**2. Physiological and biochemical mechanisms of the role of oxidative stress in HIV/AIDS & TB disease complications**

After initial infection of the human host, the pace of immunodeficiency development, susceptibility to infection and malignancies become manifest and are generally associated with the rate of CD4+ decline (Enger *et al.*, 1996). The rate of CD4+ decline varies considerably from person to person and is not constant throughout all the stages of HIV infection. Though the virological and immunological process that take place during the period of rapid fall in the number of CD4+ T-cells are poorly understood, Koot *et al.* (1996) reported that acceleration of the decline of CD4+ T-cells heralds the progression of the disease that is associated with the increasing rate of HIV-1 replication *in vivo* and declining cell-mediated immune response. Studies have shown that the host immunological alterations due to HIV infection result in progressive development of opportunistic infections and malignancy and is chiefly mediated /induced by deregulation of a cytokine profile production of ROS which also plays a role in the viral replication. *In vitro* studies have shown activation of viral replication by induction of TNFαβ (Allard *et al.,* 1998).

Das and co-workers (1990) stated that excessive production of reactive oxygen species (ROS) such as superoxide anions, OH- radicals and H2O2, may be related to increased activation of PMN leucocytes during infection. This is influenced by the pro-oxidant effect of TNFα produced by the activated macrophages during the course of HIV infection and secretion of pro-inflammatory cytokines IL-1, IL-6, and IL-8 (Kiedzierska and Crowe, 2001). Gil *et al.* (2003) further established the presence of substantial oxidative stress in HIV infection which they attributed to the role of viral proteins that increases ROS intracellularly, therefore increasing the apoptotic index and depleting the CD4+ T-lymphocyte population. The ROS thus produced can attack the double bonds in polyunsaturated fatty acids, inducing lipid peroxidation which may result in more oxidative cellular damage to the membrane lipids, proteins or DNA. Chronic oxidative stress experienced by patients infected by HIV leads to a condition in which there is increased consumption of antioxidants (such as Vitamin C, and E , selenium, and carotenoids) as well as micronutrients/ trace elements (Januga *et al.*, 2002). Stephen (2006), therefore, concluded that persistent chronic inflammation such as found in HIV infection places a long-term strain on antioxidant defenses, impair immune functions, increases the severity of the disease as well as increases the antioxidant requirement by the infected individual.

Progression of HIV to AIDS in developed countries after initial infection is about 10-12 years for adults in the absence of antiviral therapy. However, some individuals manifest full blown AIDS within 5 years of infection whereas others survive long term (>10 years) asymptomatic HIV-1 infection without a significant decline in CD4+ T-cell count. Such delay in the progression of HIV to AIDS may be attributed to either infection with genetically defective HIV-1 variants or effective host antiviral immune response where the individual has active cytotoxic T-cell responses against HIV-1 infected cells (Haase, 1999).

Ever since Robert Koch made the landmark discovery that tuberculosis is caused by the infectious agent *Mycobacterium tuberculosis* (Koch, 1882), it has remained a major global health threat. Although in developed countries the rates of infection has fallen in the past century, the number is now again increasing which results in over 2000 deaths in developed countries annually due to changes in social structures in cities, the HIV epidemic, and failure to improve treatment programs (Frieden *et al.*, 1995). The increased death rate recorded as a result of poverty, poor living conditions and inadequate medical care in

**2. Physiological and biochemical mechanisms of the role of oxidative stress** 

After initial infection of the human host, the pace of immunodeficiency development, susceptibility to infection and malignancies become manifest and are generally associated with the rate of CD4+ decline (Enger *et al.*, 1996). The rate of CD4+ decline varies considerably from person to person and is not constant throughout all the stages of HIV infection. Though the virological and immunological process that take place during the period of rapid fall in the number of CD4+ T-cells are poorly understood, Koot *et al.* (1996) reported that acceleration of the decline of CD4+ T-cells heralds the progression of the disease that is associated with the increasing rate of HIV-1 replication *in vivo* and declining cell-mediated immune response. Studies have shown that the host immunological alterations due to HIV infection result in progressive development of opportunistic infections and malignancy and is chiefly mediated /induced by deregulation of a cytokine profile production of ROS which also plays a role in the viral replication. *In vitro* studies

have shown activation of viral replication by induction of TNFαβ (Allard *et al.,* 1998).

Das and co-workers (1990) stated that excessive production of reactive oxygen species (ROS) such as superoxide anions, OH- radicals and H2O2, may be related to increased activation of PMN leucocytes during infection. This is influenced by the pro-oxidant effect of TNFα produced by the activated macrophages during the course of HIV infection and secretion of pro-inflammatory cytokines IL-1, IL-6, and IL-8 (Kiedzierska and Crowe, 2001). Gil *et al.* (2003) further established the presence of substantial oxidative stress in HIV infection which they attributed to the role of viral proteins that increases ROS intracellularly, therefore increasing the apoptotic index and depleting the CD4+ T-lymphocyte population. The ROS thus produced can attack the double bonds in polyunsaturated fatty acids, inducing lipid peroxidation which may result in more oxidative cellular damage to the membrane lipids, proteins or DNA. Chronic oxidative stress experienced by patients infected by HIV leads to a condition in which there is increased consumption of antioxidants (such as Vitamin C, and E , selenium, and carotenoids) as well as micronutrients/ trace elements (Januga *et al.*, 2002). Stephen (2006), therefore, concluded that persistent chronic inflammation such as found in HIV infection places a long-term strain on antioxidant defenses, impair immune functions, increases the severity of the disease as well as increases the antioxidant

