The viruses that gave rise to SARS-CoV-2 have been circulating in horseshoe bats and related mammals across Asia for millennia, and most of them have never spilled over into people. Yet a small number of these bat sarbecoviruses clearly can infect humans, as the COVID-19 pandemic demonstrated. A central question for pandemic preparedness has therefore been whether scientists can look at the properties of a newly discovered bat coronavirus and make an evidence-based judgement about how dangerous it might be. A new study published in PLOS Biology suggests that one measurable property, the breadth of species whose ACE2 receptor a virus can use, may be a surprisingly informative signal, predicting not only which animals a virus can infect but also how closely related it is to SARS-CoV-2 in the eyes of the human immune system.

Sarbecoviruses, the subgenus of coronaviruses that includes SARS-CoV and SARS-CoV-2, attach to their host cells through the receptor-binding domain, or RBD, of the Spike protein. This domain grips the angiotensin-converting enzyme 2 receptor, ACE2, on the surface of host cells, and it is also the principal target of neutralising antibodies. That dual role creates an intimate link between host range and antigenicity: the same molecular surface that determines which species’ receptors a virus can engage also determines how well antibodies raised against one virus recognise another. The research team, led by scientists at The Pirbright Institute together with collaborators including researchers at King’s College London, set out to map that relationship systematically across a diverse collection of bat sarbecoviruses.

The experimental strategy combined three complementary approaches. First, the researchers used binding assays to test whether the Spike proteins of different sarbecoviruses could attach to ACE2 proteins from a wide panel of mammalian species. Second, they used pseudotype-entry assays, in which harmless lentiviral particles are decorated with each coronavirus Spike protein, to test whether receptor binding actually translates into cell entry. Third, they measured how sera from SARS-CoV-2 convalescent individuals and monoclonal antibodies from vaccinated people who had experienced breakthrough infections neutralised the different viruses. By running the same viruses through all three assays, the team could directly correlate receptor usage with antigenic behaviour.

The results revealed a striking pattern. Sarbecoviruses in clade 1, the group that contains SARS-CoV-2 itself and the BANAL viruses isolated from bats in Laos, tended to be generalists. Their Spike proteins could productively engage ACE2 receptors from many different bat species, indicating that they are not finely tuned to a single host. In contrast, viruses from clade 3, exemplified by RhGB07, and clade 5, exemplified by Rc-o319, behaved as specialists, using a much narrower range of ACE2 receptors. Rc-o319, which was previously known to be unable to use human ACE2 efficiently, fits this specialist profile, whereas the BANAL viruses, which can use human ACE2, sit firmly in the generalist camp alongside SARS-CoV-2.

To understand the structural basis of this specialism, the team solved a novel structure of the RhGB07 Spike protein. The structure allowed them to identify specific residues within the RBD that are associated with the restricted receptor usage of this clade 3 virus. These residues presumably shape the receptor-binding interface in ways that favour particular bat ACE2 variants while excluding others. Such structural insights are valuable because they point to the molecular features that distinguish viruses capable of flexible receptor engagement from those locked into narrow host ranges, and they may help predict the properties of newly discovered sarbecoviruses from sequence data alone.

When the researchers extended their receptor panel beyond bats to include more diverse mammalian ACE2 proteins, the generalist phenotype largely held. Clade 1 viruses could bind and enter cells expressing ACE2 from humans, non-human primates, livestock, and rodents, as well as from species considered potential intermediate reservoir hosts, such as civets, raccoon dogs, and pangolins. This is significant because intermediate hosts are thought to have played a role in previous coronavirus spillovers, including the emergence of SARS-CoV in 2002. A virus that can already use the receptors of many species faces fewer barriers on the path from bat to human. The specialist viruses, by contrast, showed wider phenotypic diversity across this expanded panel, with RhGB07 exhibiting a more idiosyncratic pattern of receptor usage that did not simply mirror its bat-host profile.

