S CIENCE’ S C OMPASS 65 received a biopsy from another young gay common contaminants of cultured cells, an oped countries. In 1987, the first anti-HIV 64 male patient (MOI), who was infected with infectious pseudotype virus (LAI associated drug, AZT, which blocks HIV RT activity, 63 both HTLV and the new lymphadenopathy- with M. pirum) may have caused several was introduced. With the arrival of the HIV 62 associated virus. If MOI had been our first pa- contaminations between 1983 and 1984 in protease inhibitors and triple drug therapy 61 tient, we would have been very confused. different laboratories. in 1995, many patients are alive today who 60 A few months later, I received a blood New evidence that this strange retrovirus would otherwise have died. 59 sample from a young hemophiliac (LOI) was the cause of AIDS came from our team But we must not be complacent—the task 58 with full-blown AIDS, and blood and in the fall of 1983 and the winter of 1984 (7). ahead is immense. We still do not understand 57 lymph node samples from a young gay We observed a high frequency of antibodies the origin of the AIDS epidemic; the slow 56 man (LAI) with advanced Kaposi’s sarco- against the virus in lymphadenopathy pa- destruction of the immune system by factors 55 ma. The LAI virus could be isolated from tients, and noted the favored tropism of this in addition to HIV infection of CD4+ T cells; 54 the patient’s blood cells and grew very virus for CD4+ T lymphocytes. Our results the importance of cofactors in AIDS pro- 53 quickly in the patient’s cultured T lympho- were still controversial, however, and we had gression and virus transmission; and the na- 52 cytes, killing them as well as killing T difficulty in obtaining the funding needed to ture of the HIV reservoir that resists triple 51 lymphocytes from blood donors. In better characterize the virus and to develop a drug therapy. The next wave of advances in 50 September, we isolated a similar virus blood test. The tide only turned in France the fight against this worldwide scourge will 49 from the blood of a Zairian woman, ELI, when Robert Gallo and his group in the Unit- require the contribution and energy of us all. 48 who died of AIDS a week later. All of the ed States made a similar discovery. In the 47 isolated viruses showed cross-reactivity spring of 1984, Gallo published more con- References and Notes 1. P.Vigier, L. Montagnier Int. J. Cancer 15, 67 (1975). 46 between their gag proteins (p25 and p18) vincing evidence that HIV causes AIDS (8) 2. F. Barré-Sinoussi et al., Ann. Microbiol. (Inst. Pasteur) 45 (5). The viruses isolated from full-blown (see the Viewpoint by Gallo on page 1728), a 130 B, 349 (1979). 44 AIDS patients were more aggressive than finding that was confirmed by Jay Levy’s 3. M. Crepin, Biochem. Biophys. Res. Commun. 118, 324 (1984). 43 the BRU virus, and so I called them im- group (9). In 1985 came the cloning and se- 4. F. Barré-Sinoussi et al., Science 220, 868 (1983). 42 mune deficiency–associated viruses quencing of the HIV genome with identifica- 5. L. Montagnier et al.,inHuman T Cell Leukemia and 41 (IDAV). The viruses like BRU that were tion of new open reading frames specific for Lymphoma Viruses,R.C.Gallo, M. E. Essex, L. Gross, 40 Eds. (Cold Spring Harbor Laboratory, New York, 1984), isolated from patients who only suffered lentiviruses (10). This was followed by identi- pp. 363–379. 39 from lymphadenopathy were termed lym- fication of the HIV large surface glycoprotein 6. S.Wain-Hobson et al., Science 252, 961 (1991). 38 phadenopathy-associated viruses, or LAV. (11) and of T cell CD4 as the receptor for 7. Between 1983 and 1985 the team included the su- 37 This classification corresponded to the lat- HIV (12, 13). In 1986, HIV-2 was isolated perb retrovirologists Jean-Claude Chermann and Françoise Barré-Sinoussi and the following talented 36 er terminology of syncitium and nonsynci- from West African patients (14). individuals to whom I am indebted: M. Alizon, C. 35 tium-inducing strains. Over the past 20 years, the scientific and Axler-Blin, F. Brun-Vezinet, J. B. Brunet, S. Chamaret, F. 34 The retrovirus was new, as was the dis- legal controversies between our team and Clavel, S. Cole, O. Danos, C. Dauguet, J. C. Gluckman, J. Gruest, D. Guetard, D. Klatzmann, B. Krust, N. T. 33 ease. My collaborator, the electron micro- Gallo’s group have faded. We are left with Nugeyre, F. Rey, C. Rouzioux, W. Rozenbaum, P. Soni- 32 scopist Charles Dauguet, showed me pic- the salient fact that HIV was identified and go,E.Vilmer, and S. Wain-Hobson. 