CNS inflammation and macrophage/microglial biology associated with HIV-1 infection

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) can result in neurological dysfunction with devastating consequences in a significant proportion of individuals with acquired immune deficiency syndrome. HIV-1 does not infect neurons directly but induces damage indirectly through the accumulation of activated macrophage/microglia (M/M) cells, some of which are infected, that release neurotoxic mediators including both cellular activation products and viral proteins. One mechanism for the accumulation of activated M/M involves the development in infected individuals of an activated peripheral blood monocyte population that traffics through the blood-brain barrier, a process that also serves to carry virus into CNS and establish local infection. A second mechanism involves the release by infected and activated M/M in the CNS of chemotactic mediators that recruit additional monocytes from the periphery. These activated M/M, some of which are infected, release a number of cytokines and small molecule mediators as well as viral proteins that act on bystander cells and in turn activate them, thus amplifying the cascade. These viral proteins and cellular products have neurotoxic properties as well, both directly and through induction of astrocyte dysfunction, which ultimately lead to neuronal injury and death. In patients effectively treated with antiretroviral therapy, frank dementia is now uncommon and has been replaced by milder forms of neurocognitive impairment, with less frequent and more focal neuropathology. This review summarizes key findings that support the critical role and mechanisms of monocyte/macrophage activation and inflammation as a major component for HIV-1 encephalitis or HIV-1 associated dementia.

Fig. 1. Model of monocyte / macrophage involvement in CNS inflammation in HIV-1 neuropathogenesis

In the periphery, chronic immune activation develops as a result of anti-HIV-1 immune responses, elevated levels of LPS due to microbial translocation from the gut, and viral proteins such as gp120 and Tat. Immune activation is believed to drive systemic immunopathogenesis but also leads to an expanded subset of activated monocytes (characterized by CD16 and CD163 expression), some of which are also infected. These monocytes have enhanced migratory capacity and traffic through the blood brain barrier (BBB), whose integrity is comprised by viral proteins, pro-inflammatory mediators and LPS (“push” mechanism). In the CNS these cells differentiate into macrophages and release infectious virus that infects other cells through the CD4/CCR5 receptor complex. They also release viral proteins (such as gp120, which can activate bystander cells through CD4/CCR5, and Tat), cytokines and chemokines that activate bystander macrophages and microglia to perpetuate the M/M inflammation as well as activating astrocytes. Chemokines such as MCP-1 and SDF-1α are released, which further recruit monocytes into the CNS (“pull” mechanism). Some of these factors also upregulate adhesion molecules (ICAM-1, VCAM-1) on various cell types including brain microvascular endothelial cells (BMVEC), which further enhances inflammatory cell recruitment. Together these processes lead to accumulation of activated M/M in the brain that correlates with neurological injury. Neuronal injury results from the combined effects of viral proteins with neurotoxic effects released from infected M/M, cytokines that injure neurons released from both infected and noninfected activated cells, and other soluble M/M activation products like quinolinic acid (QA) and platelet activating factor (PAF) that lead to neuronal cell death. Astrocyte dysfunction contributes as well, including dysregulated homeostasis of the excitotoxic neurotransmitter glutamate.