Ten-year patent dispute between the United States and France: Who discovered the HIV virus first? | Forty years of the "incurable disease of the century"

AIDS is the most important new infectious disease of the 20th century. It was first discovered in 1980. Over the past 40 years, many stories have happened around the discovery of the pathogen HIV, the exploration of the pathogenic mechanism, and the research and promotion of treatment methods. In the main theme of a series of exciting major discoveries, there are also discordant noises such as transnational patent wars, Nobel Prize disputes, interference from HIV/AIDS deniers and the tragic loss of life caused by them. Looking back on the live dramas that have been performed on the HIV/AIDS stage over the past 40 years, it is enough to make people excited, thoughtful, or sigh.

Written by He Xiaosong (Retired Professor of University of California, Davis School of Medicine)

One of the most serious challenges facing contemporary medicine is infectious diseases caused by emerging pathogens, such as Ebola hemorrhagic fever, which first occurred in Africa, highly pathogenic avian influenza in Asia, SARS coronavirus pneumonia in 2003, and multi-organ disease caused by the new coronavirus SARS-CoV-2 in 2019. AIDS, once known as the "disease of the century", is the most important emerging infectious disease in the 20th century. Its pathogen is the human immunodeficiency virus (HIV). It is generally believed that HIV originated in the African jungle in the first half of the 20th century. A virus carried by wild apes entered the body of a hunter through the blood. After a series of mutations, it eventually evolved into a new virus that can efficiently infect humans. Since the 1980s, it has spread widely around the world. According to estimates by the World Health Organization (WHO), as of 2018, the cumulative number of people infected with HIV worldwide has reached 75 million, and the cumulative number of deaths has reached 32 million. African countries have suffered the most[1].

The Mystery of AIDS The world's first official report on a case of AIDS was published in 1981.

In October 1980, Cedars-Sinai Medical Center in Los Angeles, California, USA, admitted a young male patient who suffered from a rare pneumonia caused by fungi, referred to as PCP. He also suffered from a rare cancer called Kaposi's sarcoma (KS). The patient was cared for by David Ho, a young doctor born in Taiwan, who graduated from Harvard Medical School and was interested in medical research. He was undergoing internal medicine residency training and was looking for a research topic. In 1980, the medical community already knew that PCP complicated by KS, which generally only occurred when the immune system was damaged. Immune system defects can be congenital or acquired. Known acquired factors include anti-cancer chemotherapy drugs and immunosuppressive drugs. However, this patient was originally healthy, had no congenital immune defects, and had never been exposed to drugs that could damage the immune system.

The patient received a series of treatments including antifungal therapy in the hospital, but his condition did not improve. He died a few weeks later, leaving an unsolved mystery for David Ho and his medical team: What exactly damaged the patient's immune function? David Ho was very interested in this case and wanted to focus his research on "diseases related to immunodeficiency." His mentor disagreed, thinking that such cases were too rare and difficult to produce results. However, David Ho was determined. After completing his residency training in 1982, he moved to several medical schools and research institutions on the east and west coasts of the United States, working tirelessly in the same direction and finally making a contribution that attracted worldwide attention. Of course, this is a story for later, and we will see his name again later.

Over the next eight months, four more cases of PCP were admitted to three hospitals in the Los Angeles area. Like the first patient, all four were previously healthy gay men with a history of drug abuse and low levels of CD4 T lymphocytes (helper T cells) in their blood, a key immune cell.

After the case report of these five patients[2] was published in June 1981, it attracted the attention of the medical community. Similar cases were subsequently found among gay men in New York, San Francisco, and France, so that this strange new disease was once called "gay-associated immunodeficiency syndrome."

Soon after, Myron Essex, a virologist at Harvard University, also found similar cases of immunodeficiency in hemophiliacs. Hemophilia is a genetic disease in which patients lack certain clotting factors in their blood, so that even a small injury can cause severe bleeding. These patients need to receive frequent blood transfusions or concentrated clotting factors made from blood. Essex's discovery showed that this immunodeficiency disease could be an infectious disease that spreads through pathogens in the blood. As the number of cases increased dramatically, in September 1982, the Centers for Disease Control and Prevention (CDC) in the United States officially used "acquired immunodeficiency syndrome" (AIDS) as the name for this type of disease. Finding its cause became an urgent task for researchers from all over the world to compete.

