fully understood, the prevailing hypothesis is based on the structural similarity between the catalytic region of the HIV-1 protease and two homologous

also acts on the suppression of lipolysis mediated by hormones [46].

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

**5. Mechanism of HAART-associated lipid disorders**

CRABP-1 exhibits 58% homology in its amino acid sequence of the C-terminal region in the catalytic area of the HIV-1 protease. CRABP-1 usually binds intracellular retinoic acid and presents it to Cytochrome P450 3A4 (CYP3A4) (EC 1.14.13.97) enzymes, which convert retinoic acid to cis-9-retinoic acid, bind to retinoid X receptor-peroxisome proliferator-activated receptor γ (RXR-PPARγ) heterodimer, stimulating adipocyte differentiation and inhibiting apoptosis [22, 48, 59]. Hepatic CYP enzymes are responsible for the metabolism of xenobiotic and many pharmaceuticals, but they also utilize endogenous compounds as substrates, such as cholesterol and fatty acids [60]. CRABP-1 shows homology with the viral protease, therefore, it is suggested that PIs bind to CRABP-1 and thereby inhibit the formation of 9-cis retinoic acid, leading to a reduction RXR-PPARy activity, increased apoptosis, and decreased proliferation of peripheral of adipocytes. Such events would cause peripheral lipoatrophy syndrome and hyperlipidemia because of adipocyte loss, decreased lipid storage and lipid release into the bloodstream. The inhibition of CYP3A by ritonavir is another possible mechanism involved in lipid abnormalities in HIV-1 patients and associated PI-based therapy and would promote a reduction in the formation of cis-9-retinoic acid and reduced enzymatic activity of RXR-PPARy. The decrease in RXR-PPARγ activity results in apoptosis of peripheral adipose stores, decreased adiponectin, and insulin resistance. However, central and visceral adipose stores are spared and expand with weight gain, contributing to insulin resistance [22, 48, 60].
