In 2012, University of Melbourne immunologist Damian Purcell read a study that, he said, “blew my socks off.” Published by a physician in a remote town in Australia’s red center called Alice Springs—known as Mparntwe to its original inhabitants, the Arrernte people—the paper reported that a devastating retrovirus was at around 40 percent prevalence in the region’s indigenous communities.
That retrovirus was human T-lymphotropic virus type 1 (HTLV-1). Similar to its better-known relative, human immunodeficiency virus (HIV), HTLV-1 is predominantly transmitted through blood and bodily fluids, and causes chronic, lifelong infections. It can also be transmitted from mother to child through long-term breastfeeding—a common practice in Indigenous communities. Affecting an estimated 10–20 million people worldwide, HTLV-1 can result in a range of debilitating and often fatal comorbidities, including immunodeficiency, neuroinflammatory disease and paraparesis, lung disease, and cancer.1,2 Despite being the first human retrovirus to be discovered, there are no effective treatments for HTLV-1, no rapid diagnostic tests, and no vaccines to prevent the spread. Today, after decades of research, scientists like Purcell and others could finally be on the cusp of developing effective treatments for the First Nations people around the world who are disproportionately affected by HTLV-1.
High Prevalence of HTLV-1 in Remote Indigenous Communities
Damian Purcell, an immunologist at Melbourne University, has applied learnings from HIV research to the development of an mRNA vaccine for HTLV-1.
Damian Purcell, University of Melbourne
Purcell was in the early phase of his PhD researching gibbon ape leukemia virus when he first heard about the discovery of HTLV-1. Although he was curious, he lacked the opportunity to pursue it. After graduating, he met the scientist who discovered both HIV and HTLV-1, Robert Gallo, at a conference. Gallow gave Purcell some advice that would change the trajectory of his career: “You should be working on one of the real human viruses, and you should work on HIV.”
Purcell did just that. “That was at the time when people were just dying from HIV because there were no active drugs,” he recalled. It was decades later, when scientific research transformed HIV from a death sentence into a manageable disease, that he read the shocking statistics about HTLV-1 in Australia’s remote Indigenous communities.
He was sure there was a link between lifelong infection with the retrovirus and the poor health of indigenous Australians. “At that point, I thought, really, we owe it to people in Central Australia to work very hard to find [treatment] options,” Purcell remarked. He has worked intensively on HTLV-1 ever since, both investigating its impact on health and attempting to develop medicines to prevent its transmission.
The ‘Poor Cousin’ of HIV: Lack of funding for HTLV-1 research
HIV and HTLV-1 share many similarities; they both infect CD4+ helper T cells and have single-stranded RNA genomes which they convert into DNA using a reverse transcriptase enzyme. Once they randomly integrate into the human genome, they become serious lifelong infections that drive disease.
That’s where the similarities end, and not just biologically. Because it predominantly affects indigenous communities and is therefore not a major public health concern, HTLV-1 has suffered from chronic underfunding that has prevented researchers from developing effective treatments. Edward Harhaj, an immunologist at Penn State University who has worked on HTLV-1 since the 1990s, said that the lack of funding has driven many researchers away. “When I first started, it was a very vibrant research community, there were a lot of people working on it, but it’s completely changed in the last 2025, years,” he remarked. “There are very few people working on it 1762762626.”
Funding constraints didn’t deter Amanda Panfil, though. A virologist at Ohio State University (OSU), Panfil’s passion for studying oncogenic viruses led her to the HTLV-1 community as a postdoctoral researcher in 2012. “I fell in love with it; it just spoke to me,” she said. According to Panfil, who went on to start her own laboratory at OSU in 2019, the small, close-knit HTLV-1 research community is full of passionate people who are happy to collaborate and share information. “By having limited resources, sometimes the field is more innovative, because you have to be,” she added.
An Ancient Retrovirus That Creates Zombie T Cells
While HIV is theorized to have crossed into humans from apes within the last 100 years, HTLV-1 is ancient; proviral DNA has been identified in 1,500-year-old mummified human remains.3 HTLV-1 also employs a unique method of propagating itself: Rather than causing the infected cell to produce numerous new viral particles and destroying it in the process, HTLV-1 primarily spreads through cell division. “It becomes very stealthy,” explained Purcell. “It goes silent—latent—very soon after infection and works by reprogramming the cells to divide using cellular mitosis.”
