Theraputic Strategies for HIV Associated Neurocognitive Impairment

In the US, HIV infection affects nearly 1 million people. HIV quickly crosses the blood brain barrier soon after infection and reservoir of HIV develops in the brain leading to HIV associated neurocognitive disorders (HAND) - impairments in neurocognition, slowed motor movements, and behavioral disturbances. Research in the Ances laboratory and collaborative group is focused on the development of novel diagnostic and therapeutic strategies for HAND.




More HIV infected (HIV+) individuals are living longer due to the introduction of medications for treating the virus, combination antiretroviral therapy (cART). While the overall incidence (the number of new cases) of HAND has not changed since cART, the prevalence (the total number of cases) of HAND has risen with ~20% of all HIV+ subjects eventually developing HAND. Even mild forms of HAND impair daily functioning, reduce quality of life, and cause greater unemployment. Since HAND is a significant burden to HIV infected persons, caregivers, and the healthcare system, the development of effective treatment strategies for diagnosing and treating HAND are of great public health importance.




HAND is difficult to detect using current diagnostic criteria such as neurological examination or pencil and paper tests administered as part of neuropsychological testing. These methods are labor intensive and can be influenced by the state of the patient (i.e. a subject had a bad night's sleep or has been worrying about a family matter). Other biological markers of HAND need to be developed and validated. The aim of the Ances laboratory is to translate discoveries of the pathophysiological mechanisms of HAND into novel therapeutics.




Functional magnetic resonance imaging (fMRI), a neuroimaging technique that provides pictures of brain activity during different behaviors, could be a powerful in vivo non-invasive biomarker of HAND. Blood oxygen level dependent imaging (BOLD) and arterial spin labeling (ASL) are utilized by the Ances laboratory to measure functional changes in cerebral blood flow (CBF), cerebral metabolic rate of oxygen consumption (CMRO2), and cerebral blood volume (CBV) during normal behaviors. Alterations in the coupling relationship between functional changes in CBF and CMRO2 may be a "stress test" of neuropathology.




Consensus cART guidelines do not provide specific recommendations concerning management of HAND. Current recommendations are based on peripheral blood markers (plasma viral load and CD4 count) and not neurocognitive status. Initiation of treatment often does not occur until significant thinking problems are observed by the subject, family member, or physician taking care of the patient. By this time the benefit of cART is reduced compared to earlier initiation of medications. Differences also exist in ability of antiretrovirals to get into the brain. The Ances laboratory is using fMRI to assess the efficacy of various cART regimens.