Immune privilege and HIV‐1 persistence in the CNS

Abstract

Human immunodeficiency virus-1 (HIV-1) neuroinvasion occurs early (during period of initial viremia), leading to infection of a limited amount of susceptible cells with low CD4 expression. Protective cellular and humoral immunity eliminate and suppress viral replication relatively quickly due to peripheral immune responses and the low level of initial central nervous system (CNS) infection. Upregulation of the brain protective mechanisms against lymphocyte entry and survival (related to immune privilege) helps reduce viral load in the brain. The local immune compartment dictates local viral evolution as well as selection of cytotoxic lymphocytes and immunoglobulin G specificity. Such status can be sustained until peripheral immune anti-viral responses fail. Activation of microglia and astrocytes, due to local or peripheral triggers, increases chemokine production, enhances traffic of infected cells into the CNS, upregulates viral replication in resident brain macrophages, and significantly augments the spread of viral species. The combination of these factors leads to the development of HIV-1 encephalitis-associated neurocognitive decline and patient death. Understanding the immune-privileged state created by virus, the brain microenvironment, and the ability to enhance anti-viral immunity offer new therapeutic strategies for treatment of HIV-1 CNS infection.

Phosphorylation of Claudin-5 and Occludin by Rho Kinase in Brain Endothelial Cells

“…38 Our previous results pointed to RhoK as a potential kinase of TJ proteins, activation of which might be the molecular mechanism mediating BBB dysfunction in neuroinflammation. 20 This study demonstrated that RhoK indeed phosphorylated cytoplasmic domains in CLD5 and OCC at specific sites.…”

Enhancement of Human Immunodeficiency Virus (HIV)-Specific CD8+T Cells in Cerebrospinal Fluid Compared to Those in Blood among Antiretroviral Therapy-Naïve HIV-Positive Subjects

“…These include tight junctions and low levels of adhesion molecule expression by capillary endothelial cells; neuronal expression of CD200, which reduces microglial cell activation; local production of neurotrophins; and transforming growth factor ␤ secretion by astrocytes and meningeal cells (31). In addition, the brain is a potential anatomic reservoir for HIV-1 replication (24,63). While inflammatory and innate immune mechanisms that involve trafficking of monocyte/macrophages are central to the pathogenesis of HIV-associated dementia (28,(84)(85)(86), viral replication also plays a major role, with viral proteins gp120 (4,5,20,34) and tat (12,49,57,60) being directly neurotoxic.…”

The Role of Host Genetics in the Susceptibility for HIV-associated Neurocognitive Disorders

“…HIV enters the central nervous system (CNS) soon after initial infection, during the initial period of systemic viremia (Palmer et al 1994;Persidsky and Poluektova 2006;Resnick et al 1985). The predominant mechanism of entry is via macrophages/monocytes (Gendelman et al 1989).…”

“…However, the brain's own defenses, including an influx of CD8+ cells, typically restrict productive HIV infection until a second wave of infected monocytes crosses the blood-brain barrier (Persidsky and Poluektova 2006). This second wave typically occurs in advanced disease and may be triggered by advanced immunosuppression outside the CNS, as marked by a decline in CD4+ cells and breakdown in the ability of the immune system to control viral replication, or by an increase in chemoattractant substances and adhesion factors in the brain (Maslin et al 2005).…”

“…Rather, these processes result from at least two sources. The first is the direct effects of neurotoxic viral proteins such as gp120, gp41, nef, and tat, which are secreted by productively infected host cells (Persidsky and Poluektova 2006). Some of these proteins enable the virions to bind to chemokine receptors on neurons, likely setting off a chain of events within the neurons that ultimately leads to cell dysfunction and/or death.…”