However, this quirk in the HTLV-1 lifecycle is also a vulnerability that researchers can exploit in the search for effective treatments. Because mitosis is such a high-fidelity method of copying the genome, HTLV-1 does not mutate nearly as rapidly as HIV. “HIV is much more variable and capable of escaping antiviral drugs and vaccines, whereas HTLV is probably a tamer target, because it’s not as capable of evolving once a person’s infected,” Purcell added.
There are two dominant subtypes of HTLV-1: subtype A and subtype C. The former is globally prevalent and is associated with a neuroinflammatory disorder known as HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), and adult T cell leukemia, an aggressive form of cancer. In contrast, the more aggressive subtype C is common in Australia and is associated with chronic pulmonary disease.
Key Viral Proteins Help HTLV-1 Survive and Thrive
Unlike HIV, HTLV-1 primarily spreads through cell division. Fortunately, this makes it an easier target for vaccines and antiviral drugs because it is unlikely to evolve resistance through mutations.
©iStock, K_E_N
As a graduate student in the 1990s—before sequencing became widely available—Harhaj was among the first researchers to discover how HTLV-1 causes cancer with the help of Tax, a viral protein. “Tax is one of the main oncogenes for the virus, so it’s important [for causing] cancer,” Harhaj explained. “Tax is also important for regulating viral gene expression, and it’s important for transmission of the virus from an infected to an uninfected cell. So, Tax does a lot for the virus.”
Another viral protein called Hbz is also involved in HTLV-1 progressing to malignancy. “It’s interesting, because it doesn’t have to produce the [Hbz] protein to have the impact that it has on the cell,” Purcell said. “It works as a non-coding RNA to reprogram the cell to proliferate and divide and also resist the processes of cellular apoptosis.” By upregulating genes important for the survival of infected T cells, Tax and Hbz activate anti-apoptosis pathways and drive the proliferation of these cells.
According to Purcell, the expansion of undead T cells is also how HTLV-1 causes disease. “[Infected T cells] also don’t perform their normal functions properly, so you end up having cells that have got the appropriate receptors to respond to antigens, but they just begin crowding out and not performing any useful function,” he remarked. “[They] essentially become immuno-zombies.”
For indigenous Australians, this commonly manifests as serious, and often fatal, chronic pulmonary disease. “In subtype C, [T cells are] reprogrammed to have what we call lung-homing markers. The T cells have the property of being able to migrate into tissues—into the lung in particular—and then just set up residency there, and they’re just not doing anything useful,” said Purcell.
Some of Purcell’s recent research has focused on exploring the differences between subtypes A and C and why they result in such different clinical outcomes. Phylogenetic analysis showed that while they share 92.5 percent similarity overall, subtype C shows higher levels of divergence.2 The gene sequence of hbz in particular is significantly more variable. “That’s probably the reason why it has different pathogenesis,” Purcell commented.
Because Hbz and Tax are so crucial in the HTLV-1 life cycle, understanding how they work has been a major research focus in the broader HTLV-1 field. While Tax is more involved in initial infection and can then be downregulated, Hbz is even more relevant as a therapeutic target. “We know you need Hbz—it’s always expressed, it’s doing something to keep the cell alive,” said Panfil. “So, I’m a firm believer that I think if we can really target Hbz, that’s going to be a very vulnerable region of the virus.”
Animal Models and Repurposing HIV Antiretrovirals
To study the virus and test potential treatments, HTLV-1 researchers have created several animal models. Purcell’s ongoing collaborations with scientists at the National Institute of Health include establishing infections in non-human primates (NHPs), which can subsequently develop relevant disease phenotypes. However, access to NHPs is limited in Australia, and besides, Purcell said, “The ethics of infecting primates is pretty challenging.”
According to Panfil, rabbit models of HTLV-1 are useful, but come with a major caveat: “You get persistent infection, very similar to what you see in humans, but they never develop disease.” In contrast, humanized mouse models are ideal for studying HTLV-1-related diseases like cancer. “We get animals that succumb to disease within five to six weeks after infection, so it’s really rapid,” Panfil added.
