Biotypes of HIV-associated neurocognitive disorders based on viral and immune pathogenesis

Abstract

Purpose of review HIV-associated neurocognitive disorders (HAND) continues to be prevalent in people living with HIV despite antiretroviral therapy. However, understanding disease mechanisms and identifying therapeutic avenues has been challenging. One of the challenges is that HAND is a heterogeneous disease and that patients identified with similar impairments phenotypically may have very different underlying disease processes. As the NeuroAIDS field is re-evaluating the approaches used to identify patients with HIV-associated neurological impairments, we propose the subtyping of patients into biotypes based on viral and immune pathogenesis. Recent findingsHere we review the evidence supporting subtyping patients with HIV-associated neurological complications into four biotypes: macrophage-mediated HIV encephalitis, CNS viral escape, T-cell-mediated HIV encephalitis, and HIV protein-associated encephalopathy.

Chronic and delayed neurological manifestations of persistent infections

“…Human immunodeficiency virus (HIV) penetrates the CNS early during acute infection and infects microglia, macrophages, and to a lesser extent astrocytes, which can result in a macrophage-mediated encephalitis [ 18 , 19 ]. Clinically this is associated with a rapidly progressing subacute subcortical dementia [ 20 ] which is treatable with antiretroviral therapies (ART). However, even with adequate ART and suppression of virus both in the periphery and the CNS, HIV can cause CNS disease years after initial infection, collectively known as HIV-associated neurocognitive disorders (HAND).…”

“…This may be due to the relationship between lower CD4+ T-cell nadirs and a larger viral reservoir and more residual viral activity [ 21 ]. This larger and more active viral presence can lead to CSF viral escape and T-cell mediated encephalitis, which presents clinically with headache, tremors, cognitive impairment, confusion, focal neurologic deficits, and seizures [ 20 ]. However, even in the absence of viral replication, expression of viral proteins can lead to CNS disease.…”

“…These proteins are toxic and alter neuronal and glial cell functioning (reviewed in [25][26][27]). Patients present with varying degrees of cognitive and psychomotor impairments that slowly progress over time, a spectrum disorder collectively known as HIV-protein associated encephalopathy [20]. As ART does not impact the production of viral proteins from integrated virus, the development of new therapies to inhibit viral transcription and translation are needed.…”

Historical and current issues in HIV encephalitis, and the role of neuropathology in HIV disease: a pathological perspective

“…A new look at how PLWH develop NCDs, whether or not they are on ART, emphasises how patients with similar clinical phenotypes may have very different underlying disease processes, thus requiring different treatments. The proposition of different ‘biotypes’ of HAND is built on the older neuropathology but its case definitions mainly eschew diagnostic tissue pathology and rely on CSF and blood profiles of immunity, virology, and neuroimaging [ 21 ]. There are four biotypes proposed: Macrophage-mediated HIV encephalitis: essentially the original classic HIVE in ART-untreated patients; CNS viral escape, in ART-treated patients, with a lymphocytic encephalitis, elevated HIV viral load in CSF (viral escape), white matter hyperintensities on neuroimaging, and related to poor CNS ART penetration and ART drug resistance; T-cell mediated encephalitis: associated with immune reconstitution reaction (IRIS) on ART, the target being HIV or opportunistic infection; pathologically there are CD4 + or CD8 + T-cell infiltrates in brain parenchyma (i.e.…”

Dual ankyrinG and subpial autoantibodies in a man with well-controlled HIV infection with steroid-responsive meningoencephalitis: A case report

“…Other causes of neuroinflammation in persons with well-controlled HIV include macrophage-mediated HIV encephalitis and CD8 encephalitis ( 3 )—a hallmark of both of which is CNS HIV escape, in which HIV RNA can be detected in the CSF ( 4 ). Persons living with HIV are also at an increased risk for immune dysregulation ( 5 , 6 ) and autoimmune disorders of the nervous system including acute and chronic inflammatory demyelinating polyneuropathy ( 7 ) (AIDP and CIDP, respectively).…”