PERSPECTIVE PERSPECTIVE The discovery of HTLV-1, the first pathogenic human retrovirus John M. Coffin1 Tufts University School of Medicine, Boston MA 02111 Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved November 11, 2015 (received for review November 2, 2015) After the discovery of retroviral reverse transcriptase in 1970, there was a flurry of activity, sparked by the “War on Cancer,” to identify human cancer retroviruses. After many false claims resulting from various artifacts, most scientists abandoned the search, but the Gallo laboratory carried on, developing both specific assays and new cell culture methods that enabled them to report, in the accompanying 1980 PNAS paper, identification and partial characterization of human T-cell leukemia virus (HTLV; now known as HTLV-1) produced by a T-cell line from a lymphoma patient. Follow-up studies, including collaboration with the group that first identified a cluster of adult T-cell leukemia (ATL) cases in Japan, provided conclusive evidence that HTLV was the cause of this disease. HTLV-1 is now known to infect at least 4–10 million people worldwide, about 5% of whom will develop ATL. Despite intensive research, knowledge of the viral etiology has not led to improvement in treatment or outcome of ATL. However, the technology for discovery of HTLV and acknowledgment of the existence of pathogenic human retroviruses laid the technical and intellectual foundation for the discovery of the cause of AIDS soon afterward. Without this advance, our ability to diagnose and treat HIV infection most likely would have been long delayed. human retrovirus | adult T-cell leukemia The late 1970s and early 1980s were banner kinase) of a number of oncogene products that lacked oncogenes, which often had no years for the study of cancer. Until 1980, re- (13), (iv) the discovery that retroviruses that visible effect on cell cultures—far superior search on molecular, genetic, and viral mech- lack oncogenes (often called leukemia viruses) to the cumbersome and insensitive electron anisms of oncogenesis was largely confined can cause cancer by rare integration of their microscope techniques then in use. As we to experimental animal models—particularly DNA in the vicinity of protooncogenes, shall see, this tool turned out to be a two- mice and chickens, and cells derived from thereby altering the regulation of their ex- edged sword. Third, by validating a plausible them—that dated back to near the beginning pression (14), (v) the recognition that many molecular mechanism by which certain of the century. The applicability of the findings human cancers (including Burkitt’slym- RNA viruses—now called retroviruses—could of these studies, and of the tools used in them, phoma) contained protooncogenes altered by modify the genomes of normal cells to trans- to human disease remained to be established. mutation or chromosomal rearrangement in form them into cancer cells, it provided a Indeed, the 1979 Cold Spring Harbor Sympo- ways similar to what happens in retrovi- significant impetus to the Special Virus Can- — “ ”— sium entitled Viral Oncogenes focused ruses, but in the absence of viral involve- cer Program (SVCP), originated about 10 y – entirely on animal viruses and cancers, and ment (15 17), and (v) the discovery that a earlier, which was to become a major part of not one of the 125 talks from most of the relatively common and widespread cancer the “War on Cancer” proclaimed by then US leading tumor virology laboratories discussed (cervical carcinoma) was caused by infec- President Richard Nixon and made real by ’ human cancer (1). At that time, only Burkitt s tion with a DNA virus, human papilloma the passage of the National Cancer Act in lymphoma, a rare disease limited to malaria- virus (18). Rounding out this list is the dis- 1971 (24). rich regions of Africa, was known to be asso- covery of human T-cell leukemia virus The availability of new tools, including ciated with virus infection (2), and there was (HTLV; now known as HTLV-1), the first “ ” reverse transcriptase assays, as well as sub- only one human retrovirus, an uncommon pathogenic human retrovirus, reported in the stantial funding available through SVCP nonpathogenic spuma (or foamy) virus caus- paper reprinted in this issue of PNAS as part contracts, led many well-established investi- ing occasional zoonotic infections after trans- of the 100th anniversary series (19). gators to join in renewed efforts to identify mission from infected chimpanzees (3). This The discovery of retroviral reverse tran- retroviruses associated with human cancer, situation was soon to change dramatically. scriptase (RT) in 1970 (20, 21) had a number and, as incisively reviewed by Weiss and This time period was noteworthy for many of consequences beyond providing dramatic coworkers (25, 26), the early 1970s saw discoveries, based on earlier virus studies, that proof for the provirus theory of retrovirus provided the foundation for modern cancer replication put forward by Temin years ear- research, as