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.

Grant Number: 5R01DA049657-05
NIH Institute/Center: NIH
Principal Investigator: Saurabh Aggarwal