31 tures of the viral particles whose dark, shown to be the cause of AIDS less than 8. R. Kulstad, Ed., AIDS: Papers from Science, 1 1982–1985 (AAAS,Washington DC, 1986). 30 cone-shaped centers suggested that this 2 /2 years after this disease was first identi- 9. J. A. Levy et al., Science 225, 840 (1984). 29 virus was not the same as HTLV. Fellow vi- fied. It took only another 2 years for blood 10. S. Wain-Hobson et al., Cell 40,9 (1985). 28 rologist Edwald Edlinger suggested that I tests to become commercially available, re- 11. J. S. Allan et al., Science 228, 1091 (1985). 12. A. G. Dalgleish et al., Nature 312, 763 (1984). 27 compare the new virus with animal ducing almost to zero the transmission of 13. D. Klatzmann et al., Nature 312, 767 (1984). 26 lentiviruses, and, indeed, the pictures of vi- AIDS through blood transfusion in devel- 14. F. Clavel et al., Science 233, 343 (1986). 25 ral particles we obtained in June 1983 24 looked identical! As I told Robert Gallo, I VIEWPOINT: HISTORICAL ESSAY 23 was convinced that we were dealing with a 22 virus quite different from the HTLV family. 21 To better characterize the new virus, we The Early Years of HIV/AIDS 20 tried (unsuccessfully) to grow the BRU iso- 19 late in different T cell lines. If we had tried Robert C. Gallo 18 the LAI isolate instead, we would have been 17 able to grow the virus without any trouble. nimal retroviruses were among the World,” culminating in the closure of certain 16 In October 1983, we were finally able to earliest viruses discovered, and by the U.S. medical school microbiology depart- 15 grow the BRU isolate in Epstein-Barr A1960s some were shown to cause can- ments and a disturbing lack of support for the 14 virus–transformed B cell lines, although we cer. These findings prompted the formation U.S. Centers for Disease Control and Preven- 13 discovered later that the LAI virus had con- of the U.S. Virus Cancer Program, which tion (CDC). In the midst of this complacency, 12 taminated our BRU culture (6). At least six aimed to identify human tumor viruses, espe- my co-workers and I made human retrovirus- 11 laboratories received the LAI sample (under cially human retroviruses. By the late 1970s, es one of our primary research objectives. We 10 the name BRU) from our group and experi- however, a mistaken consensus emerged that were interested in leukemia and began to 9 enced the same contamination. We think viruses did not cause human cancer and that characterize the DNA polymerases in blood 8 that the LAI virus readily contaminated the human retroviruses did not exist, leading to cells (1, 2). Howard Temin had proposed that 7 BRU culture because it associates with a termination of the program. Even more per- retroviruses replicate through an integrated 6 mycoplasma species, Mycoplasma pirum, plexing was the assertion that serious epi- DNA intermediate, a notion supported by his 5 usually present in T cell lines. This physical demic diseases were limited to the “Third discovery with David Baltimore of a retrovi- 4 association makes a fraction of the LAI ral reverse transcriptase (RT). 3 virus highly infectious, and, in fact, this The author is at the Institute of Human Virology and This discovery provided me with an entry 2 fraction can be neutralized with antibodies Department of Microbiology and Immunology, Uni- point into the field because RT is a DNA poly- 1 against M. pirum. As mycoplasmas are versity of Maryland, Baltimore, MD 21201, USA. merase. We developed sensitive assays to de-