In the race to find the pathogen of AIDS, the one who had the best timing, location and people was Robert Gallo, a virologist at the National Institutes of Health (NIH). In 1980, Gallo's team had just made an important research achievement, discovering the first human retrovirus - human T-cell leukemia virus type 1 (HTLV-1). Gallo also won the 1982 Lasker Basic Medical Research Award for this.

Retroviruses are a type of RNA virus. After infecting cells, they use the virus's reverse transcriptase to reverse transcribe viral RNA into proviral DNA, which is then inserted into the host cell's chromosomal DNA and becomes part of the chromosome. Along with the replication of the chromosome, it is passed on to the offspring of cell division. The proviral DNA on the chromosome can be transcribed to produce new viral RNA, which is then assembled into new viral particles. HTLV-1 infects human CD4 T cells. Most people do not have clinical symptoms after infection, but in a few people it may induce adult T-cell leukemia or lymphoma. The discovery of HTLV-1 depends on a series of important innovations in experimental technology by Gallo's team, especially the detection of reverse transcriptase activity and the in vitro culture of human T cells.

HTLV-1 infects CD4 T cells, and the typical symptom of AIDS is immunodeficiency caused by a decrease in CD4 T cells. Essex, who studies animal retroviruses, once found that a retrovirus called FTLV that infects cats' T cells can not only cause leukemia, but also cause immunodeficiency, causing cats to have symptoms similar to AIDS. Inspired by Essex, Gallo proposed that the culprit of AIDS might be an unknown retrovirus that can destroy T cells. Gallo's hypothesis spread, and searching for unknown retroviruses in T cells of AIDS patients soon became the main focus of colleagues from various countries. Gallo's team has the foundation and experience accumulated from years of research on HTLV-1, and is familiar with this work. If his hypothesis is correct, it should be easy to accomplish.

In addition to several AIDS research teams in the United States led by Gallo, Luc Montagnier of the Pasteur Institute in France also joined the race to find the culprit of AIDS at the end of 1982. There was a young female assistant in Montagnier's team, Françoise Barré-Sinoussi, who had studied T cell culture technology in Gallo's laboratory when she was a postdoctoral fellow at NIH. In January 1983, Montagnier received a special lymph node biopsy sample from a French gay patient with extensive lymphadenopathy (an early symptom of AIDS). He personally separated T cells from the sample and gave it to Barré-Sinoussi. Using the method created by Gallo's laboratory and the key reagents provided by Gallo, it took only a few weeks to detect a new retrovirus named lymphadenopathy-associated virus (LAV/BRU), BRU being the first three letters of the last name of the owner of the sample. Barré-Sinoussi and Montagnier wrote the results into a paper as quickly as possible and submitted it to Nature, but it was rejected. At Gallo's suggestion, Montagnier transferred the paper to Science, and Gallo sent a fax to the editorial office of Science, strongly recommending it. With Gallo's support, the paper was published in Science in May 1983, with Barry Synossi as the first author.

The paper by Montagnier’s team clearly stated that it remains to be determined whether LAV obtained from AIDS patients’ T cells is the cause of AIDS. Despite this, the paper is still recognized as the first official report on HIV. However, the evidence provided in the paper is far from sufficient to prove that LAV is indeed a new virus, rather than the known HTLV-1. Moreover, the paper was written in a hurry and contains many errors and omissions [3]. It was not until a year later, in April 1984, that Montagnier’s team published their follow-up work in The Lancet, clearly proving that LAV is indeed different from HTLV-1 and is a new T-cell retrovirus.

One month later, in May 1984, Gallo's team published four papers simultaneously in an issue of Science. Three of them reported that they had isolated a new retrovirus from T cells of 48 AIDS patients or individuals at high risk of AIDS, as well as the results of analyzing the characteristics of the virus using different methods. Because this virus is similar to HTLV-1 and HTLV-2 that they had previously discovered, Gallo named it HTLV-3. Importantly, the paper provided clear evidence that HTLV-3 is the pathogen that causes AIDS. In May 1986, the International Committee on Taxonomy of Viruses named LAV, HTLV-3, and similar viruses subsequently discovered by other teams as HIV.

