CHAPTER ONE
1. INTRODUCTION
1.2 PATHOGENEISIS
1.2.8 Immune Pathology
1.2.8.1 CD4
+T-cell response
The negative correlation of strong HIV-1 specific CD4+ T helper cell responses and viral load indicates that CD4+ T helper cells may also play an important role in the immune response to HIV-1 (Rosenberg et al, 1997).
Virus-specific CD4+ helper-cells (Th) play an important role in the induction and maintenance of effective CD8+ T-cell function in adults (Altfeld et al, 2001; Wilson 2006 and Kuhn et al, 2001). CD4+ helper-cells also play an important role in early immune response to HIV, but HIV infection leads to the progressive loss of CD4+ T-cells and their function, more specifically CD4+ T-cells have been shown to be preferentially depleted in the gut (Lim et al, 1993) early after infection (Lacabaratz-Porret et al, 2004; Altfeld et al, 2001). Studies in adults have shown that HIV-specific CD4+ T–cell responses may be detected during early infection (Lacabaratz-Porret et al, 2004), but they are lacking during chronic infection, except in cases of long-term non-progressors (Lacabaratz-Porret et al, 2004 and Jansen et al, 2006).
A study performed on acutely HIV-1 infected adults (Altfeld et al, 2001) has shown that the CTL responses are weak and these findings were consistent with the cross-sectional data from another study (Dalod et al, 1999) where the breadth of responses were less extensively characterized. Individuals who are treated in early HIV-1 infection may benefit from strategies which are aimed at enhancing virus-specific CTL responses, whereas individuals who are treated later in HIV-1 infection may benefit from the strategies aimed at enhancing HIV-1 specific T-helper cell functions so as to broaden the CTL responses which will help combat the viral diversity (Altfeld et al, 2001).
Effective immune control in animal models of chronic viral infections is associated with an adaptive immune response that includes CD4+ and CD8+ T-cell responses (Ramduth et al, 2005). Antiretroviral therapy in chronic HIV-1 infection has resulted in increased CD4+ cell counts but it has not resulted in the restoration of strong or persistent virus-specific CD4+ T- cell proliferative responses (Rosenberg et al, 1997).
1.2.8.2 CD8
+T-cell response
In studies like the murine lymphocytic choriomeningitis virus model, there is indication that maintenance of effective CTLs does require the presence of virus-specific T-helper cells (Matloubian et al, 1994). The inverse association between virus-specific CD4+ cell responses and viral load and the association between strong HIV-1 specific CTL and T-helper cell responses clearly suggest that CD4+ T-cells are required for the maintenance of effective CTL response in HIV-1 infected individuals (Rosenberg et al, 1997; Kalams et al, 1999).
CD8+ T-cells contribute to the partial immune control of HIV-1 in acute, chronic and the long- term non-progressing infection (Borrow et al, 1994 and Koup et al, 1994). The anti-viral effect of these CD8+ T-cells is mediated by effector mechanisms, which include the release of lytic granules and the release of cytokines and chemokines (Harty et al, 2000). The HIV- specific CD8+ T-cells play a major role by suppressing HIV replication. The diversity and specificity of these HIV-specific CD8+ T-cells are important for the efficiency of the immune response as well as control of the virus that bears immune escape mutations (Buseyne et al, 2006).
Data from animal models have shown that the depletion of CD8+ T-cells is associated with an increase in viral load (Matloubian et al, 1994) and the inverse correlation between the HIV- specific CTLs and viral loads was seen in untreated HIV-1 chronic infection (Ogg et al, 1998).
Most HIV-1 infected individuals who have poor control of viremia, progress to AIDS without antiretroviral therapy despite the antiviral activity of the CTLs in control of viremia (Altfeld et al, 2001).
Studies show that there are differences in the CD8+ T-cell repertoire of responses to the whole HIV-1 genome from adult patients during the acute and chronic phase of HIV-1 infection (Goulder et al, 2001 and Alter et al, 2007).
Immunohistochemical studies on mucosal immune cells in the gut of adults have shown that the CD4+ lymphocyte subset is depleted and the CD8+ lymphocyte subset is expanded in
AIDS subjects (Rodgers et al, 1986; Budhraja et al, 1987; Jarry et al, 1990). The increase in mucosal CD8+ lymphocytes appears to parallel the expanded blood CD8+ populations as a result of HIV infection. The importance of CD8+ T-cells in host protection has been increasingly recognized and the loss of CD4+ T-cells in HIV implies an increased role for CD8+ T-cells in host defense (Scott et al, 1991).
The initial HIV-specific CD8+ T-cell response in acute adult HIV-1 infection is of low magnitude and is narrowly directed against a limited number or epitopes. However, these responses broaden during the prolonged antigen stimulation in the chronic phase of the HIV-1 infection (Altfeld et al, 2001; Dalod et al, 1999; Oxenius et al, 2000). Viral replication tends to wane during the later stages of HIV-1 infection, although the HIV-specific CD8+ T-cell responses are generally broader and there is a vigorous immune response in the chronic phase of infection. These findings have suggested that the quality and specificity of the initial CD8+ T-cell responses may be associated with initial control of the viral replication as apposed to the magnitude of the responses (Pantaleo et al, 2004).
Some studies have shown that in chronic HIV-1 infection, the CD8+ T-cell responses are directed against HIV-1 Gag in subjects with low viral loads and slow disease progression (Addo et al, 2003; Gray et al, 1999; Kiepiela et al, 2007). CD8+ T-cells cannot adequately suppress HIV-1 infection by themselves which leads to subsequent impairment of the CD8+ T- cells (Migueles et al, 2002; Lichterfeld et al, 2004). Evidence in studies with animal models and HIV-1 clade B infection in humans indicate that long-term maintenance of effective cytotoxic T lymphocyte activity is dependent on the functionality of the CD4+ T-cells (Kalams et al, 1999; Cao et al, 2003). The preferential targeting of HIV-1 Gag responses indicates the importance of immune containment (Ramduth et al, 2005).