Contribution to characterization of oxidative stress in HIV/AIDS patients
Introduction
Human immunodeficiency virus (HIV) infection is a worldwide problem and HIV/AIDS patients suffer from several opportunistic infections that occur because of poor immune system function. The hallmark of HIV infection is cellular CD4 immunodeficiency. Different agents appear may trigger apoptosis in CD4+ T cell, including viral protein (i.e. gp 120, Tat), inappropriate secretion of inflammatory cytokines by activated macrophages (i.e. tumor necrosis factor alpha (TNF-α) and toxins produced by opportunistic microorganism. Since oxidative stress can also induce apoptosis, it can be hypothesized that such a mechanism could participate in CD4+ T cell apoptosis observed in AIDS. Oxidative stress results from the imbalance between reactive oxygen species (ROS) production and inactivation [1], [2].
Under most circumstances, oxidative stress is deleterious to normal cell functions. An emerging view, however, is that, within certain limits, cellular redox status is a normal physiological variable that may elicit cellular response such as transcriptional activation, proliferation or apoptosis [3]. Exposure to oxidants challenges cellular systems and their responses may create conditions that are favorable for the replication of viruses such as HIV [4], [5].
In HIV-infected patients increased oxidative stress has been implicated in increased HIV transcription through the activation of nuclear factor κB (NF-κB) [6]. NF-κB is bound to factor IκB in the cytoplasm in its active form, but various factors, such as TNF-α and ROS can cause the release of NF-κB from factor IκB, and NF-κB translocates to the nucleus and binds to DNA. Glutathione (GSH) is a major intracellular thiol, which acts as a free radical scavenger and is thought to inhibit activation of NF-κB [7]. NF-κB is involved in the transcription of HIV-1. Thus, ROS may potentially be involved in the pathogenesis of HIV infection through direct effects of cells and through interactions with NF-κB and activation of HIV replication [2].
It has been demonstrated that viral Tat protein liberated by HIV-1-infected cells interferes with calcium homeostasis, activates caspases and induces mitochondrial generation and accumulation of ROS, all being important events in the apoptotic cascade of several cell types. CD4+ T cell subset depletion in HIV/AIDS patients is the most dramatic effect of apoptosis mediated by redox abnormalities and induction of Fas/APO-1/CD95 receptor expression [8], [9], [10], [11], [12]. The proportion of lymphocytes expressing Fas was shown to be elevated in HIV-infected individuals. Generally these studies demonstrated that the proportion of Fas-expressing cells increases with diseases progression, the increased Fas expression was found by some investigators to be in CD4+ lymphocytes and by others in both CD4+ and CD8+ T cells [13], [14], [15], [16], [17]. Although several cellular and humoral markers have been reported to be associated with disease progression, only the viral load, which predicts progression independently of the CD4 count, has came into general use. Additional surrogate markers of progression, that add value to CD4 count, would therefore be useful in the clinical management of individual patients considering the tendency of actual antiretroviral therapy of negative viral load. Increased levels of CD38+/CD8+ cells have also been shown to correlate with a number of other markers of more severe HIV disease, including viral load [18]. The CD38 molecule is a transmembrane glycoprotein expressed at different stages of maturation or differentiation [19], [20]. Increased expression on lymphocytes is associated with cell activation, intracellular calcium mobilization [21], in CD8 cells it has been shown that the CD38+ subpopulation is in the pre-G0–G1 phase suggestive of a preapoptotic state [22].
Some micronutrients play essential roles in maintaining normal immune function and may protects immune effector cells from oxidative stress [23]. For all HIV patients it is particularly important to identify metabolic alterations and deficiencies and determine whether the supplementation will improve clinical outcome. This requires realistic and sustainable healthcare interventions in terms of costs, technology transfer and independence from sophisticated monitoring requirements.
The aim of the present work was to study the status of an extensive array of oxidative stress indices and cell subset markers that would permit examination of the role of stress target which cause damage to biomolecules related with immune markers of progression in HIV/AIDS patients. For this purpose we compared the blood levels of these markers in HIV/AIDS patients to those of healthy aged-matched control.
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Subjects and blood collection
Blood and serum samples from 85 patients infected with HIV and aged 20–47 years were used. Control subjects were 40 sex- and age-matched healthy, HIV-seronegative individuals. Subjects gave informed consent to take part in the study after verbal and written explanation of the methods and risks involved. Study procedures were reviewed and approved by both the Institute “Pedro Kourı́” (Hospital) and the Santiago de Las Vegas (Sanatorium) Committees for Research on Human Subjects. Blood samples
Results
The HIV-seropositive group consisted of 85 individuals with symptomatic or asymptomatic HIV infection (mean CD4+ 13%; range 5–17%). The HIV-seropositive patient group was subdivided in two group: A2B2 and A3B3 (Table 1). Risk factors for HIV infection included homosexual behavior (50%) and heterosexual intercourse (50%). At the time of sampling, six patients (7%) were receiving combination antiretroviral therapy, and 76 (93%) were receiving no antiretroviral therapy. The control group was
Discussion
Human monocyte-derived macrophages are involved in a variety of pathological events in HIV infection the hallmark of which is immunodeficiency with progressive CD4+ T lymphocyte depletion [2]. Our HIV+ patients exhibited the characteristic loss of CD4+ T cells (Table 1). Even if the exact cause of this loss of CD4+ T cells is unknown, the most widely accepted hypothesis is that HIV primes the cell to apoptotic death [34]. When activated, peripheral blood T lymphocytes are induced to express
Acknowledgements
We gratefully acknowledge the support from the Centre of Chemistry Pharmaceutical (Havana, Cuba) and Randox (UK), and the technical assistance of Francisco Ramos, Caridad Luzardo and Dayne Horta. This work was funded partially by Project 00408234, Ministry of Science, Technology and the Environment (CITMA), Havana, Cuba.
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