Systemic effects of inflammation on health during chronic HIV infection

Abstract

Combination antiretroviral therapy for HIV infection improves immune function and eliminates the risk of AIDS-related complications but does not restore full health. HIV-infected adults have excess risk of cardiovascular, liver, kidney, bone, and neurologic diseases. Many markers of inflammation are elevated in HIV disease and strongly predictive of the risk of morbidity and mortality. A conceptual model has emerged to explain this syndrome of diseases where HIV-mediated destruction of gut mucosa leads to local and systemic inflammation. Translocated microbial products then pass through the liver, contributing to hepatic damage, impaired microbial clearance, and impaired protein synthesis. Chronic activation of monocytes and altered liver protein synthesis subsequently contribute to a hypercoagulable state. The combined effect of systemic inflammation and excess clotting on tissue function leads to end-organ disease. Multiple therapeutic interventions designed to reverse these pathways are now being tested in the clinic. It is likely that knowledge gained on how inflammation affects health in HIV disease could have implications for our understanding of other chronic inflammatory diseases and the biology of aging.

Figure 1. Pathogenesis of inflammation-associated disease in HIV-infected adults

HIV infection causes damage to lymphoid and mucosa tissues, leading to progressive immunodeficiency, excess levels of pathogens (including HIV) and inflammation, HIV also damages the mucosa of the gut, leading to microbial translocation. HIV and its treatment also affects liver function through a variety of mechanisms. The collective effect of these initial insults is chronic monocyte and macrophage activation and hypercoagulation. These processes lead directly to vascular harm, end-organ tissue damage, and multi-moribidity, all of which theoretically may manifest later in life with onset of a variety of geriatric syndromes.

Figure 2. Impact of HIV on gut mucosa

The healthy gut mucosa is marked by functional tight epithelial junctions and a highly regulated, interrelated complex of dendritic cells, macrophages, neutrophils and T cells. This system generates protective mucus, antimicrobial peptides, and secreted antibodies. Normal gut flora is maintained and systemic exposure to microbes and microbial products limited (top). HIV infection alters most if not all aspects of gut defences, leading to breakdown in tight junctions, loss or dysregulation of resident immune cells, alterations in gut flora, and microbial translocation (bottom).

Figure 3. Impact of HIV on inflammation, coagulation and health

Root causes of inflammation in HIV disease include damage to gut mucosa and lymphoid systems, which cause exposure to microbes and high pathogen burden. Microbial translocation, inflammation, HIV replication and other factors contribute to liver dysfunction, which in turn leads to reduced clearance of microbial products and altered production of critical hepatic proteins. Liver dysfunction and chronic activation of innate immunity leads to a hypercoagulable state. Excess subclinical clotting and inflammation each contribute to end-organ tissue damage, vascular disease and a variety of diseases. The cumulative effect of these pathways in combination with other well-accepted risk factors for biologic and clinical aging is expected to affect health in older age.