1728 29 NOVEMBER 2002 VOL 298 SCIENCE www.sciencemag.org S CIENCE’ S C OMPASS 65 tect RT in order to search for retroviruses at sequences. But by early 1983, we had found grown in continuous culture (something that 64 low levels in cell supernatants, membrane HTLV-related DNA sequences in only 2 of Montagnier and Chermann believed impos- 63 preparations, and long-term cell cultures. In 33 AIDS patients and had obtained virus sible because, even to this day, their 62 1972, we reported purification of an RT from isolates with equal infrequency. LAV/BRU virus cannot be cultured). 61 human lymphocytic leukemia cells. We real- It was in 1973 that I first met Luc Mon- In late 1983, Popovic and my technician 60 ized that to detect the human retrovirus pro- tagnier of the Pasteur Institute (14). In Jan- Betsy Reed-Connole had a second break- 59 ducing the RT, we would need to culture hu- uary 1983, Montagnier and his colleague through: They grew several viral isolates in 58 man blood cells for long periods and in greater Jean-Claude Chermann were beginning to CD4+ T cells in continuous culture. Several 57 numbers than possible with the available sys- study blood cell cultures from patients with of these viral isolates—RF (1983), IIIB 56 tem of colony growth on agar. So, we began to suspected AIDS. They told me of their first (1983), and MN (early 1984)—became stan- 55 analyze conditioned medium from various cell positive result: the culturing of a virus from dard tools for AIDS researchers and crucial- 54 types, including activated T cells, for the pres- the peripheral blood cells of a patient with ly enabled development of a blood test. In 53 ence of growth factors. We found a growth lymphadenopathy. They were able to identify March 1984, we submitted four papers to 52 factor that promoted myeloid cell growth, en- the virus as a new human retrovirus, but Science (15) and shortly thereafter one to 51 abling establishment of HL-60, the first hu- were unable to characterize it in detail. Essex Lancet (16). In these papers, we described 50 man granulocytic cell line. Next, with Doris and I suggested to Montagnier and Cher- isolates of the new retrovirus, methods for its 49 Morgan, our group discovered interleukin-2 mann that we submit our findings jointly, continuous production, analyses of its pro- 48 (IL-2), which we called T cell growth (mito- and three reports from the two groups were teins, and evidence that it was the cause of 47 genic) factor (3–5). This enabled my col- published in May 1983. Montagnier and AIDS. The rapid development of a blood test 46 leagues and I together with my postdoctoral Chermann had not named the virus, but later not only safeguarded the blood supply, but 45 fellow Bernard Poiesz to isolate the first hu- called it LAV (lymphadenopathy-associated also allowed public health officials to follow 44 man retrovirus, human T cell leukemia virus, isolated from patient BRU). the course of the disease in infected individ- 43 virus–1 (HTLV-1), in 1979 from a patient with There was still another “curve ball” to uals before they developed full-blown AIDS. 42 a T cell malignancy (6–8). Independent work come. In February 1983, a clinician (Jacques The blood test also yielded a grim vision of 41 the following year from several Japanese Leibowitch) arrived from Paris with cell the future—although sera from hemophiliacs 40 groups further documented that HTLV-1 samples from AIDS patients. One of these in Japan all tested negative in early 1984, by 39 caused a very specific adult T cell leukemia samples came from a man (CC) who had re- the end of that year, 20% of the sera were 38 endemic to Japan. HTLV-1 targets CD4+ T ceived blood transfusions in Haiti. My co- positive for HIV because the hemophiliacs 37 cells; it is transmitted from mother to child, worker Mika Popovic succeeded in growing had been treated with HIV-tainted blood 36 and through blood and sexual contact (9–11). CD4+ T cells from the sample. These T cells products from the United States. 