When do models of NeuroAIDS faithfully imitate "the real thing"?

Abstract

HIV-infected patients treated with antiretroviral medicines (ART) still face neurological challenges. HIV-associated neurocognitive disturbances (HAND) can occur, and latent viral DNA persisting in the central nervous system (CNS) prevents eradication of HIV. This communication focuses on how to develop experimental models of HAND and CNS HIV latency that best imitate the CNS pathophysiology in diseased humans, which we take to be "the real thing." Models of HIV encephalitis (HIVE) with active CNS viral replication were developed in the early years of the AIDS pandemic. The clinical relevancy of such models is in sharp decline because HIVE seldom occurs in virally suppressed patients, while HAND remains common. The search for improved models of HAND should incorporate the neurochemical, neuroimmunological and neuropathological features of virally suppressed patients. Common anomalies in these patients as established in autopsy brain specimens include brain endothelial cell activation and neurochemical imbalances of synaptic transmission; classical neurodegeneration may not be as crucial. With regard to latent HIV with viral suppression, human brain specimens show that the pool of latent proviral HIV DNA in the CNS is relatively small relative to the total body pool and does not change substantially over years. The CNS pool of latent virus probably differs from lymphoid tissues, because the mononuclear phagocyte system sustains productive infection (versus lymphocytes). These and yet-to-be discovered aspects of the human CNS of virally suppressed patients need to be better defined and addressed in experimental models. To maintain clinical relevancy, models of HAND and viral latency should faithfully emulate "the real thing."

Keywords: ART; CNS; Dementia; Eradication; HAND; HIV; Latency.

Fig. 1

A marker of increased endothelial activation (PECAM1 mRNA; CD31) is correlated strongly with abnormally low GABAergic transmission in brain specimens from HIV-infected people (top panel). Four hundred forty-nine infected patients were assayed for glutamic acid decarboxylase (67 kDa) gene expression in frontal neocortex (GAD1 mRNA), which is the rate-limiting step in GABA synthesis. GAD1 correlations with a prototypal viral inflammatory interferon response marker (ISG15 mRNA; bottom panel) and a prototypal macrophage marker of brain HIV infection (CD163 mRNA; middle panel) are not as strong as the endothelial cell marker. The regression line for the endothelial cell marker has the steepest slope, and the correlations have statistically different slopes from each other (r to Z transformation; p < 0.01)

Fig. 2

In the clinic, HIV neurocognitive disorders (HAND) can appear to be one pathophysiological process on a continuum of various intensities (box at right). It is likely that multiple pathophysiologies contribute to the range of clinical intensity. A simplified “multi-hit” hypothesis addresses observations of patients with differing severities of HAND. The suggested schema shows one major hit that occurs in patients not virally suppressed. This hit results from CNS viral replication, CNS inflammation, and possibly neurodegeneration and produces severe neurocognitive impairment. Another type of hit persists in virally suppressed patients that leads to milder forms of HAND. Systemic changes due to smoldering HIV infection may drive the latter hit, and the neurovascular unit transmits systemic anomalies from blood to brain. Other potential hits that modify the intensity of the clinical picture can include substance abuse, systemic or CNS pathogens, and the aging process itself. Diverse pathophysiological changes converge to produce a clinical phenotype of variable clinical severity. Experimental models of HAND should establish precisely which pathophysiological process is imitated and exactly which patient population is emulated in the model

Fig. 3

The pie chart illustrates sizes of HIV DNA pools in human organs and body compartments. Pool sizes were determined by measuring the concentration of the HIV DNA and the mass of the compartment. Pool sizes were corrected for HIV DNA due to blood pooling in the organs. The HIV DNA pool size in the brain is relatively small in comparison to other organs. Note that a compartment such as muscle contains a relatively low concentration of HIV DNA, but the pool size is large nevertheless because the compartment is massive in size

Fig. 4

Concentrations of HIV DNA in the brain of three infected patients. The brain specimen at the left has the highest concentration of HIV DNA in neocortex. The middle specimen has highest concentration in white matter. The specimen at the right has the highest concentration in the neostriatum. Measurement of 29 human brain specimens showed that almost no patient’s brain distribution of HIV DNA conforms to the average of the group. Differing classes of patients exist with regard to the CNS distribution of the HIV DNA reservoir. Reasons for the wide variation of the CNS distribution of HIV DNA in the human population remain to be determined