Imaging brain inflammation in virally suppressed people with HIV-1

Effective antiretroviral therapy (ART) in people with HIV-1 (PWH) has had a very favorable impact on the overall incidence and prevalence of the neurocognitive problems associated with HIV-1, now collectively known as HIV-associated neurocognitive disorders (HAND). However, there are still many PWH whose cognitive performance is affected to a greater or lesser extent, with estimates ranging from 30 to 50% depending on the neuropsychological testing and other criteria used in any specific series [1,2]. Although clearly related to the underlying HIV infection, the specific mechanisms underlying these persistent abnormalities are unlikely to be homogenous. In some individuals, the cognitive concerns may be a result of ‘legacy’ effects from prior uncontrolled infection coupled with the natural effects of aging [3]. Other individuals may have ongoing inflammation associated with ART-escape viral replication mediated by persistently infected CD4+ cells or macrophages/microglia [4]. Furthermore, even within these broad categories, there is heterogeneity in the cognitive concerns. A reliable, objective marker to distinguish these major subsets would enable better diagnosis and by extension more targeted therapeutic interventions specifically intended to improve cognition. The work by Rubin et al. [5] measuring the 18 kDa translocator protein (TSPO) using PET in the CNS, published in this issue of AIDS, is a step in that direction.

TSPO is a 5-transmembrane domain protein expressed in the mitochondrial outer membranes. Because of its diazepam-binding potential, it was formerly called the peripheral benzodiazepine receptor (PBR), although it is clearly different than the central benzodiazepine receptor [6]. Although its natural ligand is still not conclusively identified, TSPO expression has been widely studied and identified in many tissues in the body; in the central nervous system (CNS), it is primarily present in astrocytes and in microglia – the CNS macrophage-like cells widely implicated in HAND [7]. Previous studies of TSPO expression in the CNS in PWH using older PET ligands have had varying results. However, newer TSPO ligands such as the [¹¹C] DPA-713 used in the work by Rubin et al. [5] can identify TSPO in specific regions of the CNS as well as globally. In this regard, increased TSPO expression has been associated with inflammation and often attributed to either increased expression in individual microglial cells or, more likely, to increased density of those cells at inflammatory sites [5]. In any case, increased TSPO signal is interpreted as evidence of a local inflammatory response, involving reactive astrocytes and microglia. For example, in Alzheimer’s disease, increased TSPO signal relates to the presence of aggregates of the protein tau, thought to be a key component of this degenerative disease, and a driver of the microglial reaction seen in it [8].

There is also a polymorphism in the TSPO gene that affects binding to [¹¹C] DPA-713; this polymorphism must be factored into any analysis as well. Whether this polymorphism also results in an underlying physiological effect is unknown.

In this work, the authors coupled [¹¹C] DPA-713 PET imaging with the NIMH Research Domain Criteria (RDoC) to analyze cognitive functioning in virally suppressed PWH as well as controls. This system breaks down cognitive performance into domains; the investigators were particularly interested in ‘cognitive control’, defined in their work as ‘a system that modulates other cognitive and emotional systems’ and in declarative memory [5]. Cognitive control is localized to the dorsal cingulate cortex (dACC), to the lateral prefrontal cortex (lPFC) and to the inferior parietal lobe, while the more easily defined declarative memory, is localized to the hippocampus and the prefrontal cortex [5]. Hypothetically, if cognitive changes in these domains and regions were related to continuing inflammation induced by HIV, they would correlate with higher [¹¹C] DPA-713 binding in their respective anatomic sites and would associate with a higher density of microglia and astrocytes at those sites.

In this small cohort (25 PWH, 28 controls), Rubin et al. [5] indeed found global increases in TSPO activity in the defined brain regions in PWH. These differences were modestly significant (generally P < 0.05) even after controlling for the genetic phenotypes that affect [¹¹C] DPA-713 binding. Interestingly, in both PWH and control groups, poorer performance in cognitive control analysis was associated with higher ligand binding in lPFC and inferior parietal lobe, and within PWH increased self-reported cognitive burden was associated with increased ligand binding in the regions affecting cognitive control as well as declarative memory. Nevertheless, measured performance was not associated with changes in ligand binding.

Previous studies from this and other groups in cognitively asymptomatic PWH using older PET markers for TSPO have demonstrated increased TSPO activity in comparison with volunteer controls [9,10]. Comparison of the specific regions involved is difficult given the difference in ligands as well as the relatively small number of participants, yet the frontal lobe seems to be a consistent site of increased activity [11]. A study performed by many of the same investigators as the study by Rubin also demonstrated abnormalities in TSPO distribution in PWH who were either neuro-asymptomatic in comparison to healthy controls or even in a comparison of PWH with or without HAND [11]. Nevertheless, that study pointed out that these studies – even with the second-generation ligand [¹¹C] DPA-713 – require exquisite attention not only to the genotype of the experimental volunteers but also to various other issues such brain volume and gray matter normalization, and that reproducibility among groups is going to be very sensitive to such issues.

The study by Rubin is a step forward in demonstrating persistent inflammatory changes in the brain even in PWH who are otherwise well and with undetectable viral loads. Further studies with a larger number of individuals will be necessary to conclusively demonstrate both the use of this TSPO marker and the extent of this potential continuing inflammation in the brain of PWH. More studies will also be required before [¹¹C] DPA-713 can be used clinically. However, if there are consistent changes in group abnormalities, targeting TSPO therapeutically may be a reasonable option based on clinical criteria of cognitive abnormalities in PWH, even without the benefit of individual radiological information.