Tag Archives: Anthony Fauci

Zika Virus, Part 3: Update on the Science, Some History, a Little Politics, and an Appearance by Pope Francis

Much has happened since our lasting posting on the Brazilian Zika outbreak (1). In particular, the major topic of our last posting was the uncertainty regarding whether Zika virus causes congenital birth defects. Recent findings may be settling the issue.

One reason for the earlier uncertainty was that although Zika virus has spread to more than a dozen countries since its discovery in Uganda more than 50 years ago, Brazil remained the world’s only country in which the virus was associated with microcephaly. However, in February 2016, Brazil’s neighbor, Colombia, now the world’s second-most Zika-affected country, reported its first cases of birth defects linked to Zika.

More direct and compelling evidence for Zika as an agent of microcephaly was reported early this March in the New England Journal of Medicine (2). Ultrasound examination of Zika-infected pregnant woman revealed that 29 percent of them carried fetuses suffering “grave outcomes, including fetal death, placental insufficiency, fetal growth restriction, and CNS injury.” Zika infection of the mothers was confirmed by reverse-transcriptase–polymerase-chain-reaction assays of blood and urine specimens. “To date, 8 of the 42 women in whom fetal ultrasonography was performed have delivered their babies, and the ultrasonographic findings have been confirmed.”

Although the above study examined only 88 women, all at one clinic in Rio de Janeiro, an article in the New York Times (March 5, 2016) quotes Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases as saying, “Now there’s almost no doubt that Zika is the cause.”

Another notable report described a case of a pregnant woman who, while living in Brazil, came down with a Zika-like feverish illness at the end of the first trimester of her pregnancy (3). The mother opted to abort her 29-week-old fetus after it showed signs (by ultrasonography) of microcephaly—subsequently confirmed by autopsy of the fetus. Importantly, a flavivirus was visualized in the fetal brain by electron microscopy, and the entire Zika genome (unambiguously identified by reverse-transcriptase–polymerase-chain-reaction assay) was recovered from it.

Next, we consider a new finding that Zika can be present in breast milk. Whereas Zika is an arthropod-borne virus that is transmitted primarily by its mosquito vector, our first posting on the Brazilian Zika outbreak noted at least one instance in which Zika was transmitted via a blood transfusion (4). In addition, there were reports of Zika being sexually transmitted (5). Now there is a report of Zika virus in the breast milk of a mother in New Caledonia (6).

The woman was feverish in July 2015 when she arrived at the hospital to give birth. Nevertheless, she breast fed her apparently healthy baby immediately after delivering it. Samples of the mother’s serum and breast milk then tested positive for Zika virus by reverse-transcriptase–polymerase-chain-reaction assay, while a test of a serum sample from the 3-day–old baby was ambiguous. The mother’s fever, now accompanied by a characteristic Zika rash, persisted for the next several days. Nonetheless, she and her baby were each healthy when they left the hospital.

This report would appear to raise considerable concern that a Zika-infected mother might transmit the virus to her baby via her breast milk.  All the same, the US Centers for Disease Control and Prevention (CDC) maintains that the benefits of breastfeeding outweigh the theoretical risks of Zika virus infection via breast milk, and recommends that infected women should breastfeed.

Next, we consider some recent history. On February 1, 2016 the WHO declared that Brazil’s Zika outbreak is as an international public-health emergency. But, uncharacteristically, the WHO put forth this pronouncement despite the fact that the scientific community was still not sure of the threat that Zika poses to humans. In point of fact, this was the first instance in which the WHO proclaimed its highest level of alarm for an agent of uncertain danger. [The CDC likewise elevated its Zika virus surveillance program to its highest priority level.]

Why did the WHO make its frightening declaration when the threat posed by Zika was still not clear? Obviously, a failure to take immediate action might allow the Zika outbreak to get well out of hand, with possibly devastating consequences.

In contrast to the hurried response by the WHO to the Zika outbreak, that agency responded more leisurely to the 2013/2014 West African Ebola outbreak, which did get out of control, and which persists even to this day. So, perhaps the more urgent response of the WHO to the Zika outbreak reflects a lesson learned from the Ebola affair.

But, why did the WHO wait longer before responding to the West African Ebola outbreak? One reason is because it was strongly criticized for “overreacting” to the risk posed by the 2009 H1N1 influenza epidemic—which turned out to be far less threatening than originally feared.

While the WHO may have learned a lesson from its somewhat unhurried response to the Ebola outbreak, its more urgent February 1, 2016 Zika declaration did not go far enough for some observers, since it stopped short of advising pregnant women not to travel to Zika-affected regions. For that reason, the WHO has been accused of taking political considerations into account, to the detriment of good public health policy. Any travel ban—even one aimed only at pregnant women—would be embarrassing and costly to Brazil, which has been moving ahead with its plans to host the Olympic Games this summer. Still, hundreds of thousands of people from around the world, including female spectators and participants, some of whom may be pregnant, are expected to attend.