well as therapy and prevention. lier and discussed by Vogt (22, 23). For one, Author contributions: J.M.C. wrote the paper. Among these discoveries were the following: it provided an important tool for molecular The author declares no conflict of interest. (i) the identification and clarification of nu- biologists, enabling them to make DNA cop- This article is a PNAS Direct Submission. merous retroviral oncogenes (4–11), (ii)the ies of RNA at will for studies using molecular This article is part of the special series of PNAS 100th Anniversary discovery that these genes are derived from hybridization, and, eventually, cloning, PCR, articles to commemorate exceptional research published in PNAS over the last century. See the companion article, “Detection and normal cellular genes (protooncogenes) of and deep sequencing. Second, because of isolation of type C retrovirus particles from fresh and cultured the host and that close homologs are present its presence in virus particles (virions), lymphocytes of a patient with cutaneous T-cell lymphoma,” on in human DNA (12), (iii) the identification RT provided a simple means of detecting page 7415 in issue 12 of volume 77. of a novel enzymatic activity (protein tyrosine and quantitating viruses—particularly ones 1Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1521629112 PNAS | December 22, 2015 | vol. 112 | no. 51 | 15525–15529 Downloaded by guest on September 27, 2021 numerous publications reporting the detec- but turned out to be complexes of cellular associations by the discovery of reverse tran- tion of new retroviruses in human cancers, RNA and DNA polymerase (particularly γ), scriptase and both its mechanistic implications all of which proved to be due to artifacts of which, under certain conditions, can use RNA and its practical utility in virus discovery. one sort or another, such as contamination as a template. By the end of the decade, most Their early papers on distinguishing viral from – of cell lines with infectious viruses of other investigators had abandoned the search. cellular DNA polymerases (28 31) were im- portant in clearing up some of the confusion species, often during transmission of hu- Prelude to the 1980 PNAS Paper man tumors as xenotransplants, or simply as to what constituted a true retroviral RT According to his autobiography (27), Robert during growth in the same laboratory. In signal. The group also made important ad- Gallo was drawn to medicine, particularly to vances in the technology for growing blood other cases, investigators were misled by cancer research, by the death of his sister cells—particularly T cells—in culture, culmi- the production in some cancer cell lines from leukemia at a very young age, and, after nating in the discovery and partial purifi- of noninfectious particles arising from ex- receiving a Doctor of Medicine degree and cation of T-cell growth factor (now called pression of certain endogenous proviruses subsequent training, he gravitated to the IL-2) from phytohemagglutinin-stimulated common to all humans. A number of in- National Cancer Institute (NCI), becoming T cells (32), and its use to establish, for the vestigators also reported the presence in head of its Laboratory of Tumor Cell Biology first time, continuous cultures of normal and some cancers of particles containing both (LTCB) in the early 1970s. Like many other malignant T cells. These tools—the culture RNA and associated reverse transcriptase, groups, the Gallo laboratory was apparently techniques and the availability of the key which could have been retrovirus virions, motivated to search for retrovirus–cancer growth factor—not only enabled the dis- covery of HTLV described in the accom- panying PNAS Anniversary paper, but also subsequently made possible the rapid dis- covery and characterization of HIV by both the Gallo and Montagnier groups several years later (33, 34). The lesson that many researchers appar- ently took from the plethora of false discov- eries of supposedly human retroviruses, dubbed “human rumor viruses” (25), was that the search was a futile one, and most turned their attention elsewhere. The Gallo laboratory, although not immune to the same problem (35), nonetheless carried on, only setting the bar much higher. According to a latermemoir(36),theynowhadalistof requirements (a sort of updated Koch’spos- tulates) that any candidate human retrovirus must pass before it could be reported (here slightly modified from the original): (i)It must be present in freshly isolated uncultured (or briefly cultured) tissue from a patient, as well as cultured cells or cell lines; (ii)itmust be novel, not closely related to any known animal retrovirus; (iii)itmustinfecthuman target cells in vitro; (iv) there must be specific antibodies against it in the patient from which it was isolated; (v) integrated (proviral) DNA must be present in the cells from which it was isolated; and (vi) there must be evidence of infection (e.g., serological) with the same virus in other patients with the same disease.