35 This human retrovirus is prevalent in parts of were highly positive for RT, and electron mi- We visited Montagnier in Paris and 34 Africa, is closely related to Old World primate croscopy revealed that they contained two gave him our cell line continuously pro- 33 leukemia viruses, and causes minor immune viral forms, which we called “mature” and ducing HIV (called HTLV-IIIB/H9), so 32 impairment. In 1982, we reported the isolation “aberrant,” believing that they were from the that he could compare it with his 31 of the second human retrovirus, HTLV-2, from same virus. The virus from these T cells LAV/BRU isolate. We agreed to a joint 30 a case of hairy cell leukemia of the T cell type cross-reacted with antibodies to HTLV core press conference if our IIIB retrovirus 29 (12). The characteristics of HTLV-1 and proteins, yet unlike HTLV, it killed target T turned out to be the same as their 28 HTLV-2 foreshadowed the discovery of an cells. Using more sophisticated methods, we LAV/BRU isolate. However, a leak from a 27 even more sinister human retrovirus. quickly discovered that these T cells con- freelance journalist prompted Margaret 26 I first heard about AIDS in 1981 from tained two distinct retroviruses: HTLV-1 and Heckler, secretary of the U.S. Department 25 newspaper reports but more informatively the aberrant form, later defined as HIV. We of Health and Human Services (DHSS), to 24 from lectures given by Jim Curran of the had assumed that we could only find HTLV- call an urgent press conference to which I 23 CDC, who challenged the audience, asking like viruses in 5 to 10% of our AIDS patients was summoned home to attend, and from 22 “where are the virologists?” Theories of the because our assays were not sensitive which, very regrettably, the French group 21 cause of AIDS abounded, but Curran was al- enough, and had not considered the possibil- was excluded. 20 ready thinking of an infectious etiology, ity that our HTLV-positive cells were in fact The scientific achievements were over- 19 most likely a new virus (13). Max Essex re- infected with two separate retroviruses. shadowed by a dispute between the United 18 minded us that the feline leukemia retrovirus In our May 1983 paper, we had not sepa- States and France over the patent rights to 17 not only causes leukemia, but that its vari- rated and adequately cultured a retrovirus the blood test, and a temporary disagreement 16 ants could also cause immune disorders. We that was free of HTLV. Thus, the paper by among the scientists. Although patents were 15 knew that the risks for HTLV-1 infection in- the Montagnier/Chermann group is un- not common at the National Institutes of 14 cluded blood exposure, sexual contact, and equivocally the first reported true isolation Health back then, we were instructed by 13 birth to a mother with the disease, and also of HIV from a patient with lymphadenopa- DHHS officials to patent the blood test so 12 that HTLV-1 targeted CD4+ T cells. The thy. However, the cause of AIDS was still that pharmaceutical companies would be 11 same risk factors were described for AIDS, unknown. By the summer of 1983, our able to rapidly deploy the test worldwide. 10 and combined with clinical evidence that group had obtained evidence for a retrovirus Because it grew so well in T cell lines, we 9 CD4+ T cells were abnormal in AIDS pa- related to HTLV in many patients with selected the IIIB isolate to develop the blood 8 tients and epidemiological hints that AIDS AIDS and pre-AIDS. With a more detailed test. The dispute over the origin of this iso- 7 may have originated in equatorial Africa, this molecular analysis of the virus from patient late became sensationalized. In fact, our IIIB 6 led us to propose that AIDS might be caused CC, we concluded that the HTLV-positive isolate was accidentally contaminated with a 5 by a new retrovirus of the HTLV family. In results in samples from 5 to 10% of AIDS sample sent to us by Montagnier. This HIV 4 May 1982, using protocols similar to those patients were due to a double infection with strain (IIIB/LAI) later contaminated the cul- 3 for isolating HTLV-1, we tested blood cells HTLV and a new human retrovirus. More- tures of several other laboratories (17). 2 from AIDS patients for cross-reactivity with over, the early 1983 experience with sample Years later, we learnt that the same HIV 1 HTLV proteins and for HTLV-like DNA CC proved that the new retrovirus could be strain had earlier contaminated viral isolates