Lastly, we note that the Zika outbreak has been stirring up a fierce religious debate in Latin America; a debate that is actually challenging the very authority of the Catholic Church in the hemisphere. But first, an earlier posting on the blog recounted how in 2002 Colin Powell, at the time Secretary of State in the George W. Bush administration, advocated that sexually active young people should use condoms to protect themselves against HIV/AIDS (7). Powell’s advocacy of condom usage was contrary to the Bush administration’s strongly held abstinence-only approach for preventing sexual transmission of HIV. Moreover, then as now, Powell’s stance was contrary to the official position of the Catholic Church on artificial contraceptives. Nevertheless, Powell asserted, “I certainly respect the position of the Holy Father and the Catholic Church. In my own judgment, condoms are a way to prevent infection. Therefore, I not only support their use, I encourage their use among people who are sexually active and need to protect themselves.”

Now, presumably in response to reports that Zika virus might be transmitted sexually, Pope Francis declared on February 18, 2016—during a mid-air news conference on his flight from Mexico back to Rome—that contraceptives could be used to block the spread of Zika virus. That same day, the WHO advised the sexual partners of pregnant women to use condoms, or to abstain from sex, if they live in a Zika-affected area, or if they are returning from one of those areas. Also, several Latin American governments asked their female citizens to delay getting pregnant.

Pope Francis after deplaning in Ciudad Juarez, Mexico, on February 17, 2016
Pope Francis after deplaning in Ciudad Juarez, Mexico, on February 17, 2016

Those suggestions, whether from Latin American governments, or from the WHO, offended many Latin American women, in part because of the strict anti-abortion laws, and laws that restrict access to contraceptives in some of those countries. Moreover, the situation is compounded in some regions of the hemisphere by rampant sexual violence against women. In any event, the Pope’s pronouncement intensified an angry debate over contraception, and abortion as well, that was already underway in Latin America.

Pope Francis did not condone abortion, which he referred to as an “absolute evil.” But, he did make a point of justifying his statement condoning contraception by citing as a precedent a 1960 judgment by Pope Paul VI, which permitted nuns in the Belgian Congo, who were in danger of being raped, to use contraceptives.

Pope Francis’ remarks, such as “avoiding pregnancy is not an absolute evil,” has encouraged Latin American opponents of the church’s longstanding ban on the use of artificial contraceptives to campaign harder against those policies. In any case, the Pope’s pronouncement, and the heated response it is provoking, shows that the Zika outbreak is now impacting religious institutions. And, as noted by Ana Ayala, the director of the Global Health Law Program at Georgetown University, “The pope’s positioning on this subject can significantly shift how governments see access to contraception.” See Aside 1.

[Aside 1: Ayala’s comment can be found in a February 18, 2016 article in the New York Times, entitled “Francis Says Contraception Can Be Used to Slow Zika”, by Simon Romero and Jim Yardley. This piece offers an extensive account of the response in Latin America, and elsewhere, to the Pope’s comments. “While international researchers are still trying to prove definitely a link between Zika and microcephaly, the pope’s comments on contraception seemed to catch up to the reality in parts of the hemisphere where many Catholics pay little heed to the church’s teachings on birth control.”]

References:

  1. Zika Virus, Part 2: The Link to Birth Defects, Is It Real?, Posted on the blog February 23, 2016.
  2. Brasil, P., Pereira, J.P., Gabaglia, C.J., et al., Zika Virus Infection in Pregnant Women in Rio de Janeiro — Preliminary Report, N. Engl. J. Med., March 4, 2016DOI: 10.1056/NEJMoa1602412
  3.  Mlakar, J., Korva, M., Tul, M., et al., Zika Virus Associated with Microcephaly, N. Engl. J. Med. 2016; 374:951-958 March 10, 2016 DOI:10.1056/NEJMoa1600651
  4. Zika Virus: Background, Politics, and Prospects, Posted on the blog February 4, 2016.
  5. Foy, B.D., K. C. Kobylinski, J.L. Foy, et al., 2011. Probable Non–Vector-borne Transmission of Zika Virus, Colorado, USA, Emerg Infect Dis. 17: 880–882.6.
  6. Myrielle Dupont-Rouzeyrol, M., Biron, A., O’Connor, O., Huguon, E., and Descloux, E., Infectious Zika viral particles in breastmilk, The Lancet 387:1056, March 2016. doi:10.1016/S0140-6736(16)00624-3
  7. Colin Powell on HIV and Condoms, Posted on the blog July 30, 2014.

 

 

 

 

 

 

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Maurice Hilleman: Unsung Giant of Vaccinology

In January 2005, more than 100 of the world’s most renowned biomedical researchers got together to pay tribute to the 85-year-old Maurice Hilleman. When it was Hilleman’s turn to address the gathering, he alluded to them as his “peers in the world of science.” Referring to Hilleman’s gracious comment, science journalist Alan Dove wrote: “By any objective measure, a gathering of Maurice Hilleman’s scientific peers would not fill a telephone booth.” (1)

Hilleman truly was a giant in the history of virology. But, if you have only a vague idea of who Hilleman was or of his achievements, you are not alone. Anthony Fauci, director of the U.S. National Institutes of Allergy and Infectious Diseases, who was present at the gathering, noted: “Very few people, even in the scientific community, are even remotely aware of the scope of what Maurice has contributed….I recently asked my post-docs whether they knew who had developed the measles, mumps, rubella, hepatitis B and chickenpox vaccines. They had no idea,” Fauci said. “When I told them that it was Maurice Hilleman, they said, ‘Oh, you mean that grumpy guy who comes to all of the AIDS meetings?’”

hillemanMaurice R. Hilleman: The greatest vaccinologist.