While no antiretroviral therapy (ART) has been developed for HTLV-1, a recent study by Purcell and his colleagues at the University of Melbourne showed that it is possible to repurpose existing ARTs that were developed for the treatment of HIV. By combining these ARTs with drugs that inhibit the anti-apoptosis protein MCL-1, Purcell and his colleagues were able to kill HTLV-1c-infected cells, both in vitro and in vivo in humanized mice, reducing transmission and disease progression.4
However, more research is needed before this combination therapy can be used for widespread treatment. “MCL-1 is probably a more difficult thing [to target] because it could have toxicities in cells other than the T cells,” said Purcell. “Ideally, we need to find a formulation that’s going to be specific for the T cells. There’s research now underway looking at RNA-based methods of delivering anti-MCL-1 activity into the cell.”
Targeting Viral Proteins with Small Molecules
Immunologist Edward Harhaj has spent his entire career working on HTLV-1, and recently demonstrated that KDR inhibitors can kill infected cells.
Edward Harhaj, Penn State University
Harhaj published a recent study in Nature Communications that he hopes will lead to a treatment for the virus. Using short hairpin RNAs (shRNAs), Harhaj and his team screened over 600 cellular kinases to determine if any of these proteins were driving the survival of HTLV-1-infected cells. “Surprisingly, we only had like one statistically significant hit, which we weren’t expecting,” Harhaj recalled.
That hit was the tyrosine kinase KDR, which is primarily known for its involvement in forming blood vessels, and is typically expressed in endothelial cells. “We thought this was an artifact at first, because it didn’t make any sense to us, but then we did more experiments, and then we found something very interesting,” Harhaj continued.
The team demonstrated that they could induce apoptosis in Tax-expressing, patient-derived CD4+ T cells by inhibiting KDR with existing small-molecule drugs.1 The problem, Harhaj explained, is that HTLV-1-infected cells can downregulate Tax: “We found that these KDR inhibitors can cause Tax degradation through autophagy—That’s why they only worked on the Tax-positive cells. The tax negative cells, of course, don’t have Tax, so KDR inhibitors had no effect on their viability.”
Vaccine Development and CRISPR Strategies
HTLV-1 researchers have long sought to develop a preventative vaccine for the virus. Despite being an easier target than HIV, Purcell said that developing vaccines for HTLV-1 has been challenging. In the development of their current mRNA lipid nanoparticle (LNP) vaccine candidate, Purcell and his team applied key learnings from HIV vaccine development, such as the importance of presenting the authentic spike protein structure that is seen on the outside of the virus particles and virus-infected cells.
“[The vaccine] is like a spring-loaded machine; we don’t want it to pop, we want it to be in the spring-loaded form,” Purcell said. “We spent a lot of time with many, many mutations to find ones that are going to hold it in that spring-loaded, pre-fusion structure.”
Another challenge they had to overcome was HTLV-1’s propensity to bond with proteins expressed on the surface of infected cells and form a biofilm. “It’s a virus that likes to be associated with the cell very closely,” explained Purcell. “…it can produce particles, but they tend to get stuck on the surface of the cell.”
To address this, the team identified mutations that would reduce the formation of this biofilm and coded them into the mRNA sequence. These mutations also enabled the spring-loaded structure to be soluble and secreted from the cells that took up the vaccine, making it better at eliciting neutralizing antibodies.
Although Panfil is developing similar vaccine strategies, she has also been exploring less traditional treatment options. Using CRISPR gene editing technology, Panfil and her colleagues have been targeting Tax and Hbz to kill infected cells. The team have screened over 200 guide RNAs targeting these regions of the genome, selecting the candidate with the highest editing efficiency for functional knockout of the proteins. The next major obstacle, Panfil said, is getting such a therapeutic candidate into the target cells in vivo. “We have not yet delivered CRISPR in an animal. I think that’s a big challenge for this field,” she said.
Securing funding continues to be a challenge for HTLV-1 researchers, and despite her optimism, Panfil hopes for better awareness about HTLV-1 and its potential broader impacts. “This is definitely something you want to keep tabs on,” she cautioned. “You don’t want to stop testing organ donations or stop testing the blood supply.”
In Australia, Purcell continues to work with indigenous elders and advocacy groups to deliver real solutions for people in remote communities. “When we come and meet with the community leadership, they say, ‘Wow, the science is really delivering things that are going to be potentially solving problems’,” he said. “They can see that the solution lies in the science, so it’s been a beautiful two-way dialogue.”
