Changing pattern and pathophysiology of cognitive dysfunction with HIV infection in the era of antiretroviral therapy

Abstract

With the introduction of combination antiretroviral therapy (CART), there was a dramatic decline in all forms of neurological complications of HIV infection. In fact, immune suppressed individuals with neurocognitive impairment showed improvement in cognition following treatment with antiretrovirals. However, it is becoming increasingly evident that despite excellent virological control, milder forms of neurocognitive impairment seem to be on the rise. To address this concern, at the request of the editor-in-chief, Kamel Khalili, I undertook the task of putting together a special issue of the Journal of Neurovirology that would address the current epidemiology, clinical manifestations, pathophysiology, and treatment of HIV-associated neurocognitive disorders (HAND). I am grateful to the authors who were invited to submit their research for this issue and to the reviewers, editorial staff, and publishers for getting this issue together in record time. I am particularly grateful to Dr. Khalili for his guidance throughout the process. In this issue, Heaton and colleagues compared the epidemiology and clinical pattern of neurocognitive impairment in a cohort of nearly 900 patients, each from the preand post(CART) era. They found that in the asymptomatic stages of HIV infection (CDC stage A), the rate of neurocognitive impairment increased from 25% to 36% in the post-CART era. There was less motor impairment and more impairment of memory and executive function. There was no longer a correlation with viral load but nadir CD4 cell counts continue to be a risk factor. This suggests that viral entry into the brain during periods of immune suppression may be key to driving this impairment possibly due to immune reconstitution or by viral products that are not impacted by CART. Another symptom that seems to have been under appreciated previously in these populations is fatigue. Schifitto et al. found that 64% of individuals with HAND also have significant fatigue. The presence of fatigue did not correlate with viral load but correlated with lower levels of creatinine in the basal ganglia as determined by magnetic resonance spectroscopy (MRS) which suggests impaired energy metabolism. In an autopsy study, Kumar et al., found that dopamine levels were significantly decreased in the substantia nigra and correlated with HAND and increased viral loads in the basal ganglia. Zou et al., studied the mechanism by which HIV-gp120 causes neurotoxicity of striatal neurons. They observed that striatal neurons express both chemokine receptors CXCR4 and CCR5 that interact with gp120 and cause neurotoxicity via phosphorylation of Akt. They suggest that Akt may be a therapeutic target. Consistent A. Nath Department of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD, USA