Consider this. Hilleman developed nine of the 14 vaccines routinely recommended in current vaccine schedules. These are the vaccines for the measles, mumps, rubella, hepatitis A, hepatitis B, and chickenpox viruses, and for meningococcal , pneumococcal, and Haemophilus influenzae bacteria. Moreover, he was the first to forecast the arrival of the 1957 Asian flu and, in response, led the development of a flu vaccine that may have saved hundreds of thousands or more lives worldwide (2). And, independently of Robert Huebner and Wallace Rowe, he discovered cold-producing adenoviruses, and developed an adenovirus vaccine. Overall, Hilleman invented nearly 40 vaccines. And, he was a discoverer of simian virus 40 (SV40). If the above accomplishments were not enough to ensure his fame, he also was the first researcher to purify interferon, and the first to demonstrate that its expression is induced by double-stranded RNA.

[Aside: I first became aware of Maurice Hilleman 44 years ago. It was in the context of his 1959 discovery of SV40, which I came across only because I was beginning my post-doctoral studies of the related murine polyomavirus. Bernice Eddy, at the U. S. National Institutes of Health (NIH), was probably the first to discover SV40, which she detected in early lots of the Salk polio vaccine (3). Hillman, then at Merck & Co, independently discovered the same virus in rhesus monkey kidney cell cultures, in which the polio vaccine was being produced. Hilleman gave SV40 its name. It was the 40th simian virus the Merck lab found in the monkey kidney cells. In 1961, both Eddy and Hilleman found that inoculating SV40 into hamsters causes tumors in the animals. Merck withdrew its polio vaccine from the market. But, by then, live SV40 had been unknowingly injected into hundreds of millions of people worldwide! More on this in a future posting.]

We begin our account of Hilleman’s achievements with his development of the mumps vaccine. In the days before the vaccine, mumps struck about 200,000 children in the United States, annually. Yet except in rare circumstances, the infection was mild, and was generally regarded as a childhood rite of passage. There is a sweetness to the story of the mumps vaccine that I hope you might enjoy.

The tale began at about 1:00 AM, on March 21, 1963, when 5-year-old Jeryl Lynn Hilleman ambled into her father’s bedroom complaining of a sore throat. Jeryl Lynn’s father felt his daughter’s swollen glands, and knew in a flash that it was mumps. And, while I suspect that many lay parents back in the day would also have recognized Jeryl Lynn’s symptoms, few would have done what her father did after first comforting his daughter. Although it was already past midnight, Maurice hopped into his car and drove the 20 minutes to his lab at Merck & Co. to pick up some cotton swabs and beef broth. Returning home, he then awakened Jeryl Lynn, gently swabbed her throat, and immersed the swabs in the nutrient broth. Next, he drove back to his lab and put the inoculated broth in a freezer.

Hilleman made the early A.M. dashes to his lab and back because he had to leave in the morning for a conference in South America, and his daughter’s infection might have cleared by the time he returned home from there. So, upon his return from South America, Hilleman, thawed the frozen sample from his daughter’s throat and inoculated it into chick embryos. Serial passage of the mumps virus in the chick embryos eventually generated attenuated mumps virus that in 1967 would serve as a live mumps vaccine.

The virus in the vaccine was dubbed the Jeryl Lynn strain, in honor of its source. Years later, an adult Jeryl Lynn Hilleman noted that her father had a need to be “of use to people, of use to humanity.” She added: “All I did was get sick at the right time, with the right virus, with the right father.”

We’ll have a bit more to say about the mumps vaccine shortly. But first, a few words about measles and rubella.

If mumps was not a major killer, measles certainly was. Before Hilleman and his colleagues introduced their measles vaccine (Rubeovax) in 1962, there were 7 to 8 million measles fatalities worldwide each year, and virtually all of the victims were children. Hilleman developed his attenuated measles vaccine from a measles strain isolated earlier by John Enders. Hilleman attenuated the Enders isolate by putting it through 80 serial passages in different cell types.

[Aside: In a previous posting, we noted that Enders, together with colleagues Thomas Weller and Frederick Robbins, shared a Nobel Prize in Physiology or Medicine for growing poliovirus in non-nervous tissue (3). Apropos the current story, bear in mind that Salk and Sabin developed polio vaccines that have nearly rid the world of this once dread virus. Nevertheless, the Nobel award to Enders, Weller, and Robbins was the only Nobel award ever given in recognition of polio research!]

Rubeovax was somewhat tainted by its side effects; mainly fever and rash. While these reactions were successfully dealt with by combining Rubeovax with a dose of gamma globulin, in 1968 Hilleman’s group developed a new, more attenuated measles strain by passage of the Rubeovax virus 40 more times through animal tissues. Hilleman dubbed the new measles strain “Moraten,” for “More Attenuated Enders.” The new measles vaccine, Attenuvax, was administered without any need for gamma globulin.

Our chronicle continues with the rubella vaccine. Rubella poses its greatest danger to fetuses of non-immune pregnant woman, particularly during the first trimester of pregnancy. In up to 85% of these women, infection will result in a miscarriage or a baby born with severe congenital abnormalities. An outbreak of rubella began in Europe in the spring of 1963, and quickly spread worldwide. In the United States, the 1963 rubella outbreak resulted in the deaths of 11,000 fetuses, and an additional 20,000 others born with birth defects (e.g., deafness, heart disease, cataracts).