In their early paper on LAV, Montagnier's team reported that LAV could not grow in cells cultured in vitro. Gallo's team's fourth paper reported that they had established a cell line and screened a batch of HTLV-3 viruses from different American patients. This cell line grew well in continuous culture in vitro and could produce a large number of virus particles. One of the strains was named HTLV-3B. In Gallo's view, this was a more remarkable achievement than the discovery of the virus itself. He once said:

“If you ask who discovered the polio virus, I bet you can ask 20 virologists and no one will know. Who proved that polio was caused by the polio virus? Even I don’t know. But if you ask who won the Nobel Prize for polio virus, it was John Enders, because he found a way to culture the polio virus!”[4]

In Gallo's team, the person who achieved in vitro culture of HTLV-3 was the first author of this paper, Mikylas Popovich, a postdoctoral researcher from Czechoslovakia who spoke English with a stutter.

Using the mass-produced HTLV-3B virus, Gallo's team developed an immunoassay technology to detect virus-specific antibodies in the blood. This is of great significance for the clinical diagnosis of AIDS and the screening of healthy blood donors by blood banks. At that time, hemophilia patients in the United States often encountered blood products contaminated with HIV during treatment, and the proportion of AIDS infection was as high as 20%! Ensuring the safety of blood transfusions and blood products has become an urgent task that cannot be delayed, and the business opportunities are even more obvious.

Although Montagnier's team was one step ahead of Gallo's team in publishing a paper reporting HIV, the Pasteur Institute was half a beat slower than NIH in applying for a patent. Only one year after Gallo's team published the article, the U.S. Patent Office granted the patent for AIDS blood test technology to NIH, and several American companies immediately began to produce and sell related products. Although the Pasteur Institute also submitted a patent application before Montagnier's team published the first LAV paper, the approval of the patent was delayed because it could not produce a clinically practical technology at the time of application. In August 1985, the Pasteur Institute sued NIH in the patent court with a lawsuit, sparking a patent dispute that lasted ten years. One focus of the dispute is who first discovered the HTLV-3B virus that NIH used in AIDS blood test reagents?

Patent War It turns out that although Gallo and Montagnier were competitors in HIV pathogen research, they always maintained a good cooperative relationship. In addition to exchanging information, they also exchanged virus samples isolated from their respective laboratories for the other party to compare and study. The donation of samples followed the common rules of the academic community, that is, they were only for scientific research and could not be used for commercial purposes. Montagnier gave LAV/BRU to Gallo twice, and Gallo gave HTLV-3B to Montagni between the two times.

In 1985, Gallo's team reported in a follow-up paper that HTLV-3 is highly variable. Not only do viral RNA gene sequences from different patients differ, but even the viral gene sequences collected from the same patient at different time points may differ. However, the HTLV-3B virus used by the NIH to apply for a patent was strikingly similar to the second LAV/BRU virus sample that Montagnier sent to Gallo, and could only be considered to have come from the same patient. Montagnier therefore concluded that there had been sample mixing or contamination in Gallo's laboratory, and that the LAV/BRU he sent was mistaken for HTLV-3B; Gallo flatly denied it, insisting that there had been sample mixing or contamination in Montagnier's laboratory, and that the HTLV-3B he sent was mistaken for LAV/BRU and then sent back to him. Although this explanation is incredible, Gallo is not without basis: the LAV samples he received twice were clearly different viruses. The first strain could not grow in cell culture, but the second strain grew well, just like HTLV-3B[3].

In the patent court, the lawyers of both sides argued fiercely and could not reach a settlement; outside the court, the case was widely reported by the media. This transnational patent war finally alarmed the highest levels of the French and American governments. On March 31, 1987, US President Reagan and visiting French Prime Minister Chirac jointly announced at the White House that the two countries had reached an agreement to resolve the patent dispute. It is probably the only time in human history that a patent agreement has been signed and announced by the heads of government in person. The agreement emphasizes that both the French and American teams have contributed to the development of AIDS blood test technology and should be regarded as co-inventors. The rights and interests of the patent should be shared by NIH and the Pasteur Institute, and the income will be divided equally between the two, and each will donate 80% of the income to a newly established International Foundation for AIDS Research. Neither Gallo nor Montagnier personally benefited from it.

Although the patent lawsuit was withdrawn, the disagreement over whether the HTLV-3B virus strain was American or French was not resolved, and it was still a mystery as to who was responsible for the sample mix-up. While Reagan and Chirac reached a patent agreement, Gallo and Montagnier also jointly signed a 7-page document, each stating their contributions to the discovery of HIV and blood test technology, and reserving their differences of opinion. The two promised to work together to conquer AIDS and resumed their collaborative relationship.

