Molecular neuroimaging of inflammation in HIV

Abstract

People with HIV now have near-normal life expectancies due to the success of effective combination antiretroviral therapy (cART). Following cART initiation, immune recovery occurs, and opportunistic diseases become rare. Despite this, high rates of non-infectious comorbidities persist in treated people with HIV, hypothesized to be related to persistent immuno-activation. One such comorbidity is cognitive impairment, which may partly be driven by ongoing neuro-inflammation in otherwise effectively treated people with HIV. In order to develop therapeutic interventions to address neuro-inflammation in effectively treated people with HIV, a deeper understanding of the pathogenic mechanisms driving persistent neuro-inflammatory responses and the ability to better characterize and measure neuro-inflammation in the central nervous system is required. This review highlights recent advances in molecular neuroimaging techniques which have the potential to assess neuro-inflammatory responses within the central nervous system in HIV disease. Proton magnetic resonance spectroscopy (1H-MRS) has been utilized to assess neuro-inflammatory responses since early in the HIV pandemic and shows promise in recent studies assessing different antiretroviral regimens. 1H-MRS is widely available in both resource-rich and some resource-constrained settings and is relatively inexpensive. Brain positron emission tomography (PET) imaging using Translocator Protein (TSPO) radioligands is a rapidly evolving field; newer TSPO-radioligands have lower signal-to-noise ratio and have the potential to localize neuro-inflammation within the brain in people with HIV. As HIV therapeutics evolve, people with HIV continue to age and develop age-related comorbidities including cognitive disorders. The use of novel neuroimaging modalities in the field is likely to advance in order to rapidly assess novel therapeutic interventions and may play a role in future clinical assessments.

Keywords: human; immunodeficiency diseases; inflammation; viral.

Graphical Abstract

Figure 1:

Schematic representation of the potential routes for HIV entry and pathogenesis in the central nervous system. (A) Direct entry of virus into the brain parenchyma (‘free virus hypothesis’) is possible when blood–brain barrier permeability is enhanced due to dysfunction. (B) Activated monocytes infected with HIV may migrate across the blood–brain barrier, trafficking HIV into the central nervous system (‘Trojan horse hypothesis’). Once in the brain parenchyma, this virus can then infect microglial cells, astrocytes, and macrophages. (C) Activated CD4+ T cells infected with HIV may also traffic HIV across the blood–brain barrier, into the central nervous system. (D) Infected monocytes that have traversed the blood–brain barrier from the systemic circulation into the brain parenchyma may differentiate into perivascular macrophages, which allows HIV replication and the production of free virions that may infect neighbouring microglial cells. (E) Astrocytes may harbour HIV infection but are not thought to be capable of supporting HIV replication within the central nervous system. (F) Activated and infected cells may release viral proteins, neurotoxins, cytokines, and chemokines which can aid the influx of more monocytes by perpetuating increased blood–brain barrier breakdown. (G) The release of chemotactic, inflammatory factors, and neurotoxic factors maintain the inflammatory cycle within the central nervous system and ultimately results in neuronal injury and apoptosis.

Figure 2:

¹H-magnetic resonance spectra obtained from an individual living with HIV, illustrating peaks relating to creatine at 3.9 and 3.0 ppm, myo-inositol at 3.6 ppm, choline at 3.2 ppm, glutamate/glutamine at 2.1 ppm, N-acetyl aspartate at 2.0 ppm, and lactate and lipids at 0.9 to 1.3 ppm. Crea, creatine; mI, myo-inositol; Cho, choline; Glx, glutamate/glutamine; NAA, N-acetyl aspartate; a.u., arbitrary unit; ppm, parts per million. Figure obtained from authors’ own work, unpublished.

Figure 3:

Schematic illustration of PET imaging of activated microglia with radioligands that bind 18 kDa TSPO. TSPO is localized to the outer mitochondrial membrane. TSPO radioligands bind to TSPO in activated microglial cells. The radioligand decays by emitting a positron, which upon combining with an electron, culminates in the annihilation of both particles. Two gamma ray photons are concurrently released at an angle of 180° from each other. The PET scanner detects both the gamma rays and generates a three-dimensional PET image.

Figure 4:

Representative images of volume of distribution parametric maps (0–90 minutes) of [¹¹C] PBR28 PET scans registered to magnetic resonance imaging. The images illustrate the brain distribution of [¹¹C] PBR28 binding in people living with HIV on virologically suppressive antiretroviral treatment. All four individuals are high affinity binders. Images obtained from authors’ own work, unpublished.