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Posted: 24 May 2011
30 years in 30 weeks, 1985

In 1985, public fear of AIDS was higher than ever. As deaths due to AIDS continued to mount, the disease was in the news and on everyone’s minds.  Many scientists began working on this new pathogen. In the first of two commentaries featured today, Dr. Wain-Hobson recalls the excitement of the early days of HIV research, when they first sequenced the virus and stakes were high for both public health and scientific priority.  The full sequence of HIV genome later allowed researchers to reverse-engineer the virus and study its properties in detail.

Somewhat ironically, when it was discovered that AIDS was caused by a virus, it was widely expected that a vaccine against the virus would be developed quickly, whereas developing effective antiretroviral drugs would take considerably longer, if at all. As we know today,  the reality turned out to be exactly the opposite.  Despite significant recent progress, the development of a safe and effective vaccine against HIV remains an unrealized goal. In contrast, in one of the great success stories of 20th century biomedical research, the first antiretroviral drug, AZT, was identified within months after the methods to culture the virus became available. In his commentary, Dr. Broder recalls the collaborative atmosphere at NIH which allowed researchers to find and characterize the drug. Thirty years later, despite significant recent progress, the development of a safe and effective vaccine against HIV remains an unrealized goal.

Read Dr. Wain-Hobson's commentary                                             Read Dr. Broder's commentary

View the rest of the series:

1984 < All years > 1986


Commentary by Drs. Simon Wain-Hobson and Samuel Broder

Nucleotide sequence of the AIDS virus, LAV.
Cell. 1985 Jan;40(1):9-17.
Wain-Hobson S, Sonigo P, Danos O, Cole S, Alizon M.

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Dr. Wain-Hobson

The story started when Luc Montagnier asked me if I’d be interested in cloning the AIDS virus. You know the answer!

Even before the publication of Bob Gallo’s tetralogy, the trans-Atlantic squabble was essentially in place. Apart from priority and nomenclature, the AIDS virus “had” to be akin to HTLV-1 and -2, the only bona fide human retroviruses of the day. All my early HIV work was done against this tense background. Getting a retrovirus cloned and sequenced was the only way to really know what you were up against, so the goal was obvious. By August 1984 we had five full-length molecular clones. One month more and we had a good M13 shotgun library of one of these clones.

To provide context, by 1982 the Sanger group sequenced the 172 kb genome of Epstein-Barr virus by shotgun M13 dideoxy methods. They were #1, nobody else was even a log close to them, certainly not us. And we were up against the “Gallo machine” as some called it.

Raymond Dedonder, the Director of the Institut Pasteur was crucial to setting up a 5-man commando to sequence the virus. The only condition was that newcomers dropped what they were doing. It turned out to be a group of five molecular biology jocks with myself, at 31, being the oldest.

We worked in overlapping shifts from 7 am to 3 am for six weeks, weekends included. We had 90% of the sequence in six days. Closing the remaining gaps and quality control filled up the remainder. With a more than six-fold coverage we had a pretty good sequence.

The sequence was very different from HTLV, MLV and RSV, the only retroviral sequences around. Everybody knew gag, pol and env. The biggest surprises were that there was an unheard of 1.1 kb stretch between pol and env and two additional open reading frames (vif and nef) with no homology to any retroviral gene. The troublesome and highly glycosylated surface protein was there, as was the protease and other fascinating features. Yet, the sequence didn’t yield any real insight right away.

It did get us looking at lentiviruses. When we finished the sequence of the prototypic visna virus a few months later, it became clear that the AIDS virus was the first human lentivirus. Up until then, most considered development of AIDS as occurring only in a subset of infected individuals, perhaps 10%. By contrast, the animal lentivirologists knew that the majority of infected animals develop disease. The shocking insight was that the majority of people with the AIDS virus would develop the disease. Ouch!

After accepting our paper on the molecular cloning of LAV (Lymphoadenopathy Associated Virus), Nature asked to see our sequencing manuscript. When I phoned them to say it would be sent tomorrow, they said no, a decision they later regretted. For us, this refusal meant that they had Gallo’s HTLV-III sequence, which turned out to be the case. Fortunately, Cell’s editor Ben Lewin rescued us with an I-want-it-on-my-desk-tomorrow challenge. Yet tomorrow was Christmas Eve. Nevertheless, he had it by December 26th and accepted it five days later over the phone. It went to press by January 21, beating the publication of the HTLV-III sequence by a few days.

Today, HIV is the most sequenced genome in the world. It’s been PCR’d and sequenced endlessly in all shades and forms. Every existing and any new phylogenic or sequenced-based program is tested on some HIV dataset.

We knew that what we were doing was special. I guess we succeeded more because we were well organized and fearless rather than anything else.

About the author: Dr. Simon Wain-Hobson is a professor at the Institut Pasteur in Paris, France.



