**3. Lipid changes in HIV infection**

periods of time and reduce the risk for cardiovascular and atherosclerotic diseases in HIV-1 patients. In addition to known HAART regimens, new drugs and formulations have been developed to prevent infection by HIV-1. This new approach based on pre-exposure prophy‐ laxis (PrEP) has shown promising results when administering drugs orally and in vaginal and rectal microbicides. PrEP using intravaginal rings with antiretroviral drugs is emerging as a promising strategy for the prevention of sexual HIV-1 transmission. The use of vaginal rings as controlled release strategy of antiretroviral drugs may improve adherence to PrEP, and provide sustained mucosal levels independent of coitus and daily dosing. Finally, the search for new drugs and methods that allow a greater survival, quality of life or prevention of HIV-1

For HIV-1-infected patients, the 1990s were marked by the introduction of HAART, which represented a new perspective of life for these patients [1]. The use of HAART was shown to effectively suppress the replication of HIV-1 and dramatically reduce mortality and morbidity rates, which has led to a better and longer quality of life for HIV-1 patients [2]. The HAART regimens, composed of at least three different antiretroviral drugs, are effective in reducing viral load (HIV-1-RNA) to undetectable levels when adhered to recommend‐ ed prescription [3]. HAART regimens, with their different combination of drugs, inhibit viral replication by acting at different stages of infection [4]. This allows them to reach the viral cycle and/or viral enzymes and thus are classified in different therapeutic groups according to their mechanism of action: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, entry inhibitors (CC chemokine receptor-5 [CCR5] antagonists), and integrase strand transfer inhibitors (InSTIs) [5-10] (Table 1). NRTIs are nucleoside and nucleotide analogues which inhibit reverse transcription during HIV-1 infection. HIV-1 is a virus that has RNA as the genetic material, and is unable to integrate its DNA into host cell. For its integration into the chromosomal DNA of the human cell it must be reverse transcribed into DNA by a reverse transcriptase. The conversion of RNA to DNA therefore, is made by the viral protein reverse transcriptase (RT). NRTIs prevent reverse transcriptase's enzymatic activity and block completion of synthesis of the double-stranded viral DNA, this prevents HIV-1 multiplication. They are analogues of naturally occurring deoxynucleo‐ tides and competitively incorporates itself into the growing chain of viral DNA. NRTIs lack a 3′-hydroxyl (3 'OH) group on the deoxyribose moiety thus act as a chain terminator which prevents the next deoxynucleotide from forming another 5′–3′ phosphodiester bond needed to extend the DNA chain [5]. NNRTIs inhibit RT by binding to an allosteric site of the enzyme, and act as non-competitive inhibitors of RT. NNRTIs as a class of drug affect the handling of substrate (nucleotides) by RT by binding near the active site [6]. PIs on the other hand block the viral protease enzyme necessary to produce mature virions upon budding from the host membrane; ultimately these drugs prevent the cleavage of gag and gag/pol precursor proteins. In the presence of protease inhibitors, virus particles pro‐

**2. HAART as a new perspective of life for HIV+ subjects**

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

transmission are constant challenges.

The observed changes in lipid metabolism during HIV-1 infection, as shown by changes in high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL), triglycerides (TG), lipid peroxidation, and their relationship with atherosclerosis in HIV-1 patients, results from the critical role of cholesterol in the mechanism of HIV-1 replication [11, 12, 18, 19]. The HDL is widely known as "good choles‐ terol", in which many studies have demonstrated that increasing serum levels are considered normal and are associated with a lower risk of cardiovascular disease because it can transport fat molecules out of artery walls, reduce macrophage fat accumulation and therefore regress atherosclerosis [18-20]. HDL has several potential for antiatherogenic properties, for instance, cholesterol is transported from peripheral tissues such as the cells in the arterial walls to the liver by HDL components, where it is used for a composition of lipoproteins and in synthesis of bile acids, steroid hormones, or fat-soluble vitamins [20]. Unlike the HDL, LDL is an important risk factor for the development of atherosclerosis and cardiovascular disease, and, this is the main lipoprotein cholesterol transports to peripheral tissues where they are inter‐ nalized through the LDL receptor, a key mediator of plasma LDL concentrations [21]. Elevated plasma TG is emerging as an independent risk factor for the metabolic syndrome, type 2 diabetes, and cardiovascular disease, particularly if the levels of HDL are low and the levels of LDL increased [20, 21]. HIV-1 decreases plasma HDL by impairing the cholesterol-depend‐ 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 of antiretroviral drugs [13, 14, 24, 25].


**Table 1.** Antiretroviral drugs.

There is significant support in the literature showing that the PIs are associated with increased hepatic TG-synthesis, VLDL, and to a lesser extent, total cholesterol (TC) [11-14]. Moreover, it was observed that these drugs impair the hydrolysis of TG-rich lipoproteins by lipase, which reduces the storage of free fatty acids (FFA) and interferes with the normal postprandial metabolism of FFA [25, 26]. The PIs are analogous substrates of the aspartyl protease enzyme of the HIV-1 that are involved in the cleavage process of viral proteins and form smaller and functional viral particles with infective capacity. After the cleavage process, the newly formed viral and infectious particles are released from infected cells in mature form [7, 27, 28]. Once the PIs bind to the active site of the protease enzyme, they block the cleavage process, which interferes with the normal process of viral maturation and formation of infectious viral particles in HIV-1 infection [27, 28]. The different mechanisms by which PIs promote these changes remain unknown. However, the main effect of PIs seems to be suppressing the breakdown of the nuclear form of sterol-regulato‐ ry element binding protein-1 (nSREBP1) in the liver and adipose tissue. This regulator is a key element in the proteolytic pathway responsible for regulating cellular and plasma levels of fat and cholesterol [29]. Some other classes of antiretroviral drugs are available, including those with excellent activity on suppression of viral replication without adverse effects on lipid metabolism [12, 25, 30]. However, it is clear that the use and recommendation of PIs occurs in situations where other drugs and/or regimens have not achieved the desired effect, either by non-adherence to treatment, viral resistance or lack of immune response [31, 32]. Once the therapy with PIs is initiated, a change to a more conservative therapy without their use is not recommended nor used in clinical practice [33, 34]. Thus, a continuous monitoring of the patient's characteristics for each PI available is required, in order to achieve alternative HAART regimens that could maintain a suppressive response of viremia, with minor effects on lipid metabolism of HIV-1 patients [34, 35].
