The recent discovery by University of Virginia School of Medicine scientists has brought researchers closer to finding ways to flush out the dormant HIV virus and eliminate it for good. The study reveals a key reason why HIV remains so difficult to cure: subtle variations in the viral control system, known as the Rev-RRE axis, influence how efficiently the virus replicates and how easily it reactivates from latency.

HIV treatment has made remarkable progress, allowing the virus to be suppressed to undetectable levels in the blood. However, the virus never truly goes away; instead, it hides in the body in a dormant or “latent” state, and if medications are ever stopped, it can reemerge. This stealth mode poses one of the biggest challenges to finding a cure.

“The HIV treatment is lifesaving but also lifelong,” said Patrick Jackson, MD, one of the two lead authors on the paper. “Understanding how the virus stays latent in cells could help us develop a lasting cure for HIV.”

UVA’s new findings reveal a critical clue to how HIV controls this hiding act. The research shows that small changes in the Rev-RRE axis regulatory system directly impact HIV’s ability to replicate and emerge from latency. The study found that viruses with low Rev activity had a disadvantage in both replication and latency reactivation.

This variability helps explain why HIV persists despite aggressive treatment. To develop a cure, future therapies may need to account for these subtle variations that allow the virus to shift its behavior, the researchers say.

“Rev has often been overlooked in the context of latency, even though it’s essential for HIV replication,” said Godfrey Dzhivhuho, PhD, the other lead author of the study. “Our work helps explain why some current ‘shock and kill’ approaches struggle to fully reactivate the virus.”

If a portion of the viral reservoir has low Rev-RRE activity, it will be more resistant to reactivation. By enhancing the Rev-RRE axis, we may be able to induce a stronger and more complete latency reversal and bring us closer to strategies that can truly clear the virus.

The researchers hope this work brings them one step closer to a cure, not just by uncovering how the virus works, but by helping design smarter strategies to finally eliminate it. That’s what drives them every day in this research.

This work was supported by the Myles H. Thaler Research Support Gift to UVA and by the National Institutes of Health, grants R21 AI134208 and K08 AI136671.

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A New Biomarker for Skin Cancer: Unlocking the Secrets of Metastasis Risk and Treatment Opportunities

Cutaneous squamous cell carcinoma (cSCC), the most common type of metastatic skin cancer, affects a significant number of people worldwide. Despite its relatively low incidence rate compared to other types of cancers, cSCC is responsible for nearly 25% of annual skin cancer deaths. The prognosis for patients with metastatic cSCC is poor, with limited treatment options available.

Researchers have identified C5aR1 as a potential biomarker for metastasis risk and poor prognosis in patients with cSCC. This novel finding, published in The American Journal of Pathology, has significant implications for the diagnosis and treatment of this aggressive form of skin cancer.

The complement system, a part of the human innate immune system, plays a crucial role in tumor suppression by inducing inflammation or causing immunosuppression. However, studies have shown that the complement system can also contribute to tumor progression and metastasis. This complex interplay between the complement system and cancer cells has prompted researchers to investigate the interaction between C5a (a signaling molecule) and its protein receptor C5aR1.

The study’s findings reveal that C5a binds to C5aR1, activating signaling pathways within the cell, leading to changes in cell behavior. The investigators examined C5aR1 in the context of cSCC progression and metastasis by combining in vitro 3D spheroid co-culture of cSCC cells and skin fibroblasts, human cSCC xenograft tumors grown in SCID mice, and a large panel of patient-derived tumor samples.

The results showed that C5aR1 expression is linked to metastasis risk and poor survival in patients with cSCC. High C5aR1 expression was observed in both tumor cells and stromal fibroblasts, suggesting that the interplay between tumor cells and their surroundings plays a crucial role in cancer progression.

The researchers concluded that C5aR1 is a potential metastatic risk marker, a novel prognostic biomarker, and promising therapeutic target for cSCC. This discovery has significant implications for the diagnosis and treatment of this aggressive form of skin cancer, offering new hope for patients and their families.

In conclusion, the identification of C5aR1 as a potential biomarker for metastasis risk and poor prognosis in patients with cSCC is a significant breakthrough in the field of skin cancer research. Further studies are needed to fully understand the role of C5aR1 in cSCC progression and metastasis, but this discovery has the potential to unlock new treatment opportunities and improve patient outcomes.

Cohesin, a protein complex that forms loops in the human genome, plays a crucial role in determining the architecture of our genetic material and regulating gene expression. However, its function and behavior have remained somewhat mysterious until now.

Researcher Professor Eva Estébanez-Perpiñá from the University of Barcelona, along with her team and international collaborators, has made significant strides in understanding how cohesin works. Their study, published in Nucleic Acids Research, sheds light on the protein’s interaction with chromatin structure and its role in altering gene expression.

Cohesin consists of four subunits: SMC1, SMC3, SCC1/RAD21, and STAG (also known as SA or SCC2). Previous studies had identified 25 proteins that regulate these subunits and their biological function. Estébanez-Perpiñá’s team has now discovered how the NIPBL protein interacts with both MAU2 and the glucocorticoid receptor (GR), a transcription factor essential for cellular functions.

This ternary complex, comprising NIPBL, MAU2, and GR, modulates transcription by facilitating the interaction of GR with these two proteins. When GR interacts with NIPBL and MAU2, it alters chromatin structure and affects gene expression. This discovery has significant implications for understanding Cornelia de Lange syndrome, a rare disease caused by mutations in genes involved in cohesin formation.

The researchers used advanced microscopic techniques to visualize real-time molecular complexes binding to chromatin, as well as biochemical and biophysical methods to analyze the complex from different structural and cellular perspectives.

Their findings not only improve our comprehension of cohesin’s role but also highlight its potential involvement in other diseases, such as asthma and autoimmune pathologies. As research continues, scientists will likely uncover more about this enigmatic protein and its intricate relationships with chromatin structure and gene expression.