The study also examined how SARS-CoV-2’s ongoing evolution in humans has changed its receptor preferences. Comparing variants that have emerged during the pandemic, the researchers found an expanding and, in some cases, shifting pattern of generalism, particularly for Omicron and its many sub-lineages. Omicron’s Spike has accumulated numerous mutations in the RBD, and these changes appear to have broadened or reconfigured the range of ACE2 molecules the virus can engage. This observation underscores that receptor usage is not a fixed property of a virus but a dynamic trait that can evolve under immune pressure and changing transmission landscapes, with potential consequences for which animal species might serve as new reservoirs for human-derived variants.

The antigenic side of the analysis produced equally important findings. When convalescent sera from people who had recovered from COVID-19 were tested against the panel of bat sarbecoviruses, clade 1 viruses, being phylogenetically closest to SARS-CoV-2, were antigenically the most similar. There was robust evidence for cross-neutralisation of these viruses, meaning that immunity generated against SARS-CoV-2 offers meaningful protection against its closest bat relatives. Importantly, however, the team also found evidence for limited cross-neutralisation across the entire subgenus, suggesting that even the more distantly related specialist viruses are not completely invisible to immunity primed by SARS-CoV-2 infection. This graded pattern of cross-reactivity maps closely onto the phylogenetic and receptor-usage relationships the researchers had established.

Using monoclonal antibodies derived from COVID-19 vaccinees who subsequently experienced breakthrough infections, the researchers were able to pinpoint which classes of antibody epitopes are responsible for the broader neutralisation observed across the sarbecovirus panel. Because antibodies recognise specific structural features of the RBD, identifying the epitope classes that mediate cross-neutralisation provides a rational basis for designing vaccines and therapeutics with deliberately broad coverage. Antibodies directed against more conserved features of the receptor-binding interface, rather than those specific to SARS-CoV-2’s particular configuration, appear to underpin the wider neutralising activity.

Taken together, the study delivers a unifying message: generalist ACE2 usage, phylogenetic proximity to SARS-CoV-2, and antigenic similarity travel together. A bat sarbecovirus that can flexibly use receptors from many mammalian species is likely to be a close relative of SARS-CoV-2 and likely to be partially neutralised by existing human immunity. This constellation of traits offers surveillance teams a practical framework for triage. When a new sarbecovirus is discovered, characterising its receptor-binding breadth through binding and pseudotype assays could provide an early, laboratory-based assessment of both its zoonotic potential and the degree to which current vaccines and antibodies might protect against it. As bat habitats are disturbed and human-wildlife interfaces expand, such tools for distinguishing the generalists from the specialists among the thousands of circulating bat coronaviruses could prove essential for anticipating, and perhaps preventing, the next spillover.

Subject of Research: ACE2 receptor usage breadth as a predictor of host range and antigenic relatedness across bat sarbecoviruses

Article Title: Breadth of ACE2 receptor usage predicts host range and antigenic relatedness across bat sarbecoviruses

Article References: Thakur, N., Newman, J., Ni, D., Seow, J., Hay, A. L., Lee, Y., Upadhyay, A., Ekundayo, B. E., Hammond, J. A., Peacock, T. P., Lau, K., Doores, K. J., & Bailey, D. (2026). Breadth of ACE2 receptor usage predicts host range and antigenic relatedness across bat sarbecoviruses. PLOS Biology, 24(10), e3003944. https://doi.org/10.1371/journal.pbio.3003944

Image Credits: AI Generated

DOI: 10.1371/journal.pbio.3003944

Keywords: sarbecoviruses, ACE2, SARS-CoV-2, host range, receptor-binding domain, antigenicity, cross-neutralisation, bat coronaviruses, zoonotic spillover, Omicron, monoclonal antibodies, pseudotype assays

A silent liver-destroying virus continues to spread across the United States at an accelerating pace, even though the drugs that cure it have been on pharmacy shelves for nearly a decade. In a perspective article published in the Journal of General Internal Medicine, two University of California, Los Angeles physicians argue that the nation’s faltering response to hepatitis C could be rescued by borrowing the playbook that transformed the HIV epidemic, from community-based testing and rapid “test and treat” initiation to federally funded safety nets and a fundamental reframing of what treatment nonadherence actually means.

