Neuropathogenesis of HIV-1: insights from across the spectrum of acute through long-term treated infection

Abstract

This review outlines the neuropathogenesis of HIV, from initial HIV entry into the central nervous system (CNS) to chronic infection, focusing on key advancements in the last 5 years. Discoveries regarding acute HIV infection reveal timing and mechanisms of early HIV entry and replication in the CNS, early inflammatory responses, and establishment of genetically distinct viral reservoirs in the brain. Recent studies additionally explore how chronic HIV infection is maintained in the CNS, examining how the virus remains in a latent "hidden" state in diverse cells in the brain, and how this leads to sustained pathological inflammatory responses. Despite viral suppression with antiretroviral therapy, HIV can persist and even replicate in the CNS, and associate with ongoing neuropathology including CD8 + T-lymphocyte mediated encephalitis. Crucial investigation to advance our understanding of the immune mechanisms that both control viral infection and lead to pathological consequences in the brain is necessary to develop treatments to optimize long-term neurologic health in people living with HIV.

Keywords: CSF HIV escape; Central nervous system; Cerebrospinal fluid; HIV; HIV reservoir; Neurological infections; Neurovirology.

Figure 1.. Entry of HIV across the blood brain barrier (BBB) into the CNS.

It is proposed that HIV is trafficked into the blood brain barrier through CD4+ T lymphocytes and C14+ CD16+ monocytes. Dopamine can increase the trafficking of CD14+ CD16+ monocytes across the BBB into the CNS. The HIV protein Tat (trans-activator of transcription) disrupts endothelial tight junctions in the BBB, further promoting the influx of monocytes into the CNS. Infected microglia, astrocytes, and macrophages release inflammatory cytokines and chemokines, contributing to an inflammatory environment that potentiates the recruitment of lymphocytes. Created with BioRender.com.

Figure 2.. Causes of Neurological Damage in CNS HIV Infection.

HIV in the CNS can cause neurological damage through numerous mechanisms including inflammation and Tat protein activity. Biomarkers of neuronal damage include neuron-derived exosomes, increased β-amyloid and Tau protein deposition, and increased extracellular ATP. Key: Panx = pannexin, NFL = neurofilament light chain, Aβ= amyloid beta. Created with BioRender.com.

Figure 3.. CNS HIV Persistence and Mechanisms of Latency.

There are many mechanisms by which HIV remains in a latent state in the CNS, including epigenetic modifications of HIV DNA, degradation of the HIV protein Tat, and transcriptional repressors of HIV. It is thought that HIV virus is largely T-cell tropic in the earlier stages of infection and resides in T lymphocytes. The inflammatory environment and specific selection pressures in the CNS can lead to a macrophage-tropic HIV virus later in infection that resides in the macrophages and microglia of the CNS. Created with BioRender.com.