Fergan Imbert and Dianne Langford at Rowan University (Rowan-Virtua School of Osteopathic Medicine) investigated the role of SUMOylation in HIV latency within the central nervous system (CNS), particularly in microglial cells. HIV can persist in a latent state in the CNS due to the immunologically inert environment. Post-translational modifications like SUMOylation are crucial in regulating viral protein activity and latency. The study explores how SUMOylation affects innate immune signaling and viral infections in the CNS, with a specific focus on its role in HIV latency in microglia. Microglia, as a major viral reservoir and source of inflammation, are critical in understanding HIV-associated neurocognitive disorders.
The study’s main findings follow:
• SUMOylation may regulate key proteins involved in maintaining viral latency, suggesting a mechanism by which HIV evades immune detection in the CNS.
• Viral reactivation in a latent HIV microglia model induces a loss of global SUMO2/3 conjugation. When latent HIV in HC69 microglia are activated, levels of proteins modified by SUMO2/3 significantly decrease, with a marginal decrease in SUMO1 conjugation. In contrast, TNF-α treatment in the parent uninfected microglial cell line triggers an increase in proteins modified by SUMO2/3, but not SUMO1.
• In human brain tissue, the SUMO2/3 paralogue is significantly reduced in people with HIV, suggesting that decreased levels of SUMO2/3 conjugation in a reactivated HIV latent microglia model may be associated with a loss of the SUMO2/3 substrate.
• Proteomic analysis identified 5073 substrates, with Gene Ontology (GO) analysis revealing enrichment for intracellular membrane-bounded organelles, the nucleus, nucleolus, and cell-substrate junctions. Less than 1% of the identified substrates varied significantly in abundance after HIV reactivation. Comparison of protein expression changes in response to latent HIV reactivation in microglia showed decreased expression of SUMO1 and SUMO2, while levels of E1-activating enzymes (SAE1/SAE2) and SUMO proteases (SENP8; SENP3) remained relatively stable.
• Inhibiting SUMOylation with TAK-981, a SUMO-specific inhibitor, reduces HIV latency reactivation in vitro in Jurkat cells, but has little effect on the microglial model, suggesting that microglia have unique reactivation mechanisms that do not rely on SUMOylation compared to T cells. Similar results were obtained using a SUMO E2 inhibitor.
The study elucidates the relationship between the host SUMOylation system and HIV infection, revealing an increase in SUMOylation in a human microglial latent model of HIV infection. This SUMOylation appears pivotal in maintaining viral latency, with SUMO conjugation notably lost upon microglial reactivation. The research identifies potential therapeutic targets for controlling HIV reactivation and reducing the latent reservoir by targeting the SUMOylation pathway. The study provides resources for understanding the interplay between viral infections and the host SUMOylation system, offering opportunities for developing innovative HIV latency models and further research.
Imbert F, Langford D. Comprehensive SUMO Proteomic Analyses Identify HIV Latency-Associated Proteins in Microglia. Cells. 2025 Feb 6;14(3):235. doi: 10.3390/cells14030235. PMID: 39937027; PMCID: PMC11817477. https://www.mdpi.com/2073-4409/14/3/235
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