**3. HTLV-1 and HIV-1 infection and GSH active transport**

GSH is related with the transport of endogenous and exogenous molecules to extracellular medium. GSH is a physiological substrate of ABCC1. Multidrug resistance-related protein 1 (ABCC1) transports several compounds in a GSH-dependent manner; its activity could be stimulated by the GSH intracellular levels. The members of the ABCC family are ATPdependent efflux pumps, belonging to the ABC family of transport proteins, and they are also 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 Nrf2 activation and translocation to the nucleus [33].

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

T lymphocytes CD4+ and CD8+ from HAM/TSP asymptomatic and symptomatic individuals 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 these cells more resistant to chemotherapy.

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.** 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+

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**).

TCR and MHC class I associated with antigen peptide. The control of viral infection is directly

increase in surface activation molecule CD69 expression on unstimulated CD8+

is a cytotoxic T cell. They recognize the antigens through binding between

cytotoxic response [37]. The treatment with NAC induced an

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

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T lymphocytes

(**Figure 2**) [38].

lymphocyte secretion of Th1 cytokines.

T lymphocyte CD8+

linked with efficiency of CD8+
