*6.1.2. Glutathione system*

**6. Protective effects of antioxidants**

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

neutralisation of free radicals.

by a common ligand.

radiation therapy [76].

*6.1.1. Superoxide Dismutase (SOD)*

Antioxidants are groups of substances which when present at low concentrations, in relation to oxidisable substrates, significantly inhibit or delay oxidative processes while often being oxidised themselves [65]. There exists a balance between their formation and removal (redox state). To maintain an oxido/redox balance, cells protect themselves from the toxicity of excess

There are many biochemical processes that oxidise reduced antioxidant molecules to neutralise free radicals and then restore the antioxidant molecules to a reduced state. In HIV infection, antioxidants serve to aid the CD4 cells in removing the virions by reducing the oxidative stress that develops during HIV infection [66]. Antioxidants are useful to the host for defence and

Superoxide dismutase (EC 1.15.1.1) destroys the free radical superoxide by converting it to peroxide which is further destroyed by catalase or glutathione peroxidase (GHPX) reaction. It is known that SOD converts the superoxide radical to the less-reactive H202 [67]*.* In humans, the three forms of SOD are cytosolic Cu, Zn-SOD, mitochondria Mn-SOD and extracellular

reduction of the transition metal ion at the active site in a ping-pong-type mechanism with widely acknowledged high reaction rates [68]. Copper-zinc superoxide dismutase (Cu, Zn-SOD) is also known as SOD-I; the active site is constituted by a copper and a zinc atom bridged

The HIV TAT domain is a regulatory protein of the virus that enhances the efficiency of virus transcription and has been shown to carry exogenous molecules into cells [69], thus can fuse with protein transduction domains (PTDs) for effective cellular cargo delivery [70]. TAT-PTD linked-SOD1 has been shown to be ferried across the cytoplasm and even the mitochondria where superoxide is generated, making TAT-SOD1 a source of intracellular antioxidant [72]. Currently, Qing et al. [73] in 2013 provided evidence that TAT-SOD1 has protective therapeutic activity against ionisation radiation. Conversely, cells actually infected with HIV have been reported to express less Mn-SOD and to lose their ability to induce antioxidant enzyme in response to TNF. Therefore, expression of TAT protein of HIV suppresses cellular Mncontaining superoxide dismutase (Mn-SOD) [74]. Furthermore, the protective nature of Mn-SOD has been demonstrated by several authors; its overexpression provides oxidant protection against AZT or 3TC-induced endothelial dysfunction [75] and against lung cancer

▪


ROS/RNS in different ways, enzymatic and nonenzymatic antioxidants.

**6.1. Relevant HIV antioxidants: Does HIV benefit from their activities?**

SOD (ECSOD). Generally, SOD catalyses the dismutation of 02

The glutathione system (glutathione, glutathione peroxidase, glutathione transferase and glutathione reductase) is a key defence against H202 and other peroxides. The term glutathione is typically used as a collective name to refer to the tripeptide L-gamma-glutamyl-L-cysteinyl glycine in both its reduced and dimeric forms. Glutathione is necessary for maintaining immune-mediated T-cell and phagocytosis. It inhibits HIV replication by acting at the late stages of the virus' life cycle through strong suppression of the production of p24 and gag protein as well as the viral infectivity factor (Vif) [77]. This results in a dramatic decrease in both budding and release of virus particles from chronically infected cells (either macrophages or lymphocytes). Also there is a relative decrease in the expression of gp120 (the protein component of the HIV viral coat), the major envelope glycoprotein rich in intrachain disul‐ phide bonds. Experiments with rats showed that gp120 increases the accumulation of H202 and superoxides; thus, Brook et al. [78] demonstrated that the activity of this HIV protein increases that of the key glutathione peroxidase as a defensive mechanism against ROS. Also glutathione inhibits the reverse transcriptase (RT) process of HIV and its expression [79]. GSH further blocks in a concentration-dependent manner the (intracellular) activation of essential proteinsplitting enzymes, such as HIV proteases. The glutathione redox cycle is a major source of protection against low levels of oxidant stress, whereas catalase becomes more significant in protecting against severe oxidant stress [80]. Glutathione reductase enzyme (EC 1.8.1.7), which reduces glutathione disulphide (GSSG) to the sulphhydryl form GSH, is an important cellular antioxidant.