However, the apparent calm only lasted for two and a half years. On November 19, 1989, an independent investigative reporter John Crewdson published a 16-page investigative report in the Chicago Tribune, describing the discovery of HIV. The report claimed that Gallo's HTLV-3B was the LAV/BRU given to him by Montagnier, and the words accused Gallo of taking the virus discovered by the French for himself. This report was like a heavy bomb, making Gallo the target of public criticism overnight and under great pressure. As a result, the US government and Congress launched three investigations into Gallo and Popovich, which lasted for a full four years.

NIH commissioned Roche Pharmaceuticals of Switzerland to conduct RNA sequence analysis on all HIV virus strains used and exchanged in Montagnier and Gallo laboratories between 1983 and 1985, in order to determine the origin of each virus strain. The results surprised everyone: virus samples were mixed in both laboratories, and the mixing in Montagnier's laboratory happened first. A small amount of LAV/LAI, a virus from another French patient, was mixed into the LAV/BRU virus sample that Montagnier sent to Gallo. LAV/BRU cannot grow in cell culture, but LAV/LAI can grow. After LAV/LAI arrived at Gallo's laboratory, it was mixed into the HTLV-3 virus cultured by Popovich. After multiple replications, mutations occurred, and the growth became more vigorous. It was selected and named HTLV-3B. At this point, the truth came to light.

In 1991, Gallo himself finally admitted that the HTLV-3B virus used to apply for a patent for AIDS blood testing technology did come from France.

An accidental mistake? Deliberate theft? The source of HTLV-3B has been determined. The next question is, was it an accidental mistake, as Gallo said, or a deliberate theft, as Krusen accused, to mistake LAV/LAI, which originated in France, for HTLV-3B, which originated in the United States?

During the four-year investigation, NIH's Office of Research Integrity sent investigators to interview Gallo, his team members, and other relevant witnesses many times, with a total of more than 10,000 hours. The original experimental notebooks reviewed were stacked up to 4 meters high. The only misconduct found was that Popovich's experimental records were not accurate and complete, and Gallo should bear leadership responsibility for this. In addition, Gallo also added false statements that did not conform to the facts to the published papers based on these inaccurate records. Popovich was dissatisfied and filed a complaint. It was not until November 1994 that a superior arbitration committee finally withdrew all charges against Popovich and Gallo.

Although Gallo was cleared of all charges, he had no intention of continuing to work at NIH. In 1996, he left NIH, where he had worked for 30 years, and founded the Institute of Human Virology at the University of Maryland School of Medicine, where he has served as director ever since, and continued to make many contributions to HIV research. Throughout the 1980s and 1990s, Gallo was ranked first in the number of citations of scientists worldwide.

After France and the United States reached a patent sharing agreement in 1987, the Pasteur Institute withdrew the lawsuit, but was not satisfied with the arrangement of equally sharing patent income. After the source of the NIH patented virus was revealed, at the request of the Pasteur Institute, the two sides resumed negotiations in 1994 and reached a new agreement. The Pasteur Institute increased its share of patent income as expected. The patent dispute that lasted for ten years finally came to an end.

In 2002, to commemorate World AIDS Day (December 1st of each year), Science magazine invited Montagnier and Gallo to write a short article on the history of HIV discovery and publish it together. After surviving the storm, the two masters who were once involuntarily caught in the center of the vortex calmly and objectively reviewed their work 20 years ago and fully affirmed each other's contributions. Gallo once again confirmed that it was Montagnier who first isolated HIV from AIDS patients[5], and Montagnier reiterated that it was Gallo who proved that HIV was the pathogen of AIDS[6]. The two also analyzed the virus sample mixing incidents that occurred in their respective laboratories. In addition, Gallo and Montagnier also jointly published an article, jointly looking forward to the prospects of AIDS treatment.

