AIDS

Chapter 2

Downloaded by STANFORD UNIV on June 15, 2013 | http://pubs.acs.org Publication Date (Web): November 17, 2011 | doi: 10.1021/bk-2011-1083.ch002

Pathophysiological Implications of Altered Redox Balance in HIV/AIDS Infection: Diagnosis and Counteract Interventions L. Gil del Valle*, Ph.D. Clinical Pharmacology Lab, Institute of Tropical Medicine Pedro Kourí, Autopista Novia del Mediodía, km 6 ½ , La Lisa, La Habana, Cuba *E-mail: [email protected]

Oxidative stress (OS) has been detected in many tissues of HIV infected individuals using different biochemical’s markers and diverse bio-techniques. The OS characterization has been made in populations from several countries and different risk groups using case and control, cross sectional and interventions studies. During the infection course the imbalance in redox status are related to oxidative molecular damage, viral replication, micronutrient deficiency and inflammatory chronic response, all of them implicated in cellular apoptosis and decreased immune proliferation. Several OS counteract actions are developed including exogenous supply of antioxidants, both as modification in micronutrient intake from diet or extract from natural origin and antioxidant vitamins. Physical exercise with a controlled program and follow- up is used too. The general strategy and combination of these interventions represent an important complementary deal for HIV infection treatment in the era of high active antiretroviral therapy. This last are involved in others associated malignancies related to mitochondrial toxicity, that in turn increase OS.

© 2011 American Chemical Society In Oxidative Stress: Diagnostics, Prevention, and Therapy; Andreescu, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.


Introduction Human Immunodeficiency Virus (HIV) infection is a worldwide increasing pandemic. HIV/AIDS patients suffer from several opportunistic infections and other malignancies that occur in relation of poor immune system function (1). Oxidative stress (OS), as results from the imbalance between reactive oxygen species (ROS) production and the inactivation and resolution of oxidative biomolecule damage (2, 3), have been recognized since beginning of HIV infection reports (4, 5). Under most circumstances, OS 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 (6). Exposure to oxidants challenges cellular systems and their responses may create conditions that are favourable for the replication of HIV through nuclear factor κB (NF-κB) mechanism (7). The hallmark of HIV infection is cellular T CD4+ depletion and dysfunction. 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 microorganisms (8–10). Since OS can also induce apoptosis, it can be hypothesized that such a mechanism could participate in CD4+ T cell and neuronal apoptosis observed in AIDS (11, 12). Micronutrients deficiency is another aspect that contributes to OS in HIV evolution (13, 14). The nutritional requirements index of the HIV infected patients are in accordance with the chronically activation of immune system. All these aspects are involved in a vicious autocatalytic cycle which underline in recurrence of malignancies, weight loss and toxicities because of exacerbate associated metabolism (15, 16).

HIV Biology and Tropism HIV constitutes the third retrovirus discovered. It is an enveloped animal RNA virus with two positive strands. It is classified as lentivirus belonging to retroviridae family. The virus genome is formed by more than 9200 base pairs longer; including the long terminal repeat (LTR) at both ends and has three major coding regions. These regions encode core (gag), polymerase (pol), envelope (env) and several “accessory” gene products (Nef, Tat, Vpr, Vif, Rev and Vpu). The accessory genes are expressed early in cell cycle infection so they modulate activation of late transcription. When Tat and Rev reach the threshold a change in frameshift reading occurs in order to express HIV constitutive genes. The generic RNA virus, codes for antigenic envelope glycoproteins, interior structural and non-structural proteins, and polymerases used for virion replication (17). HIV infects cells utilizing CD4 as receptor. CD4 interact with gp120 HIV envelope glicoprotein and also needs certain chemokine receptors as coreceptors (CXR4 and CCR5). This last interact with gp41 transmembrane protein. The interactions between receptor and coreceptors guarantees HIV entry and infection. CD4+ T lymphocytes and macrophages are major target for HIV infection (18). 40 In Oxidative Stress: Diagnostics, Prevention, and Therapy; Andreescu, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.


Cellular tropism can be defined in terms of HIV possibility to grow in cells (examined in vitro). HIV isolates that grow productively in macrophages and but less efficiently in T cell lines is called M tropic. HIV which can grow in T cells but not in macrophages is classified as T tropic. HIV isolates that can grow in both T cells and macrophages are classified as dual tropic. Most of M tropic viruses utilize the CCR5 chemokine receptor and most T tropic strains utilize CXR4 receptor. The V3 region in gp120 is the major co-determinant for coreceptor use (19, 20). HIV infection is multifactor depending on biological and behavioural features of virus and host. Transmission occurs by sexual relations, breast feeding, contaminated blood products, contaminated intravenous injectors and through maternal-fetal circulation (vertical way). HIV is delivered to lymphoid tissues, spleen, lung, lives and the central nervous system (CNS). Persistence of parasitic viruses requires infecting host cells, pirating host resources, outmanoeuvring host immune components and replicating (20, 21).