Hilleman had been working on a rubella vaccine at the time of the 1963 outbreak. But, he was persuaded to drop his own vaccine and, instead, refine a vaccine (based on a Division of Biologics Standards’ rubella strain) that was at the time too toxic to inoculate into people. By 1969 Hilleman was able to attenuate the DBS strain sufficiently for the vaccine to be approved by the FDA.

Next, and importantly, Hilleman combined the mumps, measles, and rubella vaccines into the single trivalent MMR vaccine, making vaccination and, hence, compliance vastly easier. Thus, MMR was a development that should have been well received by many small children and their mothers, as well as by public health officials.

In 1978 Hilleman found that another rubella vaccine was better than the one in the trivalent vaccine. Its designer, Stanley Plotkin (then at the Wistar Institute), was said to be speechless when asked by Hilleman if his (Plotkin’s) vaccine could be used in the MMR. Merck officials may also have been speechless, considering their loss in revenues. But for Hilleman, it was simply the correct thing to do.

Like Jonas Salk and Albert Sabin before him (3), Maurice Hilleman was never awarded a Nobel Prize. There is no obvious reason for the slight in any of these three instances. In Salk’s case, it may have been because Alfred Nobel, in his will, specified that the award for Physiology or Medicine shall be for a discovery per se; not for applied research, irrespective of its benefits to humanity. But, Max Theiler received the Nobel Prize for producing a yellow fever vaccine. What’s more, the Nobel committee seemed to equivocate regarding the discovery that might have been involved in that instance. Regardless, the Nobel award to Theiler was the only Nobel Prize ever awarded for a vaccine! [A more complete accounting of the development of Theiler’s yellow fever vaccine can be found in The Struggle Against Yellow Fever: Featuring Walter Reed and Max Theiler, now on the blog.]

Sabin had done basic research that perhaps merited a Nobel Prize (3). But, the Nobel committee may have felt uneasy about giving the award to Sabin, without also recognizing Salk. Or, perhaps the continual back-and-forth carping between supporters of Salk and Sabin may have reduced enthusiasm in Stockholm for both of them.

Yet by virtually any measure, Hilleman’s achievements vastly exceeded those of Salk, Sabin, Theiler, and just about everyone else. His basic interferon work alone should have earned him the Prize. Hilleman’s group demonstrated that certain nucleic acids stimulate interferon production in many types of cells, and detailed interferon’s ability to impede or kill many viruses, and correctly predicted its efficacy in the treatment of viral infections (e.g., hepatitis B and C), cancers (e.g., certain leukemias and lymphomas), and chronic diseases (e.g., multiple sclerosis). What’s more, Hilleman developed procedures to mass-produce and purify interferon. And, regarding his unmatched achievements as a vaccinologist, he did more than merely emulate Pasteur’s procedures for developing attenuated viral vaccines. His hepatitis B vaccine was the first subunit vaccine produced in the United States. It was comprised of the hepatitis B surface antigen (HBsAg), which Hilleman purified from the blood of individuals who tended to be infected with hepatitis B virus (e.g., IV drug abusers). Subsequently, to avoid the potential danger of using human blood products in the vaccine, Hilleman developed recombinant yeast cells that produced the HBsAg. And, Hilleman’s meningococcal vaccine was the first vaccine to be based on polysaccharides, rather than on a whole pathogen or its protein subunits.

So, why then was Hilleman bypassed by the Nobel committee? John E. Calfree, in The American, wrote: “As the 80-plus-year-old Hilleman approached death, Offit and other academic scientists lobbied the Nobel committee to award Hilleman the Nobel Prize for Medicine, based partly on his vaccine work and partly on his contributions to the basic science of interferons. The committee made clear that it was not going to award the prize to an industry scientist.” (4) [Paul Offit, referred to here, is the co-developer of the rotavirus vaccine, Rotateq, and a biographer of Hilleman.]

Calfree also notes that Hilleman’s tendency towards self effacement, and his absence from the academic and public spotlight, may also have worked against him. And, unlike Salk, whose name was closely linked to his polio vaccine (3), Hilleman’s name was never associated with any of his nearly forty vaccines. [Yet in the case of Jonas Salk, his public acclaim is generally believed to have hurt him in the eyes of his colleagues and of the Nobel committee.]

Considering the enormity of Hilleman’s contributions, his anonymity was really quite remarkable. As Calfree relates: “In one of the most striking of the dozens of anecdotes told by Offit, Hilleman’s death was announced to a meeting of prominent public health officials, epidemiologists, and clinicians gathered to celebrate the 50th anniversary of the Salk polio vaccine. Not one of them recognized Hilleman’s name!”

