**3. Induction of stress responses and stress response genes: A coping strategy**

Oxidative stress is a potent biological stress that weakens and damages cellular components. Naturally, cells devise means of coping, avoiding and responding to this call. Perhaps, the coping mechanism may depend on the degree of the stress, allowing the cell not to overstretch its capabilities. Induction of the antioxidant response element or suppression of inflammatory reactions could limit HIV replication in the host. The master transcription factor known as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is known to regulate the expression of antioxidants through activation of antioxidant response element (ARE). Fan et al. showed that upregulation of Nrf2 increased the ARE-dependent antioxidants and that HIV-1-related proteins downregulated Nrf2 expression in HIV-1 transgenic rats [29]. Increased oxidative stress induces Nrf2 and stimulates key antioxidant defence mechanism [30] in HIV cells. Cells tend to respond differently to different levels of OS. At a medium level of OS, cells are known to undergo a halt on cell growth and differentiation [31]. In this state, the redox-sensitive transcription factors NF-κB and activator protein-1 (AP-I) are both activated and induce stress protein synthesis through ARE on stress protein genes [128]. Other factors associated with apoptotic pathways are also activated which enables the cell to undergo the characteristic changes known to apoptosis [32, 33]. A higher level of OS is characterised by the pathological changes caused by free radical damage; this becomes apparent and the cell undergoes death characterised by necrosis [34, 35].

However, response to ROS at the cellular level occurs through ARE and oxidative stressresponsive genes (Fig. 1). Following oxidative stress, a signal is transduced by interaction of specific DNA repair enzymes, antioxidant enzymes, heat shock proteins, proteases, protease inhibitors, cytokines and proliferation factors [36]. This adaptive response is biphasic: an 'early' response (1–4 h), which imparts relatively minor protection, and a 'late' response (12–16 h) which imparts major protection and involves the synthesis of proteins such as repair enzymes [37]. The response also varies with the initiating stress in that some responses are global (e.g. induction of SOD), whereas others are specific to the initiating stress and in other cases, tissue specific (e.g. induction of surfactant proteins in the lung).

threshold of OS generated and/or needed to determine entrance to the various infection stages. A possible explanation to the observed consecutive more intense overproduction of ROS in the various stages especially in stage 2 is associated partly with changes in the expression of the antiapoptotic/antioxidant compounds Bcl-2 and thioredoxin along the course of the disease by hydrogen peroxide H2O2 [26]. It is known that the free radical H2O2 plays a central role in activating NF-κB (NF-κB activates HIV replication) through the activation of a factor that binds to a DNA-binding protein; NF-κB in turn stimulates HIV gene expression by acting on the promoter region of the viral long terminal repeat (LTR). NF-κB regulates cellular responses as a 'rapid-acting' primary transcription factor. This makes it to be a first responder to harmful cellular stimuli such as H2O2. Known inducers of NF-κB activity include reactive oxygen species (ROS), tumour necrosis factor alpha (TNF-α) and interleukin-1-beta (IL-1β) [27]. If there is no adequate levels of antioxidants, the activity of NF-κB increases in excess amounts and accelerates HIV replication. It is estimated that more than one billion T4 cells are killed and over 50 million HIV replenished on a daily basis in AIDS; this characteristic causes an increase

**3. Induction of stress responses and stress response genes: A coping**

Oxidative stress is a potent biological stress that weakens and damages cellular components. Naturally, cells devise means of coping, avoiding and responding to this call. Perhaps, the coping mechanism may depend on the degree of the stress, allowing the cell not to overstretch its capabilities. Induction of the antioxidant response element or suppression of inflammatory reactions could limit HIV replication in the host. The master transcription factor known as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is known to regulate the expression of antioxidants through activation of antioxidant response element (ARE). Fan et al. showed that upregulation of Nrf2 increased the ARE-dependent antioxidants and that HIV-1-related proteins downregulated Nrf2 expression in HIV-1 transgenic rats [29]. Increased oxidative stress induces Nrf2 and stimulates key antioxidant defence mechanism [30] in HIV cells. Cells tend to respond differently to different levels of OS. At a medium level of OS, cells are known to undergo a halt on cell growth and differentiation [31]. In this state, the redox-sensitive transcription factors NF-κB and activator protein-1 (AP-I) are both activated and induce stress protein synthesis through ARE on stress protein genes [128]. Other factors associated with apoptotic pathways are also activated which enables the cell to undergo the characteristic changes known to apoptosis [32, 33]. A higher level of OS is characterised by the pathological changes caused by free radical damage; this becomes apparent and the cell undergoes death

However, response to ROS at the cellular level occurs through ARE and oxidative stressresponsive genes (Fig. 1). Following oxidative stress, a signal is transduced by interaction of specific DNA repair enzymes, antioxidant enzymes, heat shock proteins, proteases, protease inhibitors, cytokines and proliferation factors [36]. This adaptive response is biphasic: an 'early' response (1–4 h), which imparts relatively minor protection, and a 'late' response (12–16 h)

in cytokine synthesis and free radical damage of cells [28].

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

**strategy**

characterised by necrosis [34, 35].