Progression and Surrogate Marker of Disease Evolution and Management Although several cellular, humoral markers and viral load, which predicts progression independently of the absolute T CD4+ lymphocyte count, are reported to be associated with disease progression, only the CD4 count and viral load have come into general use because of precision and specificity diagnostic technique (22). In healthy adults, the T CD4+ lymphocyte counting is between 800 to 1200 units per mm3 of blood. The T CD4+ lymphocytopenia and the increase of the viral load are parameters which determine the progression of the HIV infection which reaches its peak at the final stage called AIDS, which is the most advanced phase of the virus infection. 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 anti-retroviral therapy to diminish viral load count. Highly active antiretroviral therapy (HAART) resistance and HIV mutation are affecting the prognostic value of these indexes (22, 23). Also they are used during antiviral and alternative/complementary therapy evaluation (24). Additional surrogate markers of progression, that add value to both, would therefore be useful in the clinical management of individual patients considering the tendency of actual anti-retroviral therapy of negative viral load. The study and refinement of surrogate markers of HIV disease progression continues to be an important area of research particularly with the advent of therapies that claim to halt or slow the process of immunological decline. Additional markers of progression would therefore be useful i.e. in the decision of when to start or change therapies. Increased levels of CD38+/CD8+ cells have also been shown to correlate with a number of other markers of disease progression, including viral load (24). The CD38 molecule is a transmembrane glycoprotein expressed at different stages of maturation or differentiation (25). Increased expression on lymphocytes is associated with cell activation, intracellular calcium mobilization (26). In CD8 cells it has been shown that the CD38+ subpopulation is in the pre-G0-G1 phase 41 In Oxidative Stress: Diagnostics, Prevention, and Therapy; Andreescu, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.


suggestive of a preapoptotic state (27). CD38+/CD8+ levels were increased with severity of HIV infection (24). Human monocyte-derived macrophages are involved in a variety of pathological events during HIV infection. Even if the exact cause of the loss of CD4+ T cells is unknown, the most widely accepted hypothesis is that HIV primes the cell to apoptotic death (28, 29). When activated, peripheral blood T lymphocytes are induced to express Fas/APO-1/CD95 receptors that mediate apoptosis when binding to Fas ligand (28). A correlation between Fas expressing CD4+ cells and CD4+ T cells count in blood was observed in previous report and relationship with redox status, in agreement with the increase of Fas/CD95 found in HIV+ patients (29, 30).

HIV Infection and Redox Regulation: Relation to Viral Replication and Apoptosis Altered Redox Indexes during HIV Infection HIV infections cause a chronic inflammation as shown by high plasma levels of inflammatory cytokines and increased ROS production in seropositive individuals (31–33). Of the mechanisms contributing to the HIV progression, OS, induced by the increased production of ROS, may play a critical role in the stimulation of HIV replication, the development of immunodeficiency and the degenerative evolution of individuals (21). ROS generated by endogenous manner is, in certain boundaries, essential for maintain homeostasis (2). ROS also acts as specific signalling molecules to trigger the activation of specific signalling pathways, transmitting the effect of ROS. At low levels cellular function are regulated by a proliferative response whereas at high levels certain pathway module the cellular strategies for detoxification and thus, are essentials for survival of cell and organism. OS had in turn two main consequences: activation of specific signal transduction pathway and damage to cellular components, both of which impact on physiology and the development of diseases (6, 34, 35). Many of these effects involve activation of specific transcription factors that control the expression of a range of target genes. This encodes protein/enzymes to mediate biological response to OS. Engagement of HIV envelope with T cell receptor meanly CD4 generate signals that lead to an increase in free intracellular calcium, which mediate protein kinase (PK) phosphorilation and activation of NADPH oxidase (35). In this aspect NADPH oxidase enzyme in phagocytic cell (NOX2, gp 91 phox) is critical in host defence against pathogens (2, 6). This enzyme contribute to an excessive ROS production which may be related to an increased activation of polymorphonuclear leukocytes during infections or influenced by the prooxidant effect of tumor necrosis factor-alpha (TNF-α) produced by activated macrophages during the course of HIV infection (36) The OS was shown to be related to the constitutive production of H2O2 by neutrophils at all stages of the disease, even in the early stages when the number of CD4+ T cells is still high (36). 42 In Oxidative Stress: Diagnostics, Prevention, and Therapy; Andreescu, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.


