**5. Effects of antiviral therapy in GSH levels in the CNS**

The strategy used to treat children with symptomatic CNS congenital CMV infection and immunosuppressed individuals CMV-infected is based on doses of ganciclovir. This is an acyclic deoxyguanosine nucleoside analogue [41]. In vivo *s*tudies using mice model infected with CMV demonstrated that the treatment with ganciclovir reduced a viral load and TNFα levels. Moreover, the results suggested that antiviral therapy suppressed the oxidative damage by downregulation of malondialdehyde and upregulation of GSH levels in mice serum [42]. Unfortunately, the role of ganciclovir in CNS oxidative damage related with CMV infection remains unknown.

No antiviral treatment intervention exists for HTLV-1 infection. The HAM/TSP treatment is limited to symptomatic therapy. Usually, symptomatic patients are treated with corticosteroid pulse therapy. During last decades the antiviral therapy against HIV was improved, resulting in a significant reduction AIDS-related mortality and increasing HIV-infected patient survival. The *h*ighly *a*ctive *a*ntiretroviral *t*herapy (HAART) is started with the combination of two nucleoside analogue transcriptase reverse inhibitors and one non-analogue nucleoside transcriptase reverse inhibitor or protease inhibitor plus ritonavir-boosted. The analysis of T CD4+ lymphocytes obtained from the peripheral blood of HIV-1-infected patients showed an increase in GSH levels and decrease in GSSG levels during HAART at 1 year. In this study the patients received one protease inhibitor (indinavir or ritonavir) in combination with two nucleoside analogs (lamivudine plus zidovudine or plus stavudine), suggesting that the HAART ameliorates the oxidative alterations related with HIV-1 infection [43]. However, the effects of HAART on GSH levels may be different in other cell types. Human aortic endothelial cells pre-exposed to HAART produced higher levels of ROS than untreated cells after phorbol myristate acetate stimulation. After the HAART treatment, T-lymphocyte cell adhesion on human aortic endothelial cell monolayer increases significantly. However, the addition of NAC or GSH induced the inhibition of these effects, suggesting that the modulation of antioxidant levels activated the endothelium [44].

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 could be associated with HIV-1 neurological diseases.

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, collaborating in viral load reduction and in maintaining normal T-CD4+ lymphocyte count [50].
