The origins of viruses: discovery takes time, international resources, and cooperation
Authors: Yigang Tong, Wenli Liu, Peipei Liu, William J Liu, Qihui Wang, George F Gao
Journal: The Lancet (2021)

Revealing the origins of SARS-CoV-2 is a prerequisite for cutting off the virus from the root and preventing future spillover of the virus. This work is of great significance in infection disease prevention and control in the face of Disease X.1Gao GF From "A"IV to "Z"IKV: attacks from emerging and re-emerging pathogens.Cell. 2018; 172: 1157-1159Summary Full Text Full Text PDF PubMed Scopus (199) Google Scholar Although scientists around the world are searching very hard, the origins of SARS-CoV-2 remain elusive. In fact, for many infectious pathogens, although their origins have been traced back decades, the debate around the origins remains alive. HIV is a good first example. The first official report about AIDS was made on June 5, 1981, by the US Centers for Disease Control and Prevention. 5 years later, Nahmias and colleagues2Nahmias AJ Weiss J Yao X et al.Evidence for human infection with an HTLV-III/LAV-like virus in central Africa, 1959.Lancet. 1986; 3271279Abstract Scopus (125) Google Scholar discovered a human serum sample collected in Léopoldville (now Kinshasa, Democratic Republic of the Congo) in early 1959 that suggested exposure to HIV. Phylogenetic analysis subsequently suggested that an HIV ancestor had been introduced to Africa before 1959,3Zhu T Korber B Nahmias A et al.An African HIV-1 sequence from 1959 and implications for the origin of the epidemic.Nature. 1998; 391: 594-597Crossref PubMed Scopus (353) Google Scholar and a relatively recent report, from 2008, revealed that the HIV-1 M group originated in about 1908 (CI 1884–1924) and has been circulating in the population for about 100 years.4Worobey M Gemmel M Teuwen DE et al.Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960.Nature. 2008; 455: 661-664Crossref PubMed Scopus (434) Google Scholar In 2004, human coronavirus HKU1 (HCoV-HKU1) was identified from a patient with pneumonia who returned to Hong Kong from Shenzhen, China.5Woo P Lau S Chu CM et al.Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia.J Virol. 2005; 79: 884-895Crossref PubMed Scopus (1186) Google Scholar However, since then, HCoV-HKU1 positive signals have been detected across the globe and spanning decades: in specimens from Australian children that were collected in 2004,6Sloots TP McErlean P Speicher DJ et al.Evidence of human coronavirus HKU1 and human bocavirus in Australian children.J Clin Virol. 2006; 35: 99-102Crossref PubMed Scopus (316) Google Scholar in respiratory specimens collected in Connecticut, USA, in 2001–02,7Esper F Weibel C Ferguson D et al.Coronavirus HKU1 infection in the United States.Emerg Infect Dis. 2006; 12: 775-779Crossref PubMed Scopus (116) Google Scholar in Finnish children in 1996–98,8Ruohola A Waris M Allander T et al.Viral etiology of common cold in children, Finland.Emerg Infect Dis. 2009; 15: 344-346Crossref PubMed Scopus (79) Google Scholar and in nasopharyngeal swab samples from children in Brazil that were frozen in 1995.9Goes LG Durigon EL Campos AA et al.Coronavirus HKU1 in children, Brazil, 1995.Emerg Infect Dis. 2011; 171147Crossref Scopus (11) Google Scholar The virus that causes severe fever with thrombocytopenia syndrome, SFTSV, was discovered in Henan province, China, in 2009.10Yu XJ Liang MF Zhang SY et al.Fever with thrombocytopenia associated with a novel bunyavirus in China.N Engl J Med. 2011; 364: 1523-1532Crossref PubMed Scopus (1275) Google Scholar This discovery prompted SFTSV testing of samples obtained from patients in Jiangsu province, China, who had similar clinical manifestations in 2007 but whose aetiology was elusive, with positive results.11Bao CJ Guo XL Qi X et al.A family cluster of infections by a newly recognized bunyavirus in eastern China, 2007: further evidence of person-to-person transmission.Clin Infect Dis. 2011; 53: 1208-1214Crossref PubMed Scopus (232) Google Scholar Other researchers tested serum samples from six patients with fever and thrombocytopenia in Yixing County, Jiangsu province, China, in 1996. And on the basis of epidemiological, clinical, and retrospective serological studies, the pathogen in this small cluster was confirmed to be SFTSV. 