www.sciencemag.org SCIENCE VOL 298 29 NOVEMBER 2002 1729 S CIENCE’ S C OMPASS 65 of the French group. Montagnier and Cher- and most of its proteins were defined, and References and Notes 64 mann did not realize that virus from a pa- the blood supply in most developed nations 1. M. G. Sarngadharan, M. Robert-Guroff, R. C. Gallo, 63 Biochim. Biophys. Acta 516, 419 (1978). tient called LAI had contaminated their was rendered safe as a result of screening 2. M. G. Sarnagadharan, P. S. Sarin, M. S. Reitz, R. C. Gal- 62 LAV/BRU isolate. Although Montagnier be- for HIV. Next, came identification of the lo, Nature New Biol. 240, 67 (1972). 61 lieved he was sending LAV/BRU to us— HIV receptor (CD4), the discovery of SIV 3. S. Z. Salahuddin, P. D. Markham, F. W. Ruscetti, R. C. 60 and so did we—one culture consisted pre- in chimps, and the development of the first Gallo, Blood 58, 931 (1981). 4. S. J. Collins, R. C. Gallo. R. E. Gallagher, Nature 270, 59 dominantly of LAI. The properties of LAI anti-HIV drug, AZT. 347 (1977). 58 are very different from those of LAV/BRU, The late Jonathan Mann heralded the 5. D. A. Morgan, F. W. Ruscetti, R. C. Gallo, Science 193, 57 which does not grow in cell lines. Com- years 1982 to 1985 as a period of intense 1007 (1976). 56 pounding the complexity, although IIIB was discovery, noting that the pace of research 6. F. W. Ruscetti, D. A. Morgan, R. C. Gallo, J. Immunol. 119, 131 (1977). 55 clearly derived from LAI, it is not identical was the fastest in medical history. For some 7. J. W. Mier, R. C. Gallo, Proc. Natl. Acad. Sci. U.S.A. 77, 54 with LAI, but rather is a variant that grows scientists, these were also years of disquiet 6134 (1980). 53 vigorously because of mutations in some of and frustration; years in which we would 8. F. Wong-Staal, R. C. Gallo, Nature 317, 395 (1985). 52 its regulatory genes. All of this was ac- encounter in an unprecedented manner the 9. R. C. Gallo, J. Hum. Virol. 3,1 (2000). 10. ———, Nature Med. 1, 753 (1995). 51 knowledged by our group and the French negative face of politics, the media, patient 11. M.Yoshida, Annu. Rev. Immunol. 19, 475 (2001). 50 group in 1991 (18) (see the Viewpoint by activists, and legal issues. For myself and 12. V. S. Kalyanaraman et al., Science 218, 571 (1982). 49 Montagnier, on page 1727). others trained in science and disciplined by 13. R. C. Gallo, Virus Hunting AIDS, Cancer and the Hu- man Retrovirus: A Story of Scientific Discovery (Basic 48 The period after the May 1984 publica- the rigor and analysis that are the essence Books, New York, 1991). 47 tion of our papers was marked by rapid ad- of scientific endeavor, the rough and tum- 14. J. C. Chermann, J. Hum. Virol. 4, 289 (2001). 46 vances (15, 19). The HIV-1 genome was se- ble of the outside world provided harsh and 15. R. Kulstad, Ed., AIDS: Papers from Science, 45 quenced, HIV antigenic variation was dis- bitter lessons. In retrospect, it is clear that 1982–1985 (AAAS,Washington, DC, 1986). 16. B. Safai et al., Lancet 1, 1438 (1984). 44 covered, the virus was found in the brain of these lessons needed to be learnt, and I can 17. Repetitions of IIIB/LA1 contamination occurred in 43 AIDS patients, genomic sequence variation say we are better for the experience. But Robin Weiss’s laboratory in London, at the Frederick 42 was found in viral populations from the our job is far from over, and it is up to the National Cancer Institute laboratories, at Duke Uni- 41 same patient, macrophages were found to be scientists to ensure eradication of the AIDS versity, and very likely in several other laboratories, as well as the original contamination in France. 40 targets for HIV, various modes of HIV trans- epidemic that continues to rage in many re- 18. S.Wain-Hobson et al., Science 252, 961 (1991). 39 mission were elucidated, all of HIV’s genes gions of the world. 19. R. C. Gallo, Immunol. Rev. 185, 236 (2002). 