**4. Mechanism of HIV-associated lipid disorders**

ent efflux transporter ATP-binding cassette protein A1 (ABCA1) in human macrophages, which is a condition that has a high atherogenic risk [22, 23]. The use of PI-based HAART currently constitutes a more potent option against HIV-1 infection, preventing the maturation of viral particles and effectively controlling the infection of new cells by HIV-1. However, observed changes in lipid metabolism in HIV-1 patients have been associated with this class

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

**Drug class Generic name drug Trade name/manufacturer/approval (year)**

Ziagen® ViiV Healthcare (1998) Videx® Bristol-Myers Squibb Co. (1991)

Emtriva® Gilead Sci. (2003) Epivir® GlaxoSmithKline (1995) Zerit® Bristol-Myers Squibb Co. (1994)

Viread® Gilead Sci. (2001) Retrovir® ViiV Healthcare (1987)

Hivid® Roche (1992)

Rescriptor® Pfizer (1997)

Sustiva® Bristol-Myers Squibb Co. (1998) Stocrin® Merck Sharp, Dohme (1998) Viramune® Boehringer Ingelheim (1996) Intelence® Janssen-Cilag (2008) Edurant® Janssen-Cilag (2011)

Agenerase® GlaxoSmithKline (1999) Reyataz® Bristol-Myers Squibb Co. (2003)

Prezista® Janssen-Cilag (2006) Lexiva® ViiV Healthcare (2003) Crixivan® Merck & Co. (1996) Kaletra® Abbott (2000)

Viracept® ViiV Healthcare (1997) Norvir® AbbVie Inc. (1996) Invirase® Roche (1995)

Tivicay® GlaxoSmithKline (2013) Stribild® Gilead Sci. (2012) Isentress® Merck & Co. **(**2007)

Aptivus® Boehringer Ingelheim (2005)

Abacavir (ABC) Didanozine (ddl) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (AZT) Zalcitabine (ddC)

Delavirdine (DLV) Efavirenz (EFV) Nevirapine (NVP) Etravirine (ETR) Rilpivirine (RPV)

Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir

Fusion inhibitors Enfuvirtide/T-20 Fuzeon® Hoffmann La Roche (2003)

Dolutegravir (DTG) Elvitegravir (EVG) Raltegravir (RAL)

Selzentry Maraviroc® Pfizer (2007)

of antiretroviral drugs [13, 14, 24, 25].

Nucleoside reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase

Integrase strand transfer inhibitors

**Table 1.** Antiretroviral drugs.

(CC chemokine receptor 5 [CCR5] antagonists)

(InSTIs)

Entry inhibitors

Protease inhibitors (PIs) Amprenavir

inhibitors (NNRTIs)

(NRTIs)

Lipid disorders during the course of HIV-1 infection and acquired immunodeficiency syn‐ drome (AIDS) had been observed long before the advent of antiretroviral regimens [36, 37]. In the early phase of acute HIV-1 infection, the patient has several clinical signs of immunosup‐ pression, variably characterized by fever, intestinal infections, weight loss and depletion of protein reserves [37, 38]. The possibility of the HIV-1 infection causing changes in lipid metabolism was already postulated because it is evident that plasma viremia may promote a decrease in plasma concentrations of TC, HDL and LDL, and, in later stages of infection, an elevation in the concentration of TG [37, 38]. Specifically, the reduction of HDL likely occurs as a result of an activation of the immune system in early HIV-1 infection, which promotes an increase in lipid peroxidation, alterations in the reverse cholesterol transport, and inflamma‐ tory cytokine production. Cytokines are small proteins which function to mediate communi‐ cation between immune and non-immune cells, and they are produced by various cells of the immune system such as lymphocytes, natural killer (NK) cells, macrophages, dendritic cells, as well as endothelial cells, among others. These molecules orchestrate a variety of processes 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 also acts on the suppression of lipolysis mediated by hormones [46].
