Uncovering How HIV Drives Chronic Pain

HIV-associated chronic pain is highly prevalent and often persists despite effective antiretroviral therapy (ART), making it one of the most common yet underrecognized comorbidities among people living with HIV.

Its impact extends well beyond physical symptoms, adversely affecting long-term clinical outcomes, mental health, and overall quality of life. These effects include reduced physical activity, sleep disturbances, psychological distress, feelings of hopelessness, and increased disability.

Chronic pain is now increasingly recognized as a core component of the long-term disease burden of HIV, rather than merely a complication of advanced-stage illness. However, current treatments for HIV-associated chronic pain remain limited in efficacy.

We focused on the HIV envelope protein gp120 in this study because clinical, pathological, and experimental evidence identifies it as a key mediator linking HIV infection to nervous system damage and chronic pain, particularly neuropathic pain.

Gp120 is a strong candidate due to its abundant shedding from infected cells and its ability to interact with host receptors expressed on neuronal and glial cells, leading to neurotoxicity. Moreover, application of gp120 to peripheral nerves or the spinal cord induces pain-like behaviors in preclinical models, further supporting its critical role in HIV-associated pain mechanisms.

Across multiple chronic neuropathic pain models, α2δ-1–associated NMDA receptors have emerged as a shared mechanistic target that amplifies pain transmission from peripheral sensory neurons to central spinal cord neurons.

In certain conditions, such as chemotherapy-induced neuropathic pain and postherpetic neuralgia (shingles), hyperactivity of α2δ-1–associated NMDA receptors is largely restricted to peripheral sensory neurons. In contrast, our findings in the HIV/gp120-induced pain model reveal a broader pattern of dysregulation, with hyperactive α2δ-1–associated NMDA receptors present in both peripheral sensory neurons and central spinal neurons.

This dual-site enhancement suggests a more widespread and integrated neuroplastic alteration underlying HIV-associated neuropathic pain.

ART has transformed HIV into a manageable chronic disease; however, it does not fully interrupt the gp120-mediated signaling that contributes to chronic pain. This limitation helps explain why HIV-associated neuropathic pain remains prevalent even in the ART era.

ART reduces HIV replication to very low or undetectable levels and decreases the production of new virions and viral proteins, including gp120. However, it does not eradicate latent viral reservoirs, such as macrophages and microglia, which can persistently produce low levels of viral proteins and release gp120 in a chronic, intermittent manner. As a result, gp120-mediated signaling may continue even in virally suppressed individuals. Furthermore, ART does not reverse established neural injury, allowing previously initiated neurotoxic processes to sustain chronic pain states.

Preclinical models are invaluable for elucidating specific mechanistic pathways, but they do not fully capture the clinical complexity of HIV-associated pain. Many preclinical models involve acute exposure to viral proteins such as gp120, whereas human disease is a chronic, multifactorial condition that develops over years to decades. In people living with HIV, chronic pain arises in the context of lifelong ART use, exposure to multiple viral proteins (e.g., gp120 and Tat), coexisting comorbidities (such as diabetes and substance use), and significant psychosocial stressors.

Furthermore, human chronic pain is an emergent phenomenon driven by dynamic interactions among biological, psychological, and social factors that cannot be fully replicated in preclinical models. Additionally, pain assessment in mice relies on reflexive behavioral responses, whereas human pain is inherently subjective and shaped by cognitive and emotional factors. Consequently, targeting a single mechanism, such as NMDA receptor hyperactivity, may be insufficient to address the complexity of pain in patients.