**4. Role of GSH in HIV and HTLV-1 immune response**

T CD4+ lymphocyte differentiation involves the antigen-presenting cells (APCs) that display antigen complexed with major histocompatibility complex class II (MHC II) on their surfaces. The antigens are associated to MHC II molecule that interacts with T-cell receptor of T CD4+ lymphocytes, leading the antigen recognition and, subsequently, activation. T-CD4+ lymphocyte activation can generate some profiles (named Th), which depend on molecules present in the microenvironment. The cell phenotype is related with a group of cytokines and other immune products produced by T cell, generating inflammatory or anti-inflammatory cells. During viral infections the activation of inflammatory T-cell phenotype can be associated with virus eradication. However, in the CNS the exacerbation of inflammatory response is related with neurodegeneration [37]. Mice infected with the retroviral complex LP-BM5, a murine model of AIDS, presented GSH and/or cysteine reduction in lymphoid organs (spleen and lymph nodes). This GSH down modulation was followed by change in cytokine profile. The The Role of Glutathione in Viral Diseases of the Central Nervous System http://dx.doi.org/10.5772/intechopen.76579 71

involved in resistance against anticancer drugs. ABCC1 is expressed in tumor cells [30] and normal tissues, such as the brain [31] and lymphocytes [32]. ABCC1 expression depends on

It was already described in this charter; JC virus was detected in CNS tumors, such as glioblastomas. This brain tumor is highly proliferative and invasive and presents mechanisms of multidrug resistance (MDR). It was found that MDR glioblastoma cells displayed lower levels of endogenous ROS and high levels of GSH. On the other hand, the redox state disequilibrium or down modulation of GSH made these MDR cells more sensitive to chemotherapy [9]. In JC virus-infected glioblastoma cells, it is possible to find the same MDR feature. However, the

presented a reduced ABCC1 expression and activity when compared to uninfected ones [34]. However, a lower ABCC1 expression was detected in CD4+ T lymphocytes from symptomatic patients. This result was directly correlated to the proviral load; a lower expression of ABCC1 was observed in patients with higher proviral load [34]. The pharmacological inhibition of ABCC induced a proliferation increase induced by mitogen of lymphocytes obtained from HTLV-1-infected individuals [19]. The expression and activity of ABCC1 transporter in BBB during HTLV-1 infection still remain unknown. It was suggested that dysregulations of ABC efflux transporters were implicated with the BBB breakdown during neurological diseases [35]. In infectious diseases this phenomenon can be involved in virus entrance in the CNS.

The incubation of astrocytes with gp120 enhanced the mRNA and protein levels of ABCC1. This effect was followed by the increase in substrate fluorescent or GSH transport and decreasing of GSSG efflux. Together these results suggested that the balancing of oxidative cellular status involves the increase in active GSH efflux to extracellular medium [36]. HIV protease inhibitors—ritonavir, indinavir, saquinavir, nelfinavir, and zidovudine—were described as ABCC1 substrate [35], suggesting that the overexpression of ABCC1 in infected cells makes

 lymphocyte differentiation involves the antigen-presenting cells (APCs) that display antigen complexed with major histocompatibility complex class II (MHC II) on their surfaces. The antigens are associated to MHC II molecule that interacts with T-cell receptor of T CD4+

lympho-

lymphocytes, leading the antigen recognition and, subsequently, activation. T-CD4+

cyte activation can generate some profiles (named Th), which depend on molecules present in the microenvironment. The cell phenotype is related with a group of cytokines and other immune products produced by T cell, generating inflammatory or anti-inflammatory cells. During viral infections the activation of inflammatory T-cell phenotype can be associated with virus eradication. However, in the CNS the exacerbation of inflammatory response is related with neurodegeneration [37]. Mice infected with the retroviral complex LP-BM5, a murine model of AIDS, presented GSH and/or cysteine reduction in lymphoid organs (spleen and lymph nodes). This GSH down modulation was followed by change in cytokine profile. The

from HAM/TSP asymptomatic and symptomatic individuals

influence of proteins from virus in MDR mechanisms expression remains unknown.

Nrf2 activation and translocation to the nucleus [33].

and CD8+

these cells more resistant to chemotherapy.

**4. Role of GSH in HIV and HTLV-1 immune response**

T lymphocytes CD4+

70 Glutathione in Health and Disease

T CD4+

**Figure 2.** Role of GSH in HIV-1 immune response. The infection induced generation of M2 macrophages and T lymphocytes with Th2 phenotype. However, the GSH replacement led macrophages to M1 differentiation and CD4+ lymphocyte secretion of Th1 cytokines.

infected mice exhibited a higher increase in interleukin (IL) IL-5, IL-4, and IL-2 than IL-12 and interferon-γ (IFN-γ), suggesting an important alteration in cytokine profile from Th1 to Th2 (**Figure 2**) [38].

