Mankind has long known that a child will only be infected by the virus causing measles, mumps, and small pox once. After someone is infected and recovers they are immune.

In the last half of the 20^th century Maurice Hillman and others created vaccines that protected people from most of the childhood illnesses and children in the western world were immunized. Creating antivirals made little economic sense.

The woman who won the Nobel Prize for helping to develop our earliest drugs that treated viral disease, Gertrude Elion, was born in New York City “on a cold January night when the water pipes in our apartment froze and burst. Her father emigrated from Lithuania to the United States at the age of 12and graduated in 1914 from the New York University School of Dentistry. Her 14 year old mother came from Poland after WWI and married when she was 19.”

Gertrude went to a public school and “received a good basic education and was a child with an insatiable thirst for knowledge. In part because her grandfather died of cancer, she went to Hunter College and majored in science. Hunter was a free college. During the depression “jobs were scarce and the few positions that existed in laboratories were not available to women. I did get a three-month job teaching biochemistry to nurses in the New York Hospital School of Nursing and--by chance, she met a chemist who was looking for a laboratory assistant. Although he was unable to pay me any salary at that time, I decided that the experience would be worthwhile. I stayed there for a year and a half and was finally making the magnificent sum of $20 a week. By then I had saved some money and, with help from my parents, entered graduate school at New York University in the fall of 1939. I was the only female in my graduate chemistry class but no one seemed to mind, and I did not consider it at all strange.” After a year of graduate studies she did research work for her Master’s degree, worked as a substitute teacher, and taught chemistry, physics and general science in secondary schools and did my research work at night and on week-ends. She became a Master of Science in chemistry in 1941 and worked at a number of jobs.

Eventually she became an assistant to George Hitchings and joined the Wellcome Research Laboratories in Tuckahoe, New York, as head and sole member of the Biochemistry Department. Our numbers were always small. For several years our group was housed in one large laboratory. Support was limited, but I was free to develop my own program of research.

According to their website: “Wellcome is a global charitable foundation established in 1936. Through our work we support science to solve the urgent health issues facing everyone. With a 36.8 billion pound investment portfolio, we give researchers the time and resources they need to make breakthroughs.”

“Since very little was known about nucleic acid biosynthesis or the enzymes involved with it she was assigned to work on the purines and, pyrimidine systems.

Purines and pyrimidines are the building blocks of DNA and RNA. The main difference between the two is the structure of their rings: purines have two rings, while pyrimidines have one:

The purines (adenine and guanine) have a two-ringed structure consisting of a nine-membered molecule with four nitrogen atoms.

The pyrimidines (cytosine, uracil, and thymine) only have one single ring, which has just six members and two nitrogen atoms. DNA is made up of chains of purines joined to pyrimidines.

Purines are bigger than pyrimidines. This size difference is part of the reason that complementary pairing occurs. “From being solely an organic chemist, I soon became very much involved in microbiology and in the biological activities of the compounds I was synthesizing.”

Elion’s first major discovery, in 1950, when she was 32, was a purine compound that interfered with the formation of leukemia cells. 6-mercaptopurine, 6-MP for short. The drug often caused a complete leukemia remission . But the effect was temporary; eventually many relapsed.

In mammals nucleotides are not able to passively diffuse through cell membranes but nucleosides (nucleotides that lack a phosphate) are actively transported across the membranes of many cells.

Early in Elion's career many scientists doubted that drugs could be invented to fight viruses; any substance that would kill a virus would be too toxic for the body to endure.

Some of the chemicals synthesized and tested by scientists at Wellcome were inspired by studies performed on a massive shallow water sponge that a young organic chemist,Werner Bergmann, collected in the waters off Florida in 1945.

The previously undescribed sponge was eventually taxonomized as a new species, Tectitethyca crypta. Through experimentation, Dr. Bergmann and others discovered that these sponges possessed a new compound unknown to science. The molecule was similar to, but not exactly like, thymidine (one of the building blocks of DNA). Sea sponges lack immune systems but had evolved compounds such as spongothymidine, for survival--to protect against invading pathogens.