With Hilleman’s public anonymity in mind, we conclude our account with the following anecdote. In 1998, a Dr. Andrew Wakefield became a celebrity and hero in the eyes of the public. How this happened, and its consequences are troubling for several reasons, one of which is that it brought undeserved suffering to the self-effacing and benevolent Maurice Hilleman. The Wakefield incident merits, and will have a full-length blog posting of its own. But for now, in 1998 Wakefield authored a report in the prestigious British journal The Lancet, in which he claimed that the MMR vaccine might cause autism in children. The story had a bizarre series of twists and turns, with Wakefield and co-authors eventually issuing a retraction. The immediate cause of the retraction was the disclosure that Wakefield, on behalf of parents of autistic children, had accepted funding to investigate a link between the MMR vaccine and autism. The purpose of the investigation was to determine whether a legal case against the vaccine manufacturer might have merit. In addition to the obvious conflict of interest, Wakefield’s paper had serious technical flaws as well. At any rate, a number of independent studies subsequently demonstrated that there is no causal link between the MMR vaccine and autism. And, in 2010 Wakefield was barred by the British Medical Society from the practice of medicine. But the harm had been done. Hilleman had become the recipient of hate mail and death threats. And, more important to Hilleman I expect, many worried parents, even today, prevent their children from receiving the MMR vaccine (5). Ironically, the very success of the MMR vaccine enabled people to forget just how devastating measles and rubella could be.  Maurice Hilleman succumbed to cancer on April 11, 2005.

1. Nature Medicine 11, S2 (2005)
2. Opening Pandora’s Box: Resurrecting the 1918 Influenza Pandemic Virus and Transmissible H5N1 Bird Flu  On the blog.
3. Jonas Salk and Albert Sabin: One of the Great Rivalries of Medical Science  On the blog
4. Calfree, J.E., Medicine’s Miracle Man , The American, January 23, 2009
5. Reference 4 contains a somewhat similar tale, in which a 1992 article in Rolling Stone attributed the emergence of HIV to Hillary Koprowski’s polio vaccine. It created a sensation but, as might be expected, there was no evidence to support its premise.

How the Human Immunodeficiency Deficiency Virus (HIV) Got Its Name

This story began with the clash between Luc Montagnier and Robert Gallo over priority of discovery and, with it, the right to name the virus. In the midst of this controversy, Harold Varmus seized the initiative to find a universally accepted name for the virus that causes AIDS.

Our previous posting (Who Discovered HIV?) told how Robert Gallo, at the U.S. National Institutes of Health (NIH), and Luc Montagnier, at the Pasteur Institute in Paris, vied to be recognized as the sole discoverer of the AIDS virus. Montagnier named his isolate of the virus “lymphadenopathy associated virus” or LAV, because it came from a patient presenting with lymphadenopthy. 1 Gallo, in contrast, named the virus “human T-cell lymphotropic virus III” or HTLV-III, based on his belief that it was a variant of the human T-cell leukemia viruses-I and –II, which were isolated earlier in his laboratory.

It soon became clear that LAV was quite distinct from HTLV-I and –II. 2 Moreover, and improbably, HTLV-III was found to be identical to another LAV isolated in Montagnier’s laboratory. What’s more, Montagnier had sent a sample of his virus to Gallo before Gallo reported isolating HTLV-III. These events led to recriminations flying back and forth between Montagnier and Gallo, and, not surprisingly, to a bitter rivalry between them, as each held fast to his claim for priority of the discovery.

For the sake of completeness, Jay Levy, at the University of California, San Francisco (UCSF), was also among the first to isolate the AIDS virus, which he named the “AIDS-associated retrovirus” or ARV. Levy did not take part in the dispute between Gallo and Montagnier and, consequently, did not receive the publicity that they did. And, while Levy did not contend for recognition with the fervor of Gallo and Montagnier, his designation for the AIDS virus, and other proposals as well, also had to be considered in the deliberations described below.

The discoverer of a new virus is generally accorded the privilege of naming it. Consequently, the name that the scientific community might ultimately adopt for the AIDS virus could have implications beyond merely providing an appropriate designation for it. Specifically, if the scientific community were to acknowledge LAV or HTLV-III as the name for the virus, it would have been tantamount to recognizing Montagnier or Gallo, respectively, as its discoverer. Thus, any individuals entrusted with resolving the naming issue had to be wary of inadvertently advancing the claims of one, or the other, of the two main protagonists. There was even more at stake for Gallo, since his integrity was being called into question and, consequently, his reputation as well. Moreover, the national pride of both the United States and France were also at issue, as well patent rights to the blood test for the virus.

Although it was clear to all that HTLV-III (or LAV) is distinct from HTLV-I and –II, and that HTLV-III and LAV are one and the same virus, Gallo still went all-out to preserve HTLV-III as the designation for the virus. So, for a time, the awkward solution of the scientific community was to call the virus LAV/HTLV-III, as was recommended by the World Health Organization, or HTLV-III/LAV, as preferred by the U.S. government.

