The primary objectives of the HIV/AIDS sub-programme are to establish the effects of HIV-1 infection on regional T-lymphocyte colonization and macrophage activation in the gastrointestinal tract, as well as the effects of antiretroviral therapy on reconstitution of various sub-populations of T-lymphocytes, macrophage activation status and privileged viral reservoirs, especially in relation to anatomical site and drug resistance. The role of chronic activation of monocytes/macrophages, especially in the GIT, in driving treatment failure is a priority research initiative.
Exessive immune activation is a major force driving HIV-1 replication and progression to AIDS. In most patients, antiretroviral therapy (ART) results in a sustained reduction in plasma HIV-RNA and a decrease in AIDS-related morbidity and mortality. However, ART does not always lead to a normalization of systemic inflammation. In approximately 20% of patients, the persistence of inflammation during ART is associated with poor CD4+ T cell recovery, suboptimal therapeutic gains and an increased risk of cancer and other non-AIDS-related diseases, especially in patients who begin therapy after their CD4 T cells drop below 200cell/ml. It is our hypothesis that such patients will also have higher levels of residual viral replication and thus, will be more likely to develop drug resistance.
Cell of the monocyte-macrophage lineage play a key role in the initiation and resolution of inflammation. They respond to a wider range of antigenic and microbial stimuli and the outcome of these interactions depends on the differentiation status of the cell. If properly regulated, these responses result in the activation of effector mechanisms and the killing of invading pathogens. However, if excessive, or inappropriate, they can lead to severe immune dysregulation, secondary infection, uncontrolled sepsis and death. Activation of moncyte-macrophages occurs through both Toll-Like Receptor (TLR)-dependent mechanisms.
Recent studies have suggested that HIV-1-induced damage to the intestinal mucosa and sustained microbial translocation during ART may be responsible, at least in part, for the inability of ART to completely suppress immune activation. Interactions between LPS (a marker of microbial translocation) and the CD14/TLR4 complex on mononuclear phagocytes are associated with an increase in the cytokines that drive T-cell activation and activation-induced cell death (AICD) and high levels of LPS correlate with poor CD4 T cell recovery.
For these reasons, we are conducting an extensive investigation of the role of monocyte/macrophage activation in fuelling treatment failure, with special emphasis on the GIT. The over-riding hypothesis of this work is that it will be impossible to maximally suppress/eliminate viral replication and prevent drug resistance, until we have a thorough understanding of the mechanisms controlling HIV-1 transmission and immune pathogenesis in the GIT.