The anti=herpes drug Acyclovir (a nucleoside) is an antiviral agent only after it is phosphorylated and becomes a nucleotide. This is driven in infected cells by a viral-induced thymidine kinase. Acyclovir monophosphate is phosphorylated to diphosphate and triphosphate forms by cellular enzymes in the infected host cell where the drug is concentrated. Acyclovir triphosphate inactivates viral deoxyribonucleic acid polymerase.

( How DNA polymerase turns a single strand of paired DNA nucleotides, into two strands of DNA. step one: paired strands of nucleotides separate from one another. step 2:DNA polymerase “moves along the template strand, reads the nucleotide bases, and adds complementary nucleotides to each strand.)

Acyclovir incorporation into the growing viral deoxyribonucleic acid chain causes its termination.

The antiviral process has relatively little effect on normal, uninfected cells. An important toxic effect of acyclovir is its potential to cause obstructive nephropathy. The drug is excreted primarily by the kidney, which may require smaller doses in patients with decreased kidney function. Oral dosages of acyclovir as recommended for herpes simplex are probably not adequate for varicella zoster infections.

Other drugs her group created have been used to fight malaria, infections, and gout (allopurinol), as well as help with organ transplantations (6MP).

A screening program for antiviral drugs begun at Burroughs Wellcome in the 1960s resulted in the discovery of acyclovir in 1974 by Howard Schaeffer. The drug was similar to nucleosides isolated from the shallow-water Caribbean sponge. The sponge was first studied for medical purposes in the 1950s when few scientists or doctors isolated two chemicals—aptly named spongothymidine and spongouridine. They became models for the development of a number of anti-viral and anti-cancer drugs. (some sources say vidarabine, a chemical that inhibits dna polymerase was isolated from sponge Tethya crypta. other sources say it was inspired by the sponge but made from a streptomyces.)

Elion’s team's major breakthrough was in the development of the antiviral drug acyclovir, approved in 1977.

Acyclovir (ACV), can be used to treat herpes, chickenpox, and shingles and cytarabine (Ara-C) is a key component of cancer therapy for acute leukemias and lymphomas. Both are included on the World Health Organization’s List of Essential Medicines (drugs that should be available at all times because of universal need).

AZT is similar in structure to thymidine, one of the four fundamental nucleoside building blocks of DNA. When AZT is incorporated into growing DNA instead of thymidine, the chain stops and the DNA is unable to replicate- preventing the proliferation of cells infected with virus. AZT was synthesized in a US laboratory in the 1960s. It was originally intended as a cancer medication, When it didn’t help cancer it was placed on a shelf.

The Burroughs Wellcome Fund is a private foundation that funds research in a variety of fields. The foundation was established in 1955 as a US extension of the Wellcome Trust in England.

The Wellcome Trust was created in 1936 by Henry Wellcome, who used profits from his pharmaceutical company to fund charitable research.

The Burroughs Wellcome Fund became independent from the pharmaceutical company in 1993.

In 1984 Marty St. Clair discovered that AZT could inhibit HIV replication. She was a virologist and researcher at ViiV Healthcare (formerly Burroughs-Wellcome).

From a presentation she made.

June 30th, 1982 was a big day for me, and for probably everybody in this room, because now we actually knew that HIV/AIDS was caused by an infectious agent, To have this be caused by an infectious agent, all of a sudden made those of us who deal with infectious diseases feel like this is something we can deal with. The scientific community did not think that we could attack HIV/AIDS with an antiretroviral and didn’t think that you would be successful in discovering a drug that could be used against HIV/AIDS.

With the exception of us. We had—we, being Burroughs Wellcome—had just gotten the approval of acyclovir for herpes viruses. In fact, when I started working for Burroughs Wellcome in 1976, my job was to elucidate the mechanism of action of acyclovir. I worked with herpes viruses from 1976 until 1984. I gained a lot of experience. I gained a lot of drug discovery and drug development experience with acyclovir, but we knew about retroviruses. We assumed HIV was similar to the other retroviruses in that it infects cells with the appropriate proteins on the exterior of the cell. The core is freed from the lipid bilayer, the two strands of RNA are through activity of reverse transcriptas made into a double stranded DNA, which is then intercalated into the cellular DNA using integrase. From that way forward, it goes on through normal biology processes creating new viruses that bud out of the cell.