38 37 VIEWPOINT: HISTORICAL ESSAY 36 cells, coreceptor binding, and fusion of the 35 viral and cellular membranes (3, 4). 34 Prospects for the Future What can be done to bring anti-HIV 33 therapy to developing countries with limit- 32 Robert C. Gallo and Luc Montagnier ed infrastructure? Administering these 31 therapies is complex, and patient compli- 30 ith close to 70 million people al- ence must develop new therapies that are ance is a major challenge. If compliance 29 ready infected with HIV and practical alternatives for the developing and careful follow-up of patients is not 28 Wmore than 20 million dead, AIDS world, as well as new microbicidals that achieved, we will see a dramatic increase 27 is one of the greatest pandemics in medical block sexual transmission, until an effica- in multidrug-resistant HIV mutants whose 26 history. Not only is this a human tragedy of cious vaccine arrives. further spread will only exacerbate the unimaginable di- In developed nations, the judicious use epidemic. With our 20 years of experi- Enhanced online at mensions, it is also of combination anti-HIV drug therapy has ence, we propose the following priorities www.sciencemag.org/cgi/ a threat to world se- substantially benefited HIV-infected peo- for eliminating AIDS worldwide. content/full/298/5599/1730 curity because of ple and has ended the pediatric epidemic. the potential for po- The Global Fund to Fight AIDS, Malaria Access to Antiretroviral Treatments 25 litical destabilization. The AIDS epidemic and Tuberculosis—launched by Koffi An- One of the main objectives of the Global 24 must be halted soon. We need a policy of nan, the secretary-general of the United Fund to Fight AIDS is to make anti-HIV 23 prevention that can be adapted to the socio- Nations—is spearheading efforts to trans- drugs accessible to all of the developing 22 logical and cultural conditions of the most late these advances worldwide. However, world. The problem of cost can be partly 21 devastated countries in Africa and Asia, the challenge is huge and has been com- solved by reducing drug prices (through 20 and that encompasses sustained interna- plicated by many factors, including the lower pricing acceptable to pharmaceutical 19 tional political will. New developments in emergence of multidrug-resistant HIV mu- companies, use of generic drugs, and finan- 18 AIDS research will contribute decisively to tants. New antivirals that target not only cial help from the Global Fund). But the in- 17 the decline of the epidemic and eventually dividing cells but also “resting” cells, and frastructure necessary for performing fol- 16 its eradication. From the beginning of the strategies that augment intracellular levels low-up of patients during treatment will be 15 epidemic, science has produced the most of active drug through modulation of costly and difficult, and the duration of such 14 important practical advances: from discov- metabolic pathways, may improve the suit- treatments will make them ultimately unaf- 13 ering the cause of AIDS to developing a ability of existing drugs (1, 2). New class- fordable for patients in poor countries. This 12 blood test and anti-HIV drugs. Now, sci- es of drugs, particularly HIV entry in- is an unprecedented situation. The decrease 11 hibitors, show promise. They have the ad- in plasma viral load achieved with triple 10 R. C. Gallo is at the Institute of Human Virology and vantage of stopping HIV before it estab- drug therapy does not stabilize after treat- 9 Department of Microbiology and Immunology, Uni- lishes new infections in host cells. Prelim- ment interruption, which results in a rapid 8 versity of Maryland, Baltimore, MD 21201, USA. L. Montagnier is President of the World Foundation for inary studies show impressive results with increase in circulating virus. Moreover, 7 AIDS Research and Prevention, 1 rue Miollis, Paris F- inhibitors that block each stage of HIV en- there are severe limitations to antiretroviral 6 75015, France. try: attachment and binding to CD4+ T therapy, including toxic side effects (lipid

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