Macrophages and dendritic cells are an important group of APCs. During infections macrophages can acquire specialized functional phenotypes. Macrophages classic activated are involved in inflammatory responses and are denominated M1. Macrophages alternative activated exhibit an antagonic inflammatory profile and named M2 [37]. Macrophages HIV-1 and LP-BM5 infected exhibited a decrease in GSH and cysteine intracellular levels. In addition, low intracellular levels of GSH were correlated with defective processing of antigens in APCs, indicating that GSH may be a critical factor in antigen processing [39]. During the LP-BM5 infection, macrophage polarization into alternative profile was observed, suggesting that M2 cells were driving the T-cell phenotype. LP-BM5-infected mice treatment with GSH replacement changed the macrophage polarization to M1 profile, inducing an increase in Th1 cytokine production and augmented antiviral response [38]. Thus, GSH modulation causes immune response phenotype alteration, leading to an important impact in virus elimination (**Figure 2**).

T lymphocyte CD8+ is a cytotoxic T cell. They recognize the antigens through binding between TCR and MHC class I associated with antigen peptide. The control of viral infection is directly linked with efficiency of CD8+ cytotoxic response [37]. The treatment with NAC induced an increase in surface activation molecule CD69 expression on unstimulated CD8+ T lymphocytes obtained from HTLV-1-infected individuals. This result suggested that the increase in CD69 expression on CD8+ lymphocytes from HTLV-1 infected donors was correlated with an augmentation of GSH. Thus, increases in GSH levels could be beneficial to the activation of HTLV-1-specific CD8+ T cell and to the elimination of HTLV-1-infected cells [19].

The first approved antiretroviral drug was zidovudine (AZT), a nucleoside reverse transcriptase inhibitor. The relationship between AZT and GSH has been studied since 1998. Mice treatment with AZT did not exhibit a significant decrease in GSH in total muscle homogenate, but the GSSG concentration increases, leading an increase in GSSG/GSH ratio. Furthermore, AZT treatment induces a skeletal muscle mitochondrial peroxide production [45]. Similar results were observed in monocytic cell lines incubated in the presence of AZT. The AZT treatment induced a significant reduction in GSH levels and destruction of mitochondria [46]. AZT is the antiretroviral drug with the best intracerebral penetration, however this substance virus resistance mutations in periphery and CNS [47]. The effects of AZT in GSH levels in the CNS have been remained unknown. Zang et al. demonstrated that mouse neuron exposure for short term to AZT did not present alteration in mitochondrial DNA levels. However, the results suggested that AZT long-term exposure caused deletion of mitochondrial DNA and neuron death [48]. Furthermore, AZT or the combination AZT plus indinavir (protease inhibitor) induces oxidative stress in human brain microvascular endothelial cells. These cells represent an important model to study BBB. The combination AZT plus indinavir induced an increase in ROS production, disruption in membrane mitochondrial potential, reduction in intracellular GSH levels, augment permeability of endothelial layer, leading cell death [49]. Together these results suggested that this antiretroviral therapy compromises the BBB and

The Role of Glutathione in Viral Diseases of the Central Nervous System

http://dx.doi.org/10.5772/intechopen.76579

73

These findings suggested that the replacement of GSH, reducing the oxidative stress in HIV-1-infected patients, is an interesting therapeutic approach. In some therapeutic strategies, to restore the GSH levels NAC or pro-GSH molecules in combination with HAART have been used. Moreover, the higher levels of GSH improve the antiviral immune response, collaborat-

In this chapter we explore some aspects about neurodegenerative diseases associated with viral infection, GSH, and oxidative stress. Worldwide, many individuals are afflicted by JC, CMV, HTLV-1, and HIV-1 and develop some neurological diseases. However, studies that describe how the oxidative stress is involved in disease development remain insufficient. The oxidative stress in the CNS is associated to many neurodegenerative diseases. ROS, including reactive nitrogen species, are important mediator of brain and spinal cord damage. They are related with inflammation and mitochondrial and proteasomal dysfunction. The vulnerability of the CNS is associated with the higher consumption of oxygen than other tissues. Oxygen is important in ATP generation process, which is responsible for energy support used during normal CNS function. Physiological ROS levels are essential to neuronal functions, such as enhancing synaptic plasticity, long-term potentiation, and memory formation. However, the brain endogenous antioxidant defenses have not been enough to your demand. Moreover, the complexity of the cell composition of this tissue and the elevated oxygen levels corroborate to elevated capacity of the CNS in ROS production. All cellular macromolecules are susceptible to oxidative harm. ROS level elevation activates the detoxification and repair pathways.

lymphocyte count [50].

could be associated with HIV-1 neurological diseases.

**6. Discussion and conclusion**

ing in viral load reduction and in maintaining normal T-CD4+

The neurodegeneration is associated with decontrolled inflammatory responses into the CNS. Inflammatory cytokines induce nitric oxide (NO) and ROS production for innate immune cells and microglial cells. The incubation of microglia cells in the presence of viral protein gp120 was observed to increase in ROS production [36]. Besides, gp120 induces secretion of tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), leading to neuronal cell death, subsequently [40]. The inflammatory microenvironment reduces the glutamate uptake, inducing accumulation of this excitatory amino acid and excitotoxic neurodegeneration. Although, any study has not related the viral infection, GSH intracellular levels, and excitotoxic neurodegeneration, the literature suggested that antioxidant responses can prevent the neuron death directly or indirectly.
