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.

The plague, caused by the bacterium Yersinia pestis, has been a persistent threat to human populations for centuries. A recent study published in the journal Science sheds light on how a single gene in the bacterium allowed it to adapt and survive for hundreds of years. The research, conducted by scientists at McMaster University and France’s Institut Pasteur, reveals that changes in the copy number of the pla gene led to a reduction in virulence and an increase in the length of time it took to kill its victims.

The study examines the evolution of the plague during three major pandemics: the Plague of Justinian, the Black Death, and the third plague pandemic. The researchers found that strains of the Justinian plague became extinct after 300 years of ravaging European and Middle Eastern populations. Strains of the second pandemic emerged from infected rodent populations, causing the Black Death, before breaking into two major lineages.

One lineage is the ancestor of all present-day strains, while the other re-emerged over centuries in Europe and ultimately went extinct by the early 19th century. The researchers used hundreds of samples from ancient and modern plague victims to screen for the pla gene and perform extensive genetic analysis.

Their findings suggest that a reduction in the copy number of the pla gene led to a decrease in virulence and an increase in the length of time it took to kill its hosts. In mice models of bubonic plague, this change resulted in a 20% reduction in mortality and increased the length of infection, allowing the hosts to live longer before dying.

The scientists also identified a striking similarity between the trajectories of modern and ancient strains, which independently evolved similar reductions in pla in the later stages of the first and second pandemic. This suggests that when the gene copy number dropped, the infected rats lived longer, spreading the infection farther and ensuring the reproductive success of the pathogen.

The researchers propose that this evolutionary change may reflect the changing size and density of rodent and human populations. They also found three contemporary strains with pla depletion in a collection at the Institut Pasteur.

This study provides valuable insights into the evolution of the plague and its impact on human history. It highlights the importance of understanding the complex relationships between pathogens, their hosts, and their environments, as well as the need for continued research into the causes and consequences of pandemics.

The findings also underscore the ongoing threat posed by the plague in regions like Madagascar and the Democratic Republic of Congo, where cases are regularly reported.

Overall, this study sheds new light on the evolution of a single gene that allowed the plague to adapt and survive for centuries. It emphasizes the importance of continued research into the causes and consequences of pandemics and highlights the need for effective strategies to combat infectious diseases that continue to pose significant threats to global health.

The recent global outbreak of mpox, a disease caused by the monkeypox virus, has raised concerns about its transmission dynamics. Historically, most human infections have resulted from zoonotic transmission – from animals to humans – but during the 2022 global outbreak, the virus began spreading readily between people. A new study published in Nature has now shown that the virus was circulating long before then.

Using genomic tracing, researchers estimated that the virus’ ancestor first emerged in southern Nigeria in August 2014 and spread to 11 states before human infections were detected in 2017. The findings highlight the need for improved global surveillance and medicines, given the threat of impending pandemics.

“We could have very easily prevented the 2022 multi-country outbreak if countries in Africa were given better access to therapeutics, vaccines, and surveillance technologies,” says Edyth Parker, a professional collaborator in the Kristian Andersen Lab at Scripps Research and one of the paper’s first authors. “In a vulnerably connected world, we cannot neglect epidemics until they get exported to the Global North.”

The study’s senior author, Christian Happi, director of the Institute of Genomics and Global Health at Redeemer’s University in Nigeria, organized a Pan-African consortium to share and generate mpox genomic data. The consortium involved researchers and public health agencies in West and Central Africa, with support from international collaborators including Scripps Research.

By pooling samples and laboratory methods, the group generated a genomic dataset that is around three times larger than any previous mpox dataset. Altogether, the team analyzed 118 viral genomes from human mpox cases that occurred in Nigeria and Cameroon between 2018 and 2023. All of the sequences were identified as Clade IIb – the mpox strain endemic to West Africa.

The researchers created a phylogenetic tree, which estimates how related the different viruses are, and how recently they evolved. They found that most of the viral samples from Nigeria were the result of human-to-human transmission (105/109), while the remaining four were caused by zoonotic spillover. In contrast, all nine mpox samples from Cameroon were derived from isolated zoonotic spillover events.

“Mpox is no longer just a zoonotic virus in Nigeria; this is very much a human virus,” says Parker. “But the fact that there’s ongoing zoonotic transmission means there’s also a continual risk of re-emergence.”

The team estimated that the ancestor of the human-transmitting mpox virus emerged in animals in November 2013 and first entered the human population in southern Nigeria in August 2014. They also showed that southern Nigeria was the main source of subsequent cases of human mpox: though the virus spread throughout Nigeria, continual human-to-human transmission only occurred in the country’s south.

The study highlights the need for better wildlife surveillance, as well as better surveillance in the human populations that interface with animals in that forested border region. It also emphasizes the importance of better access to diagnostics, vaccines, and therapeutics in Africa.

“Global health inequities really impede our ability to control both zoonotic and sustained human transmission,” says Parker. “We cannot continue to neglect either the human epidemics in Africa or the risk of re-emergence – not only does it perpetuate suffering in these regions, it means that inevitably there will be another pandemic.”