Book Description

Chronic immune activation in HIV infection contributes to immune dysfunction and disease progression. To date, the majority of research has focused on elucidating the role of CD4+ T cell dysfunction in chronic immune activation and inflammation in HIV infection. However, it is becoming increasingly evident that changes in the phenotype and function of antigen presenting cells (APCs) during HIV infection also contribute to chronic immune activation in HIV infection. Therefore, we sought to determine the impact of HIV infection on APC recognition, signaling, inflammatory response to pathogenic and commensal bacteria, and anti-inflammatory receptor expression and the role of these alterations in chronic immune activation and inflammation. We found that HIV infection, whether untreated or treated with HAART, enhances the sensitivity and response of APCs to microbial stimulation by upregulating expression of PRRs, specifically TLR2 and CD36. This upregulation leads to increased p38-MAPK signaling which initiates the transcription of pro-inflammatory cytokines, IL-6, TNFalpha, and IL-12/IL23p40. Thus HIV-infected patients show heightened APC proinflammatory response to both pathogenic and commensal bacteria as evidenced by the enhanced production of inflammatory cytokines. We found that beta-cyclodextrin (2-hydroxypropyl-beta-cyclodextrin) treatment of APCs from HIV-infected patients decreases expression of TLR2 and lowers inflammatory response to microbial stimulation in APCs, further supporting the role of TLR2 in aberrant APC response. Finally, we found HIV impairs immune cell expression and upregulation of CD200R-CD200, an inhibitory receptor-ligand pair that plays an important role in down-modulating inflammatory response. Collectively, our findings demonstrate that chronic immune activation in HIV infection alters APC phenotype and function. This, in turn, causes APCs to produce heightened levels of inflammatory cytokines that contribute to the persistence of inflammation in HIV infection, suggesting the cyclical nature of chronic immune activation and inflammation in HIV infection.