Chronic inflammation mediates brain injury in HIV infection: relevance for cure strategies

Abstract

Purpose of review: Chronic inflammation is a major component of HIV infection, the effects of which can be devastating in the central nervous system (CNS). Protecting the brain is, therefore, critical as efforts proceed to cure HIV infection by reactivating latent viral reservoirs and driving immune responses. We review the clinical presentation and pathology findings of inflammatory processes in the CNS in patients managed with ART and the drivers of these processes.

Recent findings: Chronic inflammation is associated with increased mortality and morbidity and HIV infection increases the risk for chronic diseases, especially cognitive impairment. Latent viral reservoirs, including microglia and tissue macrophages, contribute to inflammation in the CNS. Inflammation is generated and maintained through residual viral replication, dysregulation of infected cells, continuously produced viral proteins and positive feedback loops of chronic inflammation. Novel therapeutics and lifestyle changes may help to protect the CNS from immune-mediated damage.

Summary: As therapies are developed to cure HIV, it is important to protect the CNS from additional immune-mediated damage. Adjunctive therapies to restore glial function, reduce neuroinflammation and systemic inflammation, and inhibit expression of viral proteins are needed.

Figure 1.. The immunopathology of HIV CNS disease.

The immune response during HIV infection can damage the CNS through direct and indirect mechanisms. Shortly after HIV infection, the virus enters the CNS and infects resident cells, inducing immune responses within this compartment that result in edema and bystander tissue damage. HIV infection is also associated with a lymphocytic meningitis, often occurring within weeks or months of initial infection (132). Encephalitis, primarily driven by CD8+ T cells can also occur in the absence of opportunistic infections (OIs) and is typically due to immune reconstitution inflammatory syndrome (IRIS). IRIS phenomena unrelated to OIs are relatively rare, but is the best direct example of a harmful effect of inflammation on neurological function (133). The immune system can also damage the CNS through indirect mechanisms. The best studied neurological complication associated with chronic inflammation is HAND. However, chronic inflammation within the context of HIV infection also contributes to the development of cardiovascular disease, a major contributor to CNS pathology in the era of ART, and neurodegenerative diseases.