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Impact of Treatment on Brain Integrity in the Earliest Stages of HIV Infection

Award Number: R01MH113560
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/25/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Impact of Treatment on Brain Integrity in the Earliest Stages of HIV Infection - ABSTRACT This study addresses a critical gap in the field of HIV neuropathogenesis. Previous investigations of brain integrity during the earliest stages of infection describe two opposing neuroimaging signatures of disease. The inconsistency likely reflects the challenges inherent in conducting this work in the US given the limited access to treatment-naïve individuals in early disease stages (Fiebig I-V). Leveraging a highly unique cohort of acutely infected individuals (AHI) in Thailand, our preliminary data reveals intact brain structure and function in treatment- naïve individuals infected for less than two weeks. However, after two years of suppressive combination antiretroviral therapy (cART) initiated within weeks of infection, neuroimaging abnormalities develop in the context of suppressive cART. Further, the degree of brain impairment corresponds to increased levels of monocytes expressing receptors involved in CNS migration and CSF levels of neuronal dysfunction. In this study we will answer the critical question of whether cART is sufficient to halt the detrimental impact of HIV on the brain when initiated within weeks of infection, or whether the brain abnormalities observed in our preliminary analyses progress beyond expectations for HIV- controls despite otherwise successful treatment. This study will overcome limitations in the existing literature because all participants in this study will start cART within days of viral exposure. This work is timely and builds on funded studies that will substantially leverage costs of data acquisition. We will examine longitudinal multimodal imaging outcomes (resting state fMRI, diffusion tensor imaging, and structural volumetrics) of AHI (n=60) as well as enrollment and data capture from demographically-similar individuals with chronic HIV infection (CHI; n=40) and HIV- controls (n=40). A mixed model design will determine if individuals with AHI develop brain injury similar to CHI despite suppressive cART and identify key mechanistic predictors to the evolution of brain abnormalities. Confirmation of our preliminary data demonstrating progressive brain abnormalities despite initiation of cART during the earliest possible period of infection would provide a strong argument that treatment administered under ideal clinical circumstances does not prevent the onset of brain abnormalities. Additionally, evidence of persistent neural injury despite cART instituted during AHI would identify key mechanisms of HIV neuropathogenesis and potential high-impact targets for clinical interventions.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$19,059 )
2024	2021	UNIVERSITY OF MISSOURI SYSTEM	1 UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Mental Health Research Grants	000	5	2/2/2024	NON-COMPETING CONTINUATION	-$19,059
														Subtotal = -$19,059

Issue Date FY: 2021 ( Subtotal = $587,255 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	ONE UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Mental Health Research Grants	000	5	6/28/2021	NON-COMPETING CONTINUATION	$587,255
														Subtotal = $587,255

Issue Date FY: 2020 ( Subtotal = $601,753 )
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	ONE UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Mental Health Research Grants	000	4	6/24/2020	NON-COMPETING CONTINUATION	$601,753
														Subtotal = $601,753

Issue Date FY: 2019 ( Subtotal = $606,617 )
2019	2019	UNIVERSITY OF MISSOURI SYSTEM	ONE UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Mental Health Research Grants	000	3	6/12/2019	NON-COMPETING CONTINUATION	$606,617
														Subtotal = $606,617

Issue Date FY: 2018 ( Subtotal = $613,537 )
2018	2018	UNIVERSITY OF MISSOURI SYSTEM	ONE UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Mental Health Research Grants	001	2	5/18/2018	NON-COMPETING CONTINUATION	$613,053
2018	2017	UNIVERSITY OF MISSOURI SYSTEM	ONE UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Mental Health Research Grants	000	1	11/15/2017	NEW	$484
														Subtotal = $613,537

Issue Date FY: 2017 ( Subtotal = $661,441 )
2017	2017	UNIVERSITY OF MISSOURI SYSTEM	ONE UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Mental Health Research Grants	000	1	8/23/2017	NEW	$661,441
														Subtotal = $661,441

Grand Total All Awards = $3,051,544

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Impact of Treatment on Brain Integrity in the Earliest Stages of HIV Infection

Award Number: R01MH113560

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/25/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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