Fighting the Plague
A Story of HIV/AIDS
In the beginning of the twentieth century, a plague was born. A new retrovirus started infecting humans that would later be named Human Immunodeficiency Virus (HIV), the virus that causes Acquired Immune Deficiency Syndrome (AIDS). Though it wasn’t the first retrovirus to infect humans, it became the most feared, deadly, studied, and written about….Though this a story about a plague, which means it’s about fear and death, it’s more about fighting for life, the extraordinary strength of humanity, and crafting new weapons against the virus using research and medicine.
Following a jump from monkeys to humans over a hundred years ago, HIV lurked in Africa near the Congo River. It was unknown to medicine until an outbreak in the gay populations of San Francisco, New York, and Los Angeles in 1980. We may never understand the full implications of the unlucky fact that HIV exploded into popular awareness as a disease associated with homosexuality. Entrenched intolerance caused a cross-pollination of stigma: this was a disease of the other.
Naming a disease “Gay Cancer” or “Gay-related immune deficiency (GRID),” as it was called in the early eighties, sounds ridiculous today. Of course, HIV doesn’t care if you’re gay or straight. The cancer component came from associations with KS (Kaposi’s Sarcoma), a type of skin cancer caused by a virus that can attack when your immune system is not functioning. This type of sickness is called an “opportunistic infection”, which means that the germ exploits an opportunity — the crack in immune defense — to infect a person. These opportunistic infections (commonly Pneumocystis pneumonia and KS, but also many others) are the executioners of the HIV/AIDS death sentence. It was the sudden appearance of these diseases among young gay men that were the harbingers of a plague.
Though popular opinion in the early eighties was largely ignorant or unsupportive, a group of heroes in the gay community, healthcare workers, and scientists became our first fighters in the new war. As an HIV researcher today, living in San Francisco and talking with the pioneers that are still alive, I feel very lucky to do my part as a new group of scientists on the front lines of HIV research. The early chapter of HIV history is incredible, and my brief exposure to it has changed my perspective, fundamentally shifted my reasons for research, and given me a deep love for the humans involved.
The early period of the HIV epidemic was written by many people. I recommend the work of Randy Shilts, a journalist from San Francisco. His writing for the SF Chronicle and the book And the Band Played On: Politics, People, