Smoldering in the sanctuary: HIV-associated brain injury in the ART era
Paraskevas Filippidis, Shelli F. Farhadian
Paraskevas Filippidis, Shelli F. Farhadian
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Smoldering in the sanctuary: HIV-associated brain injury in the ART era

Abstract

Although combination antiretroviral therapy (ART) has dramatically reduced the incidence of severe HIV-associated neurological disease, the central nervous system (CNS) remains a viral sanctuary in which inflammation and brain injury persist despite systemic viral suppression. Here, we synthesize evidence that ongoing HIV-associated brain injury is sustained not primarily by unchecked viral replication but by persistent viral transcription from defective proviruses, immune-mediated synaptic dysfunction driven by bystander activation, and long-lived microglial reprogramming shaped by epigenetic “training.” We highlight how emerging single-cell multiomics and “liquid biopsy” approaches are redefining our understanding of the CNS reservoir at high resolution. We further discuss the growing emphasis on biologically anchored, molecularly defined disease subtypes as a means to disentangle HIV-specific pathology from the confounding overlap of aging and multimorbidity, which have increased in the ART era. Finally, we underscore the necessity of human-centered translational studies to validate preclinical findings, outlining how these molecular insights pave the way for precision therapeutics and CNS-targeted cure strategies.

Authors

Paraskevas Filippidis, Shelli F. Farhadian

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Figure 1

The “smoldering secretome”: mechanisms of bystander injury during viral suppression.

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The “smoldering secretome”: mechanisms of bystander injury during viral ...
Even in the absence of productive viral replication, HIV reservoirs and persistent immune activation in the CNS drive ongoing neurotoxicity. The “smoldering” reservoir microglia (left) harbors defective or silenced proviruses that retain the capacity to transcribe viral RNA and produce viral proteins (such as Tat, Nef, or gp120) without assembling infectious virions. These viral products, along with cell-associated RNA (CA-RNA), are released into the extracellular space as soluble molecules or packaged into EVs. Adaptive immune cells also contribute to this compartmentalized inflammation. Activated CD4+ T cells, which may also harbor HIV DNA, interact with microglia and may release both pro-inflammatory cytokines and viral transcripts or proteins. Simultaneously, activated CD8+ T cells may play a role both in viral clearance and in fueling inflammation by secreting soluble inflammatory factors, such as IFN-γ. This “viral secretome” traffics to uninfected bystander cells, including microglia and neurons. Uptake of these toxic EVs triggers inflammasome activation and cytokine release in bystander microglia and induces synaptic damage, sustaining neuroinflammation and brain injury despite ART.