To establish the implication of oxidative damage it is essential to be able to measure it accurately and in accordance with progression recognized marker of disease. Different approaches are used, sometimes measuring the levels of the damaged done by ROS and evaluating antioxidant total defences or not are taken as evidences of OS (37, 38). In Table I are summarised studies that show oxidative stressed HIV-infected populations and having significantly lower antioxidant concentrations than non HIV individuals (33, 39–47). In the literature disturbs in the metabolism of glutathione (GSH), thioredoxin (TRX), ascorbic acid, tocopherol and selenium (Se), seric and tissue antioxidant diminished concentrations are reported. Increased peroxides (PO), isoprostanes (isoP), malondyaldehyde (MDA) and carbonyl (CO) concentrations and altered glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) activity have been reported. In addition, altered levels were found in both pediatrics and adults HIV patients. These findings could be explained in part by several mechanisms such as: 1chronic inflammatory activation of immune system, 2-low intake of antioxidant or their precursors from diet in relation to requirements, 3-malabsorption, 4enhanced cysteine metabolism in peripheral tissues, 5-down regulation synthesis of antioxidant enzymes by viral protein as Tat and, 6-virally encoded regulatory proteins. All influences on consequent loss of sulphur-group that may account for glutathione and antioxidant deficiency during HIV infection. Abnormally high levels of ROS as a consequence of chronic immune system activation by HIV infections could lead to a decline of antioxidant defence molecules and accumulative damage of cellular components generating augmented lipid peroxidation products, oxidized proteins and altered DNA sequences (34). Almost redox implicated enzymes and molecules are physiologically endogenous generated and are involved in detoxification and general metabolism. As a consequence of antioxidant depletion the detoxification capacity of reactive metabolites is reduced and this is probably connected to the peroxides high levels detected and drug side effects in HIV+ patients. Considering previously data OS has a dominant pathogenic action in the HIV infection (34). These characteristics favours the progression of the infection with increase of viral replication, carcinogenesis, immune dysfunction, increase in the T cells and neuronal apoptosis, and disturbed patterns in cytokine and hormone production (2, 33). Thus, the clinic significance of the OS related with the HIV is reflected by the strong association between decrease of survival of these individuals and increase of oxidative damage indexes in the plasma and the CD4+ lymphocytes. Other experiments suggesting that lipid peroxidation is much more important in the asymptomatic stage rather than in AIDS. An explanation for this may relate to the depletion of neutrophils which occurs in the late disease stages and which may be influenced by the treatments used by patients too, so increased damage indexes values may be a consequence of the multifactorial nature of the redox system (21, 23). Peroxides serve as a source for hydroxyl or peroxyl reactive radicals who can interact with cellular components inducing cell damage potentially leading to cell death (2, 6). The increase of PO observed in HIV+ patients emphasizes the higher OS, which occurs during HIV infection. It should also be noted that 43 In Oxidative Stress: Diagnostics, Prevention, and Therapy; Andreescu, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.


peroxides and aldehydes generated are not only passive markers of OS, but also cytotoxic products (38). It is thus important to evaluate the role to these oxidative products in lymphocyte death. Nuclear DNA fragmentation is a biochemical hallmark of apoptosis (2, 3) and its increase in HIV+ patients. The pathology of ROS is related to oxidation of nucleic acids and chromosomes break. Limited chromosomal damage can be repaired whereas extensive DNA damage promotes apoptosis (8).

Table I. Evidences of biomolecule oxidative damage and antioxidant deficiency in HIV/aids patients PLACE

NI

EVALUATION CRITERIA *

REFERENCES

Grenoble (France)

43

P Gluthatione , Malondialdehyde , Total peroxides

Favier et al. (1994)

Buenos Aires (Argentina)

20

P Gluthatione, Total antioxidant capacity, E Superoxide dismutase

Repetto et al. (1996)

Bonn (Germany)

102

E Gluthatione, S Gluthatione and Selenium

Look et al. (1997)

Stanford (USA)

204

P Gluthatione

Herzenberg et al. (1997)

Toronto (Canada)

29

L Gluthatione and Cistein

Walmsley et al. (1998)

Toronto (Canada)

49

P Total peroxides , EA Ethane

Allard et al. (1998)

La Habana (Cuba)

85 (Adults) 11 (Child)

P Gluthatione peroxidase (-), E superoxido dismutase (-), P Malondialdehyde (+), P hidroperoxide (+) P Total Antioxidant capacity (-), P Gluthatione (-) L percent of DNA fragmentacion (+)

Gil et al. (2003) Gil et al. (2002)

India

50

S Total antioxidant capacity (-), Malondialdehyde (+), Superoxide dismutase (-), vitamin E and C (-)

Suresh et al. (2009)

Italy

26

P hidroperoxide (+), P Total Antioxidant capacity (-), P thiol group (-)

Coaccioli et al. (2010)

Legend NI: Number of individuals. *Statistical analysis with significant difference respect control group (p

AIDS

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