Remember, we had just finished a very successful drug development program with acyclovir, which, once phosphorylated, inhibits herpes simplex virus DNA polymerase. We believed we would be successful in HIV doing exactly the same thing. When we started our screening process, we emphasized nucleosides for the purpose of inhibiting reverse transcriptase.

As I just said, we had experience and success in antivirals—shouldn't be plural, singular, acyclovir—and we initiated screening of nucleosides. By we, I pretty much mean me. There were a group of about four of us that were involved in this. We're a very small company, somewhere around 400 to 500 people in RTP Research Triangle Park North Carolina. in our little funny shaped building that we call Burroughs Wellcome. When the company made the decision that we would initiate a drug discovery development process for HIV/AIDS, I raised my hand because remember, I'd had experience with retroviruses as an undergraduate, and I had just spent from 1976 to 1984, working with herpes viruses. Believe me, I was sick to death of herpes viruses. So I said, "Please, can I be part of this effort, so I can work with retroviruses again, which is really what I want."

I started screening in June. There are some people in this room that are as old as me, so you might remember. When I talk to scientists today, nobody believes that this is the truth, but what we did for our assays, we made a sheet of cells in the bottom of a petri dish.. I have to hold up my hand like this. That's what a petri dish looks like, because nobody even knows what a petri dish If you have your cell sheet on the bottom of petri dish, you can infect your cell sheet with viruses. For every place that a virus infects the cell, it will infect adjoining cells, cells die, they fall off. At the end of your assay, when you stain that cell sheet, and our stain was purple, the places wherever there was an infectious virus, and the cells were killed and fell off, would be clear, and that's a plaque. At the end of the assay, you can hold up your plaques to the light and you can count the plaques. I had the assay set up so that each plate had 100 plaques.

Every Friday, when my assay was done, and it was about 350 plates, which, like today the way we do things, in the first place, we wouldn't have 350 plates. In the second place, we would assay hundreds more compounds that I could in my petri dishes doing everything by hand.. Every Friday, I'd be sitting at my desk. I'd hold these plates up to the light, and I'd count the plaques, and they all had 100. I would do about 350 plates per assay, so every Friday I'd count about 350 plates, and they all had 100.

Until Friday, November 16th, 1984, when I was counting my plates. I came to 16 that had no plaques. I said to my manager, who was in the office right next door, and I said, "Hey, Phil (Furman), come over and look at this. Out of this great big old assay, I have these 16 plates that have no plaques at all. Do you suppose I forgot to put the virus in these 16 plates?" To which he responded, "Yes, right, that makes a lot of sense. 350 plates and you forgot to put the virus in these 16, which all have the same compound on them?"

Obviously, Phil Furman knew. When I came back into work, my phone mail was completely full of messages from people around the company who said, "Did we hear it right? Did you find something that could be used against HIV/AIDS?" Because we were a little company and there weren't many of us doing this, but everybody knew what we were doing, and the news spread like wildfire. Between late Friday afternoon and first thing Monday morning, just about everybody in the company had heard. But of course, like everybody in this room, I'm a scientist, we never believe anything that's done the first time, so I immediately stuck back into another assay, using much lower concentrations, of course. On November 24th, 1984, we got the IC50 for AZT in the system with this virus, which was not HIV, of 4 nM, which is, like, 1000 times lower than IC50 for aciclovir against herpes viruses. It was in this system—AZT does not have that low IC50 in other more relevant systems—but it was in the system. (Half-maximal inhibitory concentration (IC50) is the most widely used and informative measure of a drug's efficacy. It indicates how much drug is needed to inhibit a biological process by half) Google.

That was the end of 1984. What happened in 1985?