12Hu JL Shi C Li ZF et al.A cluster of cases of severe fever with thrombocytopenia syndrome bunyavirus infection in China, 1996: a retrospective serological study.PLoS Negl Trop Dis. 2018; 12e0006603Crossref Scopus (22) Google Scholar MERS-CoV was first reported in a Saudi Arabian man, aged 60 years, who died in 2012.13Zaki AM Boheemen S Bestebroer TM et al.Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.N Engl J Med. 2012; 367: 1814-1820Crossref PubMed Scopus (4222) Google Scholar The transmission route of this virus from animals to humans is not well understood, but dromedary camels are considered the major intermediate host of MERS-CoV,14Azhar EI El-Kafrawy SA Farraj SA et al.Evidence for camel-to-human transmission of MERS coronavirus.N Engl J Med. 2014; 371: 1359-1360Crossref PubMed Scopus (101) Google Scholar and bats are thought to be reservoir hosts. The discovery of antibodies in serum samples collected in 2003 indicates that MERS-CoV, or a closely related virus, had been prevalent in dromedary camels in the region long before the first MERS case was identified in humans. Alagaili and colleagues15Alagaili AN Briese T Mishra N et al.Middle East respiratory syndrome coronavirus infection in dromedary camels in Saudi Arabia.mBio. 2014; 5: e00884-e00894Crossref PubMed Scopus (30) Google Scholar have proved that MERS-CoV had been circulating in camels since at least 1992 and can be phylogenically classified into clades related to human disease outbreaks. In 2014, researchers tested 189 stored dromedary camel serum samples collected in Egypt in 1997 and in Sudan and Somalia in 1983–84. 81% of the samples had neutralising antibodies against MERS-CoV, suggesting long-term virus circulation in these animals.16Müller MA Corman VM Jores J et al.MERS coronavirus neutralizing antibodies in camels, eastern Africa, 1983-1997.Emerg Infect Dis. 2014; 20: 2093-2095Crossref PubMed Scopus (237) Google Scholar As these cases show, tracing the origins of a virus requires long-term and extensive sample accumulation, which can take several years or decades. The geographical origins of a virus might not rely on an initial sick patient, and in some cases the index patient might never be found. Real-time RT-PCR and high-throughput sequencing technologies will help clarify the origins of emerging viruses, and in-depth research needs to be carried out from epidemiology, genomics, aetiology, and serology to lay the foundation for research on intermediate animal hosts, virus sources, and the transition of a virus into the human population. Patients with similar symptoms before the pandemic should therefore be re-evaluated,17The Lancet Infectious Diseases"In an ocean of ashes, islands of order": WHO's SARS-CoV-2 origin report.Lancet Infect Dis. 2021; 21: 579Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar and stored samples from a broad geographical area should be re-tested. Blood and tissue banks are important resources for retrospective serological or genomics studies, especially by looking into the epidemiology of the disease in countries or regions where evidence of the virus has appeared in blood samples or environmental samples before the outbreak. Comprehensive genomic studies in animal species that are susceptible to the virus are necessary to identify the natural or intermediate hosts. Finally, the experience of on-going progress with HIV, HCoV-HKU1, SFTSV, and MERS-CoV origin studies shows that open-mindedness and close international cooperation are pivotal for tracing the origins of any viruses. Stay away from politicisation of the origins of the COVID-19 causative agents, and work together globally for science. We declare no competing interests. YT and WL contributed equally to this Correspondence.