The paper, written by Dr. Anna C. Scialli of UCLA’s Division of General Internal Medicine and Dr. Tara Vijayan of the Division of Infectious Diseases, opens with a clinical vignette that captures the paradox of modern hepatitis C care. A 34-year-old man with a history of injection drug use and unstable housing arrived at a hospital with fever, fatigue, and shortness of breath, and was found to have Staphylococcus aureus endocarditis with septic emboli. Screening revealed chronic hepatitis C virus infection. He was eager to begin treatment, and during a 39-day admission that included respiratory failure management and tricuspid valve replacement, clinicians started him on glecaprevir-pibrentasvir, obtained through the institution’s specialty pharmacy because the drug was not on the hospital formulary. It is precisely this kind of opportunistic, in-hospital treatment that the authors want to make routine.

The numbers they cite are stark. Between 2015 and 2022, the United States saw an estimated twofold increase in acute hepatitis C infections, yet only about a third of insured individuals diagnosed with the virus receive treatment within a year of diagnosis. Up to four million Americans are believed to carry the virus. By contrast, in HIV care, where the “care cascade” framework originally took root, roughly 76 percent of people diagnosed with HIV receive care and 65 percent are virally suppressed. The cascade framework, which tracks patients through sequential steps of diagnosis, linkage to care, receipt of direct-acting antivirals, and achievement of sustained virologic response, has been adopted by hepatitis C elimination strategies, but outcomes at every step have persistently lagged behind HIV milestones.

On the surface, the two viruses could hardly be more different biologically. Untreated HIV progressively depletes CD4 lymphocyte counts, producing the opportunistic infections and malignancies that define AIDS, a disease that is fatal within years for all but a rare fraction, less than half a percent, of “long-term non-progressors.” Chronic hepatitis C, meanwhile, may smolder asymptomatically for decades, gradually driving liver inflammation and fibrosis, with an estimated 5 to 10 percent of patients developing cirrhosis after twenty years and a 1 to 3 percent cumulative rate of hepatocellular carcinoma after thirty years. But the authors emphasize that the two epidemics share a critical social anatomy: both concentrate in the most marginalized communities, among people with limited access to prevention and treatment and distinct socioeconomic disparities. Their public health histories, they argue, overlap enough to yield forty years of transferable lessons.

The parallels run deep from the very beginning. HIV was first observed in New York as early as 1978 but was not formally reported until 1981, when Los Angeles physicians described Pneumocystis pneumonia in five men who have sex with men in the CDC’s Morbidity and Mortality Weekly Report. By 1990, more than 100,000 Americans had died of AIDS, and the disease, pejoratively labeled a “gay cancer,” became a vehicle for stigma and the marginalization of sexual minorities. Hepatitis C followed an eerily similar timeline. First described in 1975 as “non-A, non-B hepatitis” among transfusion recipients, accounting for up to 90 percent of transfusion-associated hepatitis, it was not definitively identified until 1989, when researchers isolated HCV RNA and developed an antibody test. Widespread blood-supply screening followed by 1992, and screening recommendations evolved from risk-based targeting to universal one-time screening of all adults by 2020, as rising infection rates among younger people shifted the epidemic’s demographics.

Treatment histories also rhyme. HIV therapy evolved from poorly tolerated early regimens to the 1996 introduction of combination antiretroviral therapy, then single-tablet regimens in the 2000s that improved adherence and reduced toxicity, and most recently long-acting injectables such as cabotegravir and rilpivirine, which maintain viral suppression with dramatically reduced adherence barriers. Hepatitis C treatment traveled its own arc, from interferon-alpha with cure rates low enough and durations long enough, up to 72 weeks, to be nearly prohibitive, through pegylated interferon plus ribavirin combinations marked by flu-like symptoms, depression, and hemolytic anemia, to the revolutionary direct-acting antivirals of the 2010s. The pan-genotypic regimens first approved by the FDA in 2016, including glecaprevir-pibrentasvir and sofosbuvir-velpatasvir, now offer eight-to-twelve-week, once-daily courses with rare side effects, no laboratory monitoring, and cure in over 95 percent of those treated. Because the cure is short, simple, and complete, the authors note, the technical barriers to hepatitis C eradication should be far lower than for HIV. That they are not is the central problem.

