| dc.description.abstract | Viral infections are becoming more common daily around the world, and acquired immunodeficiency syndrome (AIDS) (the end phase of human immunodeficiency virus [HIV] infection) has been one of the most dreaded infectious diseases causing mortality in individuals. The survival of HIV inside the CD4<sup>+</sup> lymphocytes depends on cells properly signaling pathways. Some of these pathways are necessary for viral replication and also for host-cell physiology. Among them are the pathways generating free radicals (generically reactive oxygen species [ROS]), which are considered the second messengers of the cell. The ROS produced inside cells are maintained by complex intracellular regulatory systems that maintain ROS neutralized by antioxidant defense systems. The virus-host cell contact, installation, replication, proliferation, and dissemination are accompanied by metabolic changes resulting in pro-oxidant activities with higher free-radical production. Hence, the role of oxidants in viral diseases is more complex because it includes metabolic regulations for both host metabolism and viral replication. There is clear evidence that oxidative stress may contribute to several aspects of HIV disease, including viral replication, inflammatory response, and decreased immune cell proliferation. The role of oxidative stress in disease progression has been shown to be more complicated in HIV-infected individuals receiving HAART compared with those who remain untreated. Hence, oxidative stress has been proven to play an important role in the progression of HIV infection, and perturbations in antioxidant defense systems and, consequently, redox imbalance are present in many cells in this infection. Before the ARV/HAART era, we had learned that protein-energy malnutrition impairs not only the optimal cellular functions but also the body's immune system. Today, we are learning from our overweight/lipodystrophy patients who lack specific trace elements in their diet, such as minerals and vitamins, thus adversely influencing the redox status of the body. Studying oxidative stress in HIV-infected patients has opened new doors for cellular ROS researchers to use antioxidants as novel drugs to decrease HIV-1 pathogenesis in human. Therefore, the exogenous supply of antioxidants, as natural compounds and new generation antioxidants, might represent an important additional strategy for the treatment of HIV infection in the era after ARV/HAART therapy. One of such example is the tripeptide glutathione (GSH), a major component involved in the control and maintenance of cellular redox state and cellular homeostasis. The presence of sufficient concentration of cellular GSH protects cells from any bacterial, viral, and fungal infections. The infection is subsequently flushed out from the system by normal means, which reduces viral load. GSH may cause intervention at different steps of HIV-1 replication and inhibits the expression of p24 antigenic proteins of HIV-1 required to form the viral coat. AIDS is associated with a deficiency of GSH that leads to the generation of higher levels of oxidative stress that damage and kill otherwise healthy cells including the immunity of the body. The consumption of GSH is not increased in HIV infection; rather, it is suggested that GSH in patients is low because of a decreased systemic synthesis of GSH. GSH biosynthesis can be controlled by its enzymes and by the availability of its precursor amino acids. Studies by our group have evaluated the isolated effects of two GSH precursors amino acids, cysteine (Cys) and glutamine (Gln), in HIV-positive patients that lead to significant increases of plasma GSH levels. The study used a randomized crossover design to test the diet supplemented with Cys precursor NAC (N-acetyl cysteine) or Gln as compared with the regular diet, with a short washout period between the two dietary periods in a group of HIV-positive (HAART-treated) patients. A group of healthy subjects served as control. The results showed that NAC and Gln, through difft mechanisms, were able to increase GSH up to normal levels. NAC acted by sparing Hcy and Cys, whereas Gln acted by replenishing Gly pool. However, neither of the two supplements had significant effects on the GSH antioxidant capacity (GSSG/GSH ratio), indicating the need for an additional supplement (perhaps riboflavin). | |