In his retrospective article, Montagnier quoted the famous saying of Louis Pasteur, the founder of modern microbiology and founder of the Pasteur Institute: "Opportunities in science favor those who are determined." Undoubtedly, both Montagnier and Gallo were favored by opportunities. However, opportunities also played a big joke on the two of them. If Montagnier had first obtained LAV/LAI that grew well in cell culture instead of LAV/BRU that could not grow, his patent application would not have been delayed. When Gallo screened out HTLV-3B, he had already isolated HTLV-3 viruses from 48 American patients, five of which had grown in continuously cultured cells. However, he inexplicably chose the LAV/LAI that was mixed in, which triggered the multinational patent war and endless scrutiny of him!

Gallo wrote at the end of his retrospective article: "… the four years from 1982 to 1985 were the fastest-growing and most intensively discovered period in medical history. They were also the four years that brought anxiety and depression to some researchers, as well as unprecedented negative influences from politics, the media, patient rights movements, and legal affairs. For me and other colleagues who have undergone scientific training and have the rigorous analytical attitude required for scientific research, the difficulties and setbacks in the outside world have taught us painful lessons. Looking back, those are the lessons we must remember, and they have enabled us to improve ourselves. Our work is far from complete, and eradicating the AIDS epidemic that is still raging around the world still depends on the efforts of scientific workers." [5]

Nobel Prize Controversy As one of the most important achievements in medical research in the 20th century, the discovery of HIV won Montagnier and Gallo numerous honors, including the Lasker Award for Clinical Medicine shared with the three Essex scientists in 1986. Gallo thus became the only person to win the Lasker Award twice. The Lasker Award is often regarded as a bellwether for the Nobel Prize, and Montagnier and Gallo became the most anticipated candidates for the Nobel Prize. However, when the results of the 2008 Nobel Prize were announced, Gallo was not on the list. Montagnier and Barry-Senoussi of the Pasteur Institute shared half of the Physiology or Medicine Prize for their discovery of HIV, and the other half was awarded to German virologist Harald zur Hausen, who discovered that human papillomavirus (HPV) can cause cervical cancer.

Gallo's failure to win the Nobel Prize in Medicine made the results of that year's selection the most controversial in history. 106 famous scientists jointly published an open letter in Science to express their dissatisfaction with Gallo.[7] The Nobel Prize selection committee stated that the basis for selecting the winner was who first discovered HIV, not who proved that HIV was the pathogen of AIDS, nor the agreement reached later by the two parties to share patent rights. "We are a group of experts, not lawyers, to decide who has made a discovery that meets the Nobel Prize level."[8] Gallo himself simply expressed his disappointment at the failure. Montagnier said he was very surprised by Gallo's failure to win the award: "Proving that HIV is the cause of AIDS is crucial, and Gallo has made a very important contribution to this. I feel very sorry for Gallo."[9]

Winning the Nobel Prize marked the pinnacle of Montagnier's scientific achievements. However, after winning the prize, Montagnier's research career took a dramatic turn.

(to be continued)

Main references

• Vahlne A. A historical reflection on the discovery of human retroviruses. Retrovirology. 2009; 6: 40. doi: 10.1186/1742-4690-6-40.

• Warmflash D & Denmark B. David Ho: HIV Researcher. https://www.visionlearning.com/en/library/Inside-Science/58/David-Ho/241 .

• https://en.wikipedia.org/wiki/Robert_Gallo .

• https://en.wikipedia.org/wiki/Luc_Montagnier .

Other references

[1] WHO. Global Health Observatory (GHO) data. https://www.who.int/gho/hiv/en/.

[2] CDC. Pneumocystis pneumonia - Los Angeles. MMWR Morb Mortal Wkly Rep. 1981; 30: 250-2.

[3] Vahlne A. A historical reflection on the discovery of human retroviruses. Retrovirology. 2009; 6: 40. doi: 10.1186/1742-4690-6-40.

[4] Gladwell M. Science Friction. The Washington Post. December 6, 1992.

[5] Gallo RC. Historical essay. The early years of HIV/AIDS. Science. 2002; 298: 1728-30.

[6] Montagnier L. Historical essay. A history of HIV discovery. Science. 2002; 298: 1727-8.

[7] Abbadessa G et al. Unsung hero Robert C. Gallo. Science. 2009; 323: 206–7.

[8] Nobel Prize Surprise 2008. https://www.sciencemag.org/news/2008/10/nobel-prize-surprise.

[9] Cohen J & Enserink M. Nobel Prize in Physiology or Medicine. HIV, HPV researchers honored, but one scientist is left out. Science. 2008; 322: 174-5.