The first lesson concerns testing. Only an estimated 55 percent of people with hepatitis C are aware of their diagnosis, compared with an estimated 87 percent of people living with HIV. In the HIV epidemic, the shift from risk-based testing toward universal opt-out screening, launched by the CDC in 2006 when 21 percent of infections were undiagnosed, helped reduce undiagnosed infections to 15 percent by 2015. Crucially, that progress was driven by low-barrier testing outside traditional health facilities: mobile clinics, emergency rooms, community health fairs, and inpatient units. For hepatitis C, the settings with the highest testing yields today are syringe service programs and clinics treating substance use disorder, but the authors insist these cannot be the only option, particularly since syringe service programs lack federal support. They advocate a broad test-and-treat strategy, including initiating direct-acting antivirals during hospital admission. Because most hospitals will not stock the drugs, they propose a practical mechanism: prescribing through a contracted specialty pharmacy that purchases medications at 340B pricing and delivers them to the bedside, stored securely on the ward much like an unavailable home medication.

The second lesson concerns insurance and funding. Many state Medicaid programs still impose sobriety requirements and fibrosis-stage restrictions on hepatitis C treatment, and states with such restrictions treat fewer patients, despite explicit recommendations from the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases to remove them. Private insurers are even less transparent, denying more than half of hepatitis C treatment claims in one national specialty pharmacy cohort study. HIV care took a different path: the Ryan White CARE Act of 1990 created a federally funded safety net covering antiretroviral therapy for uninsured and underinsured patients, now supporting 82 percent of uninsured people living with HIV. Early hospital initiation of antiretroviral therapy has been shown to improve linkage to care, especially for patients with substance use disorder. No equivalent exists for hepatitis C, even though an estimated 60 percent of people with the virus are covered by public insurance, and the 2025 One Big Beautiful Bill cut nearly one trillion dollars from Medicaid over the coming decade. Meanwhile, budget pressures threaten HIV’s own safety net: as of February 2026, twenty states were tightening AIDS Drug Assistance Program eligibility, and models estimate up to a 73 percent increase in new HIV infections across thirty states if that funding disappears.

The third lesson is the most philosophical. Provider hesitancy, particularly toward people who use drugs, remains a powerful barrier to hepatitis C treatment, with physicians frequently citing concerns about nonadherence. Yet studies show people who use drugs complete hepatitis C treatment more than 96 percent of the time. HIV advocacy movements, notably ACT UP, forced a reframing: nonadherence was reinterpreted not as a moral failing of the patient but as a failure of systems in which marginalized groups face enormous barriers. Current CDC guidelines now explicitly state that homelessness, substance use, and mental health conditions are not justifiable reasons to defer antiretroviral therapy, and federally funded supports, from Ryan White case management and patient navigation to the Housing Opportunities for Persons with AIDS program, address the social determinants that undermine adherence. Peer navigation programs and drug user unions are emerging as hepatitis C analogs, but without matching federal investment.

The Norway-based OPPORTUNI-C trial provides the empirical anchor for the authors’ central proposal: among people who inject drugs, 68 percent of those who began hepatitis C treatment while hospitalized completed it, compared with just 35 percent of those referred to outpatient care. For a population with frequent admissions and siloed inpatient care, the hospital bedside may be the single best opportunity to deliver a cure. As antiretroviral therapy became simpler and its community-level benefits clear, the authors write, reducing time to treatment initiation became not merely a public health measure but a moral imperative. With a twelve-week cure available, they argue, hepatitis C elimination now depends on treating patients where they are.