Harold Varmus now steps up to become the key player in the resolution of the naming dispute. But first, here is his bio in brief. Varmus, born in 1939, shared a 1989 Nobel Prize with Michael Bishop for demonstrating that retroviral oncogenes (e.g., v-src) have their counterparts (proto-oncogenes; e.g., c-src) in normal cells. 3 In turn, this led to the realization that mutations in particular host genes, or the inappropriate expression of those genes, might be the underlying basis for human cancers.

varmusHarold Varmus (1981)

To appreciate the huge significance of Varmus’ and Bishop’s 1976 findings, bear in mind that most of the scientific community of the day were skeptical of the notion that cancer had a genetic basis, until Varmus and Bishop provided direct evidence in its support.  Moreover, as Varmus later stated: “In recent years, after our prize was awarded, mutant proto-oncogenes and the proteins they encode have become critical tools for the classification of cancers and promising targets for drugs and antibodies-treatments that have, in some cases, proven to be effective for a significant and growing number of cancers, including leukemias and lymphomas, lung, gastrointestinal, and kidney cancers: and cancers of the breast.” 4

Varmus was a professor at UCSF during the happenings recounted here. Later, between 1993 through 1999, he served as Director of the U.S. National Institutes of Health, and from 2000 through 2010, as President of the Memorial Sloan Kettering Cancer Center. He is currently Director of the National Cancer Institute. On a personal note; I got the idea for this posting from Varmus’ brief account in his book, The Art and Politics of Science (2009). This is a marvelous book that I strongly recommend to all readers of this blog.

At the time of our story, Varmus also was serving as chairman of the Retrovirus Study Group of the International Committee on Taxonomy of Viruses (ICTV). [The ICTV, through its various study groups, has the task of developing and maintaining the commonly accepted virus taxonomy.] As chairman of his study group, Varmus assumed responsibility for resolving the AIDS virus naming dispute. To advise him in that effort, he created an international panel of eminent retrovirologists, which included Howard Temin, 5 Peter Vogt, Myron Essex, Ashley Haase, Steven Oroszlan, Natalie Teich, Kumao Toyoshima, Robin Weiss, John Coffin, and Jay Levy, as well as Gallo and Montagnier. Moreover, Varmus solicited written opinions from more than fifty additional prominent scientists and clinicians, not on his panel.

The panel was soon considering more than a dozen names. Some of these were suggested within the panel, while others were suggested by Varmus’ outside correspondents.

After the panel invested more than a year deliberating these proposed names, which included the two that Montagnier and Gallo originally adopted, it finally settled on “human immunodeficiency virus,” or HIV, as the AIDS virus is now universally known. In reaching its conclusion, the panel considered many issues, including the controversy over priority of discovery, the phylogentic relationship between the AIDS virus and HTLV-I and -II, 2 the immunosuppressive properties of the virus, and the desirability of including the term “AIDS” in its designation. Finally, the panel considered how its preferences squared with established naming conventions and precedent. Varmus, of course, mediated all discussions within his panel.

Notwithstanding all the arguments and compromises that the panel considered, Gallo was not satisfied when all was said and done, nor did the outcome end his dispute with Montagnier. 6 Although the panel’s end result essentially nullified the right of Montagnier and his group to name the virus which they believed they had discovered, Montagnier was already prepared to accept an alternative name, although not HTLV-III. In contrast, since the panel rejected Gallo’s claim that the virus was a variant of HTLV, he, unlike Montagnier, would not sign-off on the May 1986 letter the panel sent to Nature, which proposed that the AIDS virus be called human immunodeficiency virus, or HIV. [The panel also recommended subcategories of HIV. HIV-1 designates the more common type of HIV, which Gallo and Montagnier each claimed to have discovered. HIV-2 designates the less common variety seen in West Africa, which Montagnier is acknowledged to have discovered. 6]

As Varmus later related, “However difficult this process was-with leaks to the press by Montagnier, belligerent letters to me from Gallo that were copied to most of our nation’s leaders, surly and aggressive behavior by the two rivals, and refusals to sign the final statement by Gallo and his close colleague Max Essex, a virologist at Harvard’s School of Public Health-it was interesting intellectually and socially.” 4 [It’s been said that the diplomatic skills, which Varmus acquired while leading the effort to solve the AIDS virus naming dispute, served him well later in his role as Director of the NIH. For much more on Varmus in that later role see: Varmus, H. 2009. The Art and Politics of Science. Norton Books, New York, NY.]

Some of the thorny issues that Varmus’ panel had to come to grips with with were enumerated above. Those issues and additional others, were also discussed in Varmus’s written correspondences with members of his panel, as well as with the outside experts whom he consulted. 7 We now draw on those communications to glimpse the multiple points of view that Varmus and his panel had to wrestle with.

We begin by considering why the term “AIDS” was not included in the panel’s designation for the virus. This is particularly interesting, especially in view of the naming precedent for viruses such as poliovirus, hepatitis A virus, hepatitis B virus, and the influenza viruses; all cases where the virus is designated by the clinical syndrome that it is associated with. Moreover, that naming convention is generally accepted, despite the fact that in these and other such instances, only a small minority of infected individuals ever manifest the disease. What is more, taking the cases of Hepatitis A and B viruses as an example; these are two phylogenetically unrelated viruses that have nothing whatsoever in common, other than that each causes liver disease. And, as Varmus, himself, noted: “Traditional retroviral nomenclature has worked well in this regard. The convention has been to name viruses according to the host species and the prominent pathology associated with the prototypic isolate of a single type; two examples of such names are ‘feline leukemia virus’ and ‘mouse mammary tumor virus.’” 8 And, even more to the point, there are the examples of the human T-cell leukemia viruses, which have already featured prominently in this tale, and in our previous one (Who Discovered HIV?). So, why then did the panel not choose to simply call the etiologic agent of AIDS “the AIDS virus”?