The first thing that happened in the end of 1984, is that people who know about this stuff did a patent search. We found that AZT actually existed in the literature. There is a paper from the NCI (National Cancer Institute looking at a whole list of compounds for anti-cancer activity. AZT is one of that whole list of compounds, has no activity in that assay. The fact that it was published is prior art. So we couldn't apply for a compound patents and intellectual property so our patent for AZT was the use of AZT against HIV/AIDS. Anybody can use AZT for any other disease area and not violate our patent. Our patent was specifically for the use of AZT against HIV/AIDS.

We sent AZT out to several different collaborators, some of which are actually in this room today, under code, and said, "Can you stick this compound in your assay, and see if you have any activity against HIV?"a virus.were working with HIV, and said, "Pleas use me, stick this compound in your assay and tell us what you found." In fact, everybody found that it had activity.

Remember, I told you that I was doing the mechanism of action for aciclovir, the nucleoside is phosphorylated to the triphosphate making it a nucleotide.I found out that AZT is phosphorylated too, to the triphosphate, similar to acyclovir is, and then inhibits reverse transcriptase.

We determined that AZT was safe in animal models. That's a relative term, isn't it? We submitted the IND Investigational new drug application to the FDA. Then we announced our discovery at the ICAAC. Does anybody remember ICAAC 1985, it was in Minneapolis. We submitted abstracts, and our collaborators that we sent AZT to, submitted abstracts, and the organizers of ICAAC put them all in one session. We all had oral presentations. While I'm old and experienced now, I was really young and scared to death back then, and had never talked to more than five people at once in my life.

The night before I went to see what room our session was in, and it was in the basketball stadium, which holds 30,000 people. Oh my God, I was absolutely terrified. I talked to Trudy. People know Gertrude Ellion. She's a Nobel laureate (1988) and is actually the person who hired me at Burrough Wellcome all those years ago. I talked to Trudy and I said, "Oh my God, it's in a basketball stadium. I can't do this." Trudy said "If you aren't nervous or anxious, or in some way up, you aren't going to do a good job.Use that, use the fact that you're nervous about speaking in front of all of these people, and you'll do a better job."

I don't know that I did a better job or not, but I do know the entire front row was full of reporters.

The company sent samples to the FDA researchers had to be sure that it was safe and that it would indeed stop HIV in some way, even if it didn’t cure people of their infection. At the time, such tests, overseen by the FDA, took eight to 10 years. After 16 weeks, Burroughs Wellcome announced that they were stopping the trial because there was strong evidence that the compound appeared to be working.. The company reasoned that it wouldn’t be ethical to continue the trial and deprive one group of a potentially life-saving treatment.

The results were heralded as a “breakthrough” and “the light at the end of the tunnel” by the company, and the FDA approved the first AIDS medication on March 19, 1987, in a record 20 months.

AZT became was a best-seller for Burroughs Wellcome, generating about $4 billion in sales before its patent expired.

While still under patent the treatment would usually cost about $8,000 a year for the average patient with full-blown AIDS. Company officials defended its high price by saying that its research costs were expensive and that the drug would have a limited market. Further, they said, they feared that AZT would be short-lived as other antiviral drugs were developed.

"Worldwide after-tax cumulative profits for Retrovir (zidovudine/AZT) during the period 1987-1992 are estimated by the report at $592 mil., or 42% of worldwide sales. The study projects cumulative U.S. and world sales of AZT to reach $1.57 bil. and $3.3 bil., respectively, by 1996."

https://www.natap.org/2005/HIV/092005_02.htm

https://time.com/4705809/first-aids-drug-azt//

https://www.latimes.com/archives/la-xpm-1989-09-19-mn-111-story.html

https://www.nobelprize.org/prizes/medicine/1988/elion/biographical/

https://libwiki.cshl.edu/confluence/display/AT/3.1+Marty+St.+Clair%3A+Discovery+of+AZT+as+the+First+Anti-HIV+Drug

http://www.pfeist.net/ALL/arac/

https://www.google.com/search?client=firefox-b-1-e&q=The+Burroughs+Wellcome+Fund+is+a+private+foundation+thatfunds+

https://ocean.si.edu/ocean-life/invertebrates/sea-sponge-hiv-medicine