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Chronic Widespread Pain in HIV: Novel Mechanisms and Therapeutics

Award Number: R01DA049657
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Chronic Widespread Pain in HIV: Novel Mechanisms and Therapeutics - PROJECT SUMMARY/ABSTRACT The advent and access to new treatments have made infection with human immunodeficiency virus (HIV) a chronic disease, allowing patients to have a nearly normal life expectancy. However, the prevalence of chronic widespread pain (CWP) in individuals infected with HIV is high, ranging from 25% to 85%, despite low viral load and adequate CD4 count. CWP is one of the most common associated comorbidities of HIV infection and is associated with high rate of disability and decreased quality of life. However, the specific mechanisms that contribute to CWP in HIV are not understood. Thus, pharmacological and non-pharmacological approaches to mitigate CWP have had minimal benefits, contributing to an overreliance on opioids and alarming rise in addiction and overdose. The overall objective of this proposal is to address the gap in the knowledge of the pathogenesis of CWP and identify potential biomarkers and therapeutic targets to mitigate CWP in HIV. Specifically, we will explore the role of cell-free heme in impairment of endogenous opioid synthesis/release from peripheral leukocytes in HIV patients with CWP. Our novel preliminary findings demonstrate that HIV patients who self- report having CWP have elevated plasma levels of cell-free heme, coupled with decreased leukocyte β- endorphin levels, relative to HIV patients without CWP. Heme is a pro-inflammatory molecule that can induce endoplasmic reticulum stress, as well as inhibit function of leukocytes. Heme also promotes the transition of M0 macrophages toward an M1-like pro-inflammatory rather than M2-like proresolution phenotype. Compared to M2 cells, M1 macrophages contain and release lower amounts of opioid peptides. Therefore, we hypothesize that cell-free heme reduces endogenous opioid peptide-dependent analgesia and enhances pain sensitivity in PWH. We will accomplish our overall objective by addressing the following specific aims: 1) establish a direct link between plasma concentration of cell-free heme and peripheral endogenous opioid peptides with quantitative sensory measures in HIV patients with CWP, 2) to determine in a translational manner the mechanisms through which heme contributes to diminished peripheral opioid release and pain, and 3) test whether heme scavenging is a therapeutic option to increase leukocyte endogenous opioids and attenuate pain hypersensitivity. This work is novel as the impact of endogenous opioid peptide synthesis and release by leukocytes on CWP in HIV has never before been directly examined. Furthermore, the proposed work is innovative in that it combines clinical and preclinical experiments, including the use of the HIV-1 transgenic rat model, to identify potential biomarkers and mechanisms of CWP in HIV. The proposed research is significant because, if our hypotheses are confirmed, we will identify: 1) heme as a major driver of pain in HIV, and 2) heme scavenging by hemopexin as a novel, non-opioid therapeutic for HIV-associated pain.


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 = $360,638 )
2025	2025	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	003	5	6/6/2025	NON-COMPETING CONTINUATION	$360,638
2025	2024	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	001	4	10/30/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$301,670
2025	2024	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	002	4	11/6/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	3	10/30/2024	NON-COMPETING CONTINUATION	-$301,670
														Subtotal = $360,638

Issue Date FY: 2024 ( Subtotal = $368,750 )
2024	2024	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	001	4	7/30/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$368,750
2024	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	3	7/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $368,750

Issue Date FY: 2023 ( Subtotal = $371,250 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	3	5/11/2023	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2022 ( Subtotal = $371,250 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	2	5/9/2022	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2021 ( Subtotal = $371,250 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	1	5/12/2021	NEW	$371,250
														Subtotal = $371,250

Grand Total All Awards = $1,843,138

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Chronic Widespread Pain in HIV: Novel Mechanisms and Therapeutics

Award Number: R01DA049657

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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