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HIV Tat-associated Sensory Neuropathy and the Contribution of Toll-like Receptor Pathway

Award Number: R01NS132674
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/19/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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HIV Tat-associated Sensory Neuropathy and the Contribution of Toll-like Receptor Pathway - Summary Peripheral neuropathies are the most frequent neurological complications associated with HIV, within which HIV sensory neuropathy (HIV-SN) is the most common form, affecting nearly half of HIV/AIDS patients with the prevalence ranging from 1.2 – 69.4%. HIV-SN frequently manifests with hard-to-manage pain and is often under-diagnosed and/or under-treated, yet, the large variation in prevalence does not allow for detection of significant differences in prevalence between HAART-exposed vs. HAART-non-exposed individuals. There is no specific FDA-approved treatment for HIV-SN. Tat, trans-activator of transcription, a regulatory protein among the first proteins expressed following HIV infection, is a key activator of HIV transcription and can affect both HIV infected cells and non-infected neighboring cells via its secretion by infected cells. Although human studies are lacking, recent animal studies using two models of doxycycline-inducible HIV-1 Tat transgenic (iTat) mice from our lab and others provided convincing evidence that HIV Tat contributes to the development of HIV-SN. Therefore, in this proposal, we will further investigate the underlying mechanisms of Tat-associated SN. Our preliminary study identified potential regulation of Tat of Toll-like receptor (TLR) signaling pathway. Given the widely accepted involvement of TLR pathway in neuropathic pain and surprising lack of studies exploring the role of TLR pathway in HIV-SN, we will focus on TLR pathway in Tat-associated SN in this study. We will take advantage of bioinformatic tools to identify FDA-approved drugs without significant interactions with existing antiretroviral drugs that could potentially reverse Tat-induced changes in TLR pathway, and then test their effectiveness in treating Tat-associated SN in vivo. Altogether, we hypothesize that TLR signaling pathway is involved in the development of HIV-Tat-associated SN and it is possible to identify potential treatment for HIV-SN by examining existing drugs via a combined bioinformatics and pre-clinical model approach. This will be tested through 2 Specific Aims. Aim 1 will determine the contribution of Tollip (a key regulator of TLR pathway)-regulated TLR pathways in HIV Tat-associated SN using genetically modified animal models in combination with behavioral and physiological tests. Aim 2 will identify potential drugs for HIV-SN by targeting TLR pathway via a combined bioinformatics and pre-clinical model approach. If successful, we will fill in the knowledge gaps regarding Tat-associated SN and TLRs’ role in HIV-SN. Our comprehensive combination drug discovery strategy will help identify potential drugs for HIV-SN, which can be further tested in other animal models before clinical assessment. Throughout the process, we will prioritize drug candidates that are mechanistically-sound, and potentially easily accessible to all patients.


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: 2025 ( Subtotal = $355,000 )
2025	2025	UNIVERSITY OF NEW ENGLAND	11 HILLS BEACH RD	BIDDEFORD	ME	04005	YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/11/2025	NON-COMPETING CONTINUATION	$355,000
														Subtotal = $355,000

Issue Date FY: 2024 ( Subtotal = $355,000 )
2024	2024	UNIVERSITY OF NEW ENGLAND	11 HILLS BEACH RD	BIDDEFORD	ME	04005	YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/2/2024	NON-COMPETING CONTINUATION	$355,000
														Subtotal = $355,000

Issue Date FY: 2023 ( Subtotal = $355,000 )
2023	2023	UNIVERSITY OF NEW ENGLAND	11 HILLS BEACH RD	BIDDEFORD	ME	04005	YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/18/2023	NEW	$355,000
														Subtotal = $355,000

Grand Total All Awards = $1,065,000

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HIV Tat-associated Sensory Neuropathy and the Contribution of Toll-like Receptor Pathway

Award Number: R01NS132674

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/19/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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