HIV-1 gp120 and morphine induced oxidative stress: role in cell cycle regulation

Abstract

HIV infection and illicit drugs are known to induce oxidative stress and linked with severity of viral replication, disease progression, impaired cell cycle regulation and neurodegeneration. Studies have shown that morphine accelerates HIV infection and disease progression mediated by Reactive oxygen species (ROS). Oxidative stress impact redox balance and ROS production affect cell cycle regulation. However, the role of morphine in HIV associated acceleration of oxidative stress and its link to cell cycle regulation and neurodegeneration has not been elucidated. The aim of present study is to elucidate the mechanism of oxidative stress induced glutathione synthases (GSS), super oxide dismutase (SOD), and glutathione peroxidase (GPx) impact cell cycle regulated protein cyclin-dependent kinase 1, cell division cycle 2 (CDK-1/CDC-2), cyclin B, and cell division cycle 25C (CDC-25C) influencing neuronal dysfunction by morphine co-morbidity with HIV-1 gp120. It was observed that redox imbalance inhibited the GSS, GPx and increased SOD which, subsequently inhibited CDK-1/CDC-2 whereas cyclin B and CDC-25C significantly up regulated in HIV-1 gp120 with morphine compared to either HIV-1 gp120 or morphine treated alone in human microglial cell line. These results suggest that HIV positive morphine users have increased levels of oxidative stress and effect of cell cycle machinery, which may cause the HIV infection and disease progression.

Oxidative Stress during HIV Infection: Mechanisms and Consequences

“…In line with this, drugs such as morphine and amphetamine can per se trigger ROS production and dysregulate the antioxidant defense system, augmenting the pathogenic properties of Gp120 (Figure 2) [79, 123]. This may account for a more severe progression of the disease in the intravenous drug users.…”

“…Several groups reported a decrease in SOD (SOD3 in particular), CAT, and GPx activities in plasma of the HIV-infected individuals [61, 63, 75, 122]. The data on Gp120 is controversial; it was shown to either enhance [123] or not affect the expression of sod2 gene [82]. However, the individual Tat protein causes an opposite effect: it suppresses the expression of MnSOD through inhibition of binding of Sp1 and Sp3 transcription factors to sod2 gene promoter and binding to its mRNA [124, 125].…”

“…Both downregulate the expression of glutathione synthase (GSS), glutathione reductase (GR), and GPx, leading to a decrease in the total glutathione content and an increase of the GSSG/GSH ratio [83, 84, 123, 126]. Gp120 also shows a strong ROS-dependent inhibitory effect on the expression of glutamine synthase (GS) [127].…”

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

“…Furthermore, Gp120 increases the induction of ROS by neurons and glial cells by various mechanisms. It decreases the expression of various antioxidant enzymes such as SOD2, glutathione peroxidase, and glutathione synthase in neurons and glial cells [139, 140]. It increases the production of ROS in microglia by increasing the expression of voltage-gated potassium channels, which is reversed by pretreatment with curcumin [141,142].…”

HIV gp120 in the Lungs of Antiretroviral Therapy–treated Individuals Impairs Alveolar Macrophage Responses to Pneumococci

“…In COPD there is not only reduced caspase 3/7 activation but also an altered balance between mROS generation and superoxide dismutase (SOD) 2 expression, which suggests increased ability to neutralize baseline mROS. Recent observations show gp120 also upregulates SOD in microglia (29). It is noteworthy that, like COPD, HIV-1 has been associated with chronic increases in oxidative stress in mononuclear phagocytes, despite antiretroviral therapy (30,31), and adaptions to this in both conditions are predicted to impair the capacity to generate a microbicidal response.…”