Circulating extracellular vesicles from HIV-1 gp120-treated mice act as endogenous algogens, mediating and maintaining HIV-associated chronic pain

Yuan, S.; Liew, J. Y.; Bei, J.; Pal, A.; Qiu, Y.; Shang, J.; Araya, K.; Tat, V.; Hao, H.; Gamez, I.; Haines, C.; Chang, Q.; Saito, T. B.; Khanipov, K.; Gong, B.

doi:10.1101/2025.02.07.637192

bioRxiv · 10.1101/2025.02.07.637192

Circulating extracellular vesicles from HIV-1 gp120-treated mice act as endogenous algogens, mediating and maintaining HIV-associated chronic pain

Yuan, S.·Liew, J. Y.·Bei, J.·Pal, A.·Qiu, Y.·Shang, J.·Araya, K.·Tat, V.·Hao, H.·Gamez, I.·Haines, C.·Chang, Q.·Saito, T. B.·Khanipov, K.·Gong, B.

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Abstract

HIV-associated chronic pain (HIV-PAIN) remains prevalent in the post combined antiretroviral therapy era, affecting 30-60% of HIV patients worldwide. The underlying mechanism responsible for the development and maintenance of chronic pain remains unclear. gp120 is a causal factor of the HIV-PAIN and functions as an exogenous algogen. The pain experienced by human HIV-PAIN has been modeled in mice (referred to as mHIV-PAIN) using intrathecal (i.t.) injections of gp120. gp120 is a relatively short-term, static, exogenous algogen that is exhaustible in vivo. In authentic infection, HIV virions serve as the primary source of exogenous gp120, which initiates the early phase of clinical HIV-PAIN. Interestingly, while the source of replenishing gp120 decreases after antiretroviral therapy by suppressing viremia, the prevalence of chronic HIV-PAIN remains stable. To induce chronic pain in mice, gp120 needs to be repeatedly applied by the i.t. route. This raises a key question: Is an endogenous inexhaustible algogen responsible for maintaining the chronicity of HIV-PAIN? In the present study, we isolated circulating small extracellular vesicles (sEV) from mice using our mHIV-PAIN model that is i.t. injected with gp120. We refer to such sEV as gp120-sEV herein. We observed that gp120 is absent in gp120-sEV. Following transfusion of gp120-sEV intrathecally, naive recipient mice exhibit an extensive pain phenotype, including cold pain tested with we newly invented dry ice vapor cold test. RNA-sequence analysis suggests that gp120-sEVs induced expression of genes related to nociception and neuroinflammation pathways. These findings provide direct evidence that circulating sEV function as endogenous long-term "dynamic" algogens that enhance initial pain and extend the chronification of HIV-PAIN in mice, suggesting that chronic HIV-PAIN requires an exogenous algogen (gp120) paired with endogenous algogen (gp120-sEV), and that these components work synchronically to initiate and extend pain chronification. This double algogen concept provides a new insight into the pathogenesis of HIV-PAIN chronification. Our new mechanistic understanding will also assist in identifying new therapeutics to alleviate HIV-PAIN by targeting pathological gp120-sEV.

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Yuan, S., Liew, J. Y., Bei, J., Pal, A., Qiu, Y., Shang, J., Araya, K., Tat, V., Hao, H., Gamez, I., Haines, C., Chang, Q., Saito, T. B., Khanipov, K., Gong, B.. 2025-02-08. Circulating extracellular vesicles from HIV-1 gp120-treated mice act as endogenous algogens, mediating and maintaining HIV-associated chronic pain. https://doi.org/10.1101/2025.02.07.637192

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