3'-Azido-3'-deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro.
Proc. Nati. Acad. Sci. USA Vol. 82, pp. 7096-7100, October 1985
Hiroaki Mitsuya, Kent J.Weinhold, Phillip A. Furman,  Marty H. St. Clair, Sandra Nusinoff Lehrman, Robert  C. Gallo, Dani Bolognesi, David W. Barry, and Samuel Broder 

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Dr. Broder

Thirty years ago, AIDS emerged as a fatal, hopeless, and terrifying disease, now known to be caused by HIV-1. Our paper was the first description of AZT (zidovudine; 3’-azido-3’-deoxythymidine), today recognized as the first antiretroviral treatment, a DNA-chain-terminating thymidine analog, capable of suppressing the replication and cytopathic effects of HIV-1 by targeting the viral reverse transcriptase. Our work was animated by a collaboration with scientists at Duke University and the Burroughs-Wellcome Company (now GlaxoSmithKline). The paper marks the beginning of the road toward modern highly active antiretroviral therapy (HAART). In wealthy nations, HAART has led to a dramatic reduction in the death due to AIDS, and is credited with prolonging life and transforming the disease into a chronic and manageable condition.

This paper was submitted for publication on June 28, 1985. AZT received approval by the US Food and Drug Administration on March 19, 1987. Here, I revisit this exciting period and attempt to put the science in context.

The identification of HIV-1 was a landmark scientific achievement that affected almost every aspect of public health. However, the realization that a previously unknown pathogenic retrovirus was the cause of AIDS immediately fostered a sense of futility or “false hopelessness” in physicians and patients alike. Retroviruses like HIV-1, by their very nature, were thought to be inherently untreatable, an opinion based primarily on their capacity to integrate into the host genome and rapidly mutate due to the error-prone reverse transcriptase. Many retrovirologists at the time were unfamiliar with drug development, classic pharmacology, and the principles of metabolism and activation of nucleoside analogs. Hence, they were convinced that antiretroviral therapy was “impossible” within the known parameters of the science at hand.

We reasoned that, by protecting uninfected cells by blocking viral infection and the iterative cycles of replication and cytopathic effects, we might prevent further destruction of the immune system, and thereby confer clinical benefit. This now seems self-evident, of course, with the clarity that hindsight brings. We also hypothesized that it would be possible to achieve durable benefit without viral eradication (a supremely difficult challenge then and now). This gave us a sharp and practical focus on translation of knowledge from our lab to the patients we saw in the clinic, and most importantly, attainable goals for one (small) research group. There were no reliable animal models at the time, and we could not await their development.

The paper served as the foundation for advancing AZT (and related dideoxynucleosides) within our programs at the US National Cancer Institute.  Some of the salient features were as follows:

1. AZT was active against widely divergent HIV-1 isolates in vitro;

2. There was a large differential between the concentration needed to block HIV-1 replication (and cytopathic effect) compared to its toxicity for uninfected cells;

3. The cytoplasmic level of the activated drug was a critical factor in determining antiretroviral activity, providing support for the likely mechanism of action;

4. The structure-activity relationship for drugs within the AZT family quickly became evident, providing insights for the development of second-generation nucleoside/nucleotide analogs (i.e., this line of drug development would likely not lead to a “dead-end” or one-time event).

Dr. Broder, ca.1985
We observed clinical activity in our very first studies administering AZT to patients with AIDS. At the same time, we also knew that AZT was not a cure, and the limitations of AZT as a single agent, or monotherapy with any available agent for that matter, were clear, manifest mainly as the emergence of drug-resistant virus when incomplete viral suppression occurs during treatment. To cope with drug-resistance, one would need the arrival of combination therapies, especially second-generation agents, preferably given in fixed-dose combinations at full strength. However, this clinical experiment proved that HIV-1 infection is treatable, confounding the many prophesies to the contrary. Of special note, AZT and related drugs altered the strategic thinking of pharmaceutical and biotechnology companies, whose long-term commitments to antiretroviral drug research and development were critical to progress.  

 There are now approximately 30 antiretroviral products, formulated either singly or in fixed-dose combinations, approved by the US Food and Drug Administration to treat patients with AIDS and related conditions. Several have been formulated as fixed-dose, generic-drug combinations given on convenient schedules for greater utility in resource-poor nations.

 This paper symbolizes a tradition at the National Institutes of Health, in which research labs are located adjacent to clinical wards, and physician-scientists are strongly encouraged to adopt an uninterrupted movement of knowledge from the lab to the bedside and then back to the lab. I cannot overstate how important this philosophy was to success of the early antiretroviral therapy programs, and how much its absence would have impeded progress. This research model is worth preserving and defending, despite pressures to establish a clear division of labor between basic and clinical research.

Read additional opinion articles by Dr. Samuel Broder:

The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic (pdf)

Twenty-Five Years of Translational Medicine in Antiretroviral Therapy: Promises to Keep (pdf)

About the author:  Dr. Broder is an American oncologist and medical researcher. He was a co-developer of some of the first effective drugs for the treatment of AIDS and was Director of the National Cancer Institute (NCI) from 1989 to 1995.

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