Despite the widely acknowledged success of combination antiretroviral therapy (cART) in the incidence of HIV- 1 associated dementia (HAD), HIV-1-associated neurocognitive disorders (HAND) continue to afflict up to 50% of patients on cART. Neurological complications of HIV infection are the biggest challenge facing HIV researchers, and there is a critical need to develop treatment approaches for HAND. Using the HIV-1 transgenic (Tg) rat model in a prospective longitudinal design, we will explore the hypothesis that the progression of neurocognitive dysfunctions associated with HIV-1 are consequent to central nervous system (CNS) synaptodendritic pathology, neuroinflammation and oxidative stress, and that the progressive neurocognitive losses will be slowed or halted with a restorative therapeutic approach administered early in the course of transgene expression.
The specific aims are: 1) To establish the progression of neurocognitive decline in the HIV-1 Tg rat on measures of attention and executive function; as distinct from potential changes in sensory, activity, and motivational confounds. The progression of neurocognitive dysfunction will be assessed with periodic tests from pre-adolescence through advanced age, given the exponential growth of 65+ year old HIV+ patients. Both males and females will be examined. 2) To establish the progression of CNS synaptodendritic pathology, neuroinflammation and oxidative stress, in the HIV-1 Tg rat. Investigations will focus on quantifying dendritic branching and spine parameter alterations with respect to the prefrontal cortex and medium spiny neurons of the nucleus accumbens. 3) We will protect (and restore) neurocognitive function and synaptodendritic complexity with S-equol, a metabolite produced via the gut microbiome following ingestion of soy isoflavone daidzein. Having established and replicated proof- of-concept (preliminary studies), we will assess the in vivo efficacy of S-equol to delay the progression to neurocognitive decline; synaptodendritic complexity, neuroinflammation and oxidative stress will be assessed in different time-sequential cohorts as the basis of the preserved neurocognitive function. Initially we will establish the optimal 2-month therapeutic window. Subsequently, we will establish the functional role of alterations in synaptodendritic complexity, neuroinflammation and oxidative stress as neurobiological mechanisms contributing to, if not mediating, the neurocognitive impairments consequent to chronic expression of the HIV-1 transgene. The program goal is to advance the field by establishing 1) the progression of neurocognitive decline in a translationally relevant model of HAND, 2) the efficacy of a regenerative approach targeted at synaptodendritic complexity in protecting (slowing or halting) the neurocognitive decline in the core cognitive components of attention and executive function, and 3) proof-of- principle for the microbiota-gut-brain axis as an innovative therapeutic approach for HAND.

Public Health Relevance

Despite the widely acknowledged success of combination antiretroviral therapy (cART) in the incidence of HIV- 1 associated dementia (HAD), HIV-1-associated neurocognitive disorders (HAND) continue to afflict up to 50% of patients on cART. Neurological complications of HIV infection are the biggest challenge facing HIV researchers, and there is a critical need to develop treatment approaches for HAND. We are uniquely poised to advance the field with a translational model of the core components of cognition relevant to HAND with which we will establish the progression of neurocognitive decline and its mechanistic basis in synaptodendritic loss, neuroinflammation, and oxidative stress, and more importantly, establish proof-of-principle for the microbiota- gut-brain axis as an important therapeutic approach for HAND.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH106392-03
Application #
9415101
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rao, Vasudev
Project Start
2016-03-08
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of South Carolina at Columbia
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
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