*3.3.3.1. Cytokine dysregulation*

Infection with HIV results in dysregulation of the cytokine profile *in vivo* and *in vitro*. During the course of HIV-1 infection secretion of T-helper 1 (Th1) cytokines, such as interleukin (IL)-2 and antiviral interferon (IFN)-gamma important for intracellular infection is generally decreased, whereas production of T-helper 2 (Th2) cytokines required for extracellular infection such as IL-4, IL-10, proinflammatory cytokines (IL-1, IL-6, IL-8) and tumour necrosis factor (TNF)-alpha, is increased [13, 14, 17]. This altered balance of Th1 and Th2 responses may partially explain the susceptibility of HIV-infected individuals to infection by intracellular microbes. In addition, Th2 cytokines also may inhibit macrophage-mediated killing of microbes [13] and consequently lead to failure of macrophage activation in the killing process of the virus.

Tumour necrosis factor-alfa (TNF)-α, IL-1 and IL-6 which are produced by monocytes and macrophages, play an important role in activation of neutrophils, monocytes and macrophages to initiate bacterial and tumor cell killing, increase adhesion molecule expression on the surface of neutrophils and endothelial cells, stimulate T and B lymphocytes proliferation as well as initiate the production of other proinflammatory cytokines [1, 2]. In addition, these cytokines can cause systemic symptoms such as fever and weight loss as well as influence the production of acute phase protein in the liver [1]. Inflammation is one of the components of innate immune response. Thus, production of appropriate amounts of TNF, IL-1 and IL-6 is important in response to infection [1]. Increased production of these cytokines, particularly TNF-α has been found in acute and inflammatory conditions (e.g., trauma, sepsis, infection, rheumatoid arthritis) [18]. The observed increase in proinflammatory and inflammatory cytokines following cell injury or infection subsequently leads to immune dysfunction.

#### *3.3.3.2. Coagulopathy in HIV patients*

Normal levels of protein S, protein C and antithrombin activities are necessary for coagulation process. In HIV patients, protein S, protein C and antithrombin activities decrease with an increase in plasma D-dimer [19, 20]. Binding of viral and bacterial components to Toll-like receptors (TLRs) stimulate the procoagulant tissue factor to initiate the coagulation cascade. This leads to thrombin activation which then cleaves the fibrinogen to fibrin [21]. Plasmin cleaves the fibrin to produce fibrin degradation products. An increase in monocyte tissue factor expression leads to increase in D-dimer in HIV infection [21]. Decrease protein S, protein C and antithrombin activities as well as increase in plasma D-dimer are the predisposing factors which will increase the risk HIV patients to thrombosis.

#### **3.4. Prognostic markers of HIV infection**

Prognostic markers are important tools for monitoring the HIV disease progression. Proper monitoring of the disease may reduce the morbidity as well as mortality rate. Some markers have been identified for monitoring the HIV disease progression. The markers is classified as immunologic (CD4+ T cells), virologic (RNA viral load), serologic (serum β2microglobulin and neopterin) [22] as well as biomarkers (lipid peroxidation) [23]. Among the markers, CD4+ T cell count and RNA viral load are two most commonly used prognostic markers for clinical progression of HIV infection [24, 25].

#### *3.4.1. Immunologic marker of infection*

The CD4+ T cell count is the most important laboratory indicator of immune function in HIVinfected patients. It is also the strongest predictor of subsequent disease progression and survival according to findings from clinical trials and cohort studies [22, 26].

Measurement of CD4+ T cell count is necessary prior to the initiation of HAART. Since the CD4+ T cell count reflects the status of overall immune function of HIV-infected patients, the measurement is important as a guide for initiation of HAART to HIV patients as well as to start or discontinue the prophylaxis for opportunistic infection (OI). Most of OIs occur in patients with CD4+ T cell counts<200 cells/mm3 [27], however some patients may have OIs at higher CD4+ T cell counts. For patients who are on therapy, adequate response is defined as an increase in CD4+ T cell counts in the range of 50 to 150 cells/mm3 during the first year of HAART. Patients who has faster response will show the response within the first 3 months of treatment and subsequent increase in the range of 50 to 100 cells/mm3 per year until it reaches a steady state [27]. Patients who has undergone the therapy at a low CD4+ T cell counts [28] or at an older age [29] may have a minimal increase in CD4+ T cell counts despite virologic suppression.