Progression of HIV to AIDS in developed countries after initial infection is about 10-12 years for adults in the absence of antiviral therapy. However, some individuals manifest full blown AIDS within 5 years of infection whereas others survive long term (>10 years) asymptomatic HIV-1 infection without a significant decline in CD4+ T-cell count. Such delay in the progression of HIV to AIDS may be attributed to either infection with genetically defective HIV-1 variants or effective host antiviral immune response where the individual

Ever since Robert Koch made the landmark discovery that tuberculosis is caused by the infectious agent *Mycobacterium tuberculosis* (Koch, 1882), it has remained a major global health threat. Although in developed countries the rates of infection has fallen in the past century, the number is now again increasing which results in over 2000 deaths in developed countries annually due to changes in social structures in cities, the HIV epidemic, and failure to improve treatment programs (Frieden *et al.*, 1995). The increased death rate recorded as a result of poverty, poor living conditions and inadequate medical care in

has active cytotoxic T-cell responses against HIV-1 infected cells (Haase, 1999).

**in HIV/AIDS & TB disease complications** 

requirement by the infected individual.

developing/Third World countries is further compounded by the emergence of multi-drug resistance where antibiotics are either of inferior quality, or are not used for a sufficient period of time to control the disease (O'Brien, 2001).

The recent increase in reported pulmonary tuberculosis (PTB) cases globally can be attributed to the increased susceptibility to opportunistic infections in HIV-infected persons. The highest prevalence of cases is reported to be in Asia (China, India, Indonesia, Bangladesh and Pakistan) and Africa with over 90% of global TB infections and deaths annually. TB cases occur predominantly in the economically productive 15-49 year age group (Dye *et al.*, 1999). Like HIV infection, TB also has a long latency period with symptomatic presentation occurring from 3 months to decades after establishment of the infection (Jagirdar and Zagzag, 1996).

TB is caused by an obligate pathogen that does not replicate outside its host environment (Mathema *et al.*, 2006) and is spread by aerosolization of droplets bearing *M. tuberculosis* particles released from the lung or larynx during coughing, sneezing, or talking in poorly ventilated areas. The particles of 1-5 µm in diameter, are inhaled and phagocytosed by resident alveolar macrophages. A vigorous immune response involving cytokines and a large number of chemokines ensues (Roach *et al.*, 2002). Protective immunity is characterized by granuloma formation that consists of primarily activated *M. tuberculosis* infected macrophages and T-cells. Medlar (1955), noted tissue necrosis and cavitations in over 10% of presumed immuno-competent patients and postulated that this was due to noncontainment of continual bacterial replication (doubling time of 25-32 hours) that resulted in disease symptoms and its associated pathology. This response presumably initially limits infection to the primary site of invasion (the lung parenchyma and local draining lymph nodes known as the Ghon complex) in the majority of immuno-competent individuals (Bloom and Murray, 1992,).

Increased reactive oxygen species (ROS) has been reported in patients with TB. Excessive endogenously produced ROS in activated phagocytes of TB patients that escape to its surroundings can damage tissue or cellular DNA as well as impair immune function (Madebo *et al.*, 2003). It has been shown that the bactericidal potency of the myeloperoxidase-H2O2 halide system of neutrophilic granules demonstrates the bactericidal activities of the phagocytes that invariably produce increased ROS and reactive nitrogen intermediates (RNI) during phagocytic respiratory burst. Lower antioxidant potential as shown by a significant reduction of enzymatic antioxidants (superoxide dismutase, catalase) and non-enzymatic antioxidants (glutathione) as well as high malondialdehyde (MDA) concentrations suggest increases in the generation of ROS due to lipid peroxidation (Reddy *et al*., 2004).

Di Massio and co-workers (1991), reported significantly reduced vitamin C and αtocopherol levels in TB patients. These are integral components of antioxidants, which, when present in sufficient quantity, may act synergistically to protect cells from oxidative stress induced damage in TB patients. Several factors such as inadequate nutrients, malnutrition, nutrient malabsorption, low food intake, inadequate nutrient release from the liver, acute infections including other than HIV, may be the cause of low or impaired antioxidant capacity in TB patients (Das *et al.*, 1990).

Presentation of disease is variable as regards the pathology as well as infections in a variety of tissues such as the meninges, lymph nodes, and tissue of the spine, where response to antibiotic medication/treatment to clear the bacilli from tissues, partial reversal of the granulomatous process and subsequent clearance from the sputum may be found in clinical cases (Jargirdar and Zagzag, 1996). The progression and nature of disease may be affected by factors such as conditions that negatively impact on the host immune system (for example, poorly controlled diabetes mellitus, renal failure, chemotherapy, malnutrition or intrinsic host susceptibility (Madebo *et al*., 2003). Host susceptibility has been known to affect endogenous re-activation and exogenous re-infection by the bacilli.
