Neuroimmunology of CNS HIV Infection: A Narrative Review

Abstract

This short review provides an overview of the interactions of human immunodeficiency virus type 1 (HIV), immune and inflammatory reactions, and CNS injury over the course of infection. Systemic infection is the overall driver of disease and serves as the "platform" for eventual CNS injury, setting the level of immune dysfunction and providing both the HIV seeding and immune-inflammatory responses to the CNS. These systemic processes determine the timing of and vulnerability to HIV-related neuronal injury which occurs in a separate "compartment" with features that parallel their systemic counterparts but also evolve independently. Direct CNS HIV infection, along with opportunistic infections, can have profound neurological consequences for the infected individual. HIV-related CNS morbidities are of worldwide importance but are enhanced by the particular epidemiological, socioeconomic and environmental factors that heighten the impact of HIV infection in Africa.

Keywords: Africa; HIV; antiretroviral therapy (ART); central nervous system (CNS); cerebrospinal fluid (CSF); inflammation; neuroimmunology.

Figure 1

Interactions of HIV and immune-inflammatory responses in systemic and CNS infection. This simplified schematic outlines the systemic and CNS viral-immune interactions that determine the immunopathogenesis of CNS injury. Systemic interactions (shown in the left part of the figure) establish the foundation for CNS vulnerability that are partly echoed by interactions within the CNS (right part of the figure), though with important differences. (A) HIV targets CD4+ T lymphocytes (and to a lesser degree myeloid cells) in which viral replication both sustains viremia and establishes long-term viral persistence, leading to gradual T-cell loss and immunosuppression and to lifelong infection. Virus-induced T-cell activation, in turn, enhances viral replication and dissemination. (B) Systemic viremia is the source of CNS HIV infection, beginning early in infection, likely mainly via infected T cells that migrate through the blood-brain barrier (BBB, depicted by vertical dotted line). (C) Cells important to the CNS inflammatory response also derive from blood sources; these include CD4+ and CD8+ T cells and macrophages that elaborate cytokines and other signaling and toxic molecules that contribute to the compartmentalized CNS inflammatory response within the CNS and are reflected in CSF. (D) HIV can replicate locally within these migrating CD4+ T cells and macrophages sustaining a genetically independent infection and perhaps establishing a longer-lived second viral reservoir within the CNS. (E) The interaction of the local HIV infection with “imported” inflammatory cells and native CNS cells (including astrocytes and microglia) establish an independent inflammatory milieu that evolves over the course of disease and is particularly heightened in HAD/HIVE. (F) Both HIV gene products and (G) host inflammatory reactions likely contribute to ‘indirect’ CNS injury. (H) inflammatory reactions can disrupt the blood-brain barrier, further exacerbating this injury. (I) CNS OIs may involve a similar pathway, first with loss of systemic immune surveillance allowing entry or activation of pathogens that then invade the CNS and cause neurological disease by direct injury or through a local inflammatory response. (J) ART reverses or mitigates all of these processes. By suppressing HIV replication, treatment fosters a variable degree of CD4+ T cells restoration and partial reversal of these pathological processes. Abrupt restoration of immunity may lead to robust local inflammation and the immune restoration inflammatory response (IRIS) with exacerbation of neurological symptoms and signs. The blood-brain barrier variably impedes CNS concentrations of certain drug components of ART, delaying or reducing local antiviral effects and, in rare cases, contributing to the development of neurosymptomatic CSF escape despite systemic viral suppression.