Michael Gottlieb was one of Varmus’ correspondents who spoke out strongly on this issue. He, and his colleagues at UCLA, command our attention, since, in 1981, they were the first to realize that individuals suffering from persistent infections with the protozoan Pneumocystis carinini, and those with the rare cancer, Kaposi’s sarcoma, were all afflicted with the same underlying disease that specifically targeted their CD4 T cells for destruction. That is, they were the first to recognize and report the existence of the disease that subsequently was named AIDS. Here, then, is an excerpt from Gottlieb’s April 25, 1985 letter to Varmus.

“I am writing to convey my concerns as a clinician about sentiment for nomenclature which would identify the agent as the ‘AIDS virus.’ I believe that this nomenclature would be unfortunate. It is estimated that over one million persons in the U.S. alone have serum antibodies. The fully expressed AIDS syndrome is well publicized to be a lethal intractable illness associated with considerable suffering. In my view the term ‘AIDS virus’ would create considerable distress among all individuals found to have previous exposure…I am hopeful that your Study Group will also wish to avoid creating widespread social distress…”  [My note: Gottlieb’s comments, as well as others quoted below, reflect that it was not yet appreciated that virtually all HIV-infected individuals would eventually succumb to AIDS. That disheartening state of affairs would begin to change dramatically with the development of antiretroviral therapy. 6]

Mark Kaplan (North Shore University Hospital), Jerome Groopman (New England Deaconess Hospital), and several other clinicians spoke on the same issue in their April 29, 1985 letter to Varmus:

“The last major aspect to consider in determining the nomenclature of this virus must be the emotions of the patient who is infected with this agent. Patients told that they have infection with the AIDS virus develop devastating psychological symptoms that have been witnessed by all clinicians dealing with these patients and their families. It is a cruel name for the virus for it leaves no hope for the patient, implying that the patient will inevitably develop and die from AIDS. If we were to have called the EB virus by the disease it was first felt to produce, it would have been called the Burkitts Lymphoma virus. By analogy, one can imagine the distress caused to a patient with EBV if told that he had the Burkitts lymphoma virus…”  [My note: EBV, for the Epstein-Barr virus, is a ubiquitous herpesvirus that occasionally causes the non-fatal illness, infectious mononucleosis. It also is associated with Burkitt’s lymphoma, a malignant B-cell lymphoma seen in children living in equatorial Africa and New Guinea.]

Addressing the same issue in her April 22, 1985 letter to Varmus, panel member Natalie Teich, at the Imperial Cancer Research Fund Laboratories, wrote the following :

“Poliovirus was acceptable even though the vast majority of infected persons remained asymptomatic. However, with AIDS, the social and economic implications and stigma may be too overriding.”

Yet in the case of this issue, and others as well, there was no immediate consensus among those contributing to the discussion. Here is what Jay Levy, also a panel member, wrote in his May 10, 1985 letter to Varmus:

“The concern about frightening individuals with the term ‘AIDS’ virus should not be a consideration…no matter what term is given to the AIDS retrovirus, individuals will easily recognize its connotation.”

Levy adds the following: “I favor classifying the AIDS virus in a category by itself. It is most likely the prototype of a human lentivirus and should not be confused with other human retroviruses. My group prefers to maintain our initial nomenclature, that of AIDS-associated retrovirus (ARV) as it best defines the agent linked to this distinct clinical disease.”

Irrespective of whatever scientific merits Levy’s proposal may have brought to the table, it was not seriously considered by the discussants. For example, Natalie Teich dismissed it as follows: “With due regard for Jay, this was clearly a ‘johnny-come-lately’ claim.”

And, William Haseltine, at the Dana-Farber Cancer Institute, wrote the following in his August 7, 1985 letter to Varmus. “…Dr. Jay Levy’s proposed name has no merit as his report merely repeated the original isolations using previously published methods.”

Notice that both Teich and Haseltine rebuff Levy’s preference solely on the basis of right-of-discovery. With that in mind, here is Haseltine’s take on the appropriateness of calling the virus HTLV-III:

“I strongly favor the name HTLV-III for the virus. I would not oppose the name HTLV-III/LAV or LAV/HTLV-III. My reasons are as follows:…Unless there is good reason to the contrary, the original discoverers of the virus should have the right to call the virus the name they chose. Both the laboratories of Drs. Gallo and Montagnier have valid claims to be original discoverers of the virus. Although the Paris laboratory published first, I am convinced that Gallo had, in fact, isolated the virus at or before late 1982 to very early 1983 as did the Paris Laboratory…Given what must be considered to be a lack of consensus of the committee on the appropriate nomenclature, there is no compelling reason not to abide by the choice of the discoverers themselves…HTLV-III is a far better name than LAV. LAV refers to a specific disease state. HTLV-III does not.” [My note: This passage underscores that the controversy between Montagnier and Gallo, over priority of discovery, was still very much alive at this time.]

Anthony Fauci, as Director of the National Institute of Allergy and Infectious Diseases, also commanded attention. In his May 3, 1985 letter to Varmus, Fauci noted that he typically refers to the virus as the “AIDS retrovirus.” However, he argues against adopting that name, not quite for the reasons expressed above, but seemingly because of the mistaken belief at the time that many infected individuals will not develop AIDS. Nevertheless, even if that belief were correct, the very vast majority of individuals infected with poliovirus, and the hepatitis A and B viruses, and other viruses likewise named for the pathology with which they are associated, do not develop those diseases, as was noted above.

Fauci’s most interesting comments may be those concerned with naming the virus either “LAV” or “HTLV-III.” Regarding “LAV,” he says: “…I do believe it would be inappropriate to call this the lymphadenopathy-associated virus (LAV). The reasons for this should be obvious. First, the virus causes more than lymphadenopathy…”

Regarding “HTLV-III,” he says: “Although there are accumulating data, of which you are aware or more aware than I am, that there are significant dissimilarities between this virus and HTLV-I and –II, I still believe that there is enough reason to maintain this virus within the HTLV nomenclature that this should be continued. The reasons for this are that it surely is a human virus (H), it is a T-lymphotropic virus (TL), and it is a virus (V). Therefore, I would think that HTLV itself is a reasonable abbreviation for the virus. For that reason I would suggest naming it either HTLV-III alone or HTLV-III/LAV. However, for reasons given above concerning the disadvantage of using the terminology LAV, I would elect to call it HTLV-III.”

Fauci does not neglect to point out: “I am well aware of all the difficulties and the emotional issues that are interjected into this vis-à-vis who will get more credit related to the name that is chosen. I will try to disassociate myself from any of that and give you as objective a viewpoint as I possibly can concerning the nomenclature….”

The above comments are from but a small subset of Varmus’ correspondences. And, the comments cited above are merely a subset of the positions and arguments stated in them. Yet they enable us to better appreciate Varmus’ accomplishment in arriving at an acceptable and appropriate name for the AIDS virus, and one which did not stir up further discord. As he succinctly stated in his January 17, 1986 memorandum to his panel: “I and several committee members have come to favor HIV: it is simple; it is novel (and hence does not inflame controversies); and it is based upon the name of the disease with which the virus is readily identified, without including the term AIDS.”

I end this posting with the text of a December 19, 1984 letter from Varmus to David Kingsbury at Oxford, in which Varmus informs Kingsbury of the progress of his ICTV Retrovirus Study Group towards revising the retrovirus phylogeny. Varmus’ letter is followed by a portion of Kingsbury’s January 4, 1985 response. [Kingsbury is best known for his research on influenza viruses. I presume that Varmus was corresponding with Kingsbury here, in part because of the latter’s stature within the ICTV, which put Kingsbury in a position to help Varmus gain approval from the ICTV’s higher leadership for his study group’s recommendations.]

“Dear David:

Thanks for your newsletter. As you probably know, we have updated the summary of Retroviridae for Intervirology (a minor task), and we are anticipating some difficulty with finding a suitable name for the AIDS virus. I am waiting for the dust to settle from the nucleotide sequencing (done or almost done in four labs at least) before convening a subcommittee. But it is clear that the AIDS virus is no more related to HTLV-I than to any other retrovirus on the basis of sequence comparison. Would you like to tell Bob Gallo it shouldn’t be called HTLV-III?

Best regards,

Harold E. Varmus, M.D.”

And Kingsbury’s  reply:

“Dear Harold:

….The news about the AIDS virus is startling! Another family of human retroviruses? When you have adequate data to take a firm position on this I will be happy to tell Bob Gallo the facts. I have no vested interest in the matter.

With best wishes,

David”

Footnotes:

1.  As noted in Who Discovered HIV?, before Montagnier began his search for the AIDS agent, a group of French physicians and scientists suggested to him that the best chance to find and isolate it might be at the start of the disease, before the patient’s T cells had severely declined.The reasoning was that if a virus were found at this early stage of the disease, then it would more likely be its cause, rather than merely a consequence of the immune depression. So Montagnier and co-workers looked for a retrovirus in a lymph-node biopsy from a patient with persistent lymphadenopathy (swollen lymph glands); an early sign in patients progressing towards AIDS, but with little sign yet of the impending severe immunodeficiency.

2.  The following statement appears in Harold Varmus’ draft report (Naming the AIDS Virus), which reviews the deliberations of his panel to find a suitable name for the retrovirus that causes AIDS.

 “If an evolutionary tree is established for retroviruses by comparing the order of amino acids in the protein most characteristic of retroviruses, the enzyme that converts RNA to DNA, it is apparent that the AIDS virus is most closely related to the sheep lentivirus, called visna, whereas the human T cell leukemia viruses are in another limb of the tree, more closely related to other oncogenic viruses, leukemia and sarcoma viruses of various animals, particularly the bovine leukemia virus.”

3.  Stehelin, D., H.E. Varmus, M. Bishop, and P.K. Vogt. 1976. DNA related to transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260:170-173.

4.  Varmus, H. 2009. The Art and Politics of Science. Norton Books, New York, NY.

5.   For more on Temin, see: Howard Temin: In From the Cold, on the blog.

 6.  Who Discovered HIV? On the blog.

7. The Harold Varmus Papers, AIDS and HIV: Science, Politics, and Controversy, 1981-1993: Documents

8.  Harold Varmus’ April 10,1986 draft of his report, Naming the AIDS Virus, which reviews the deliberations of his panel to find a suitable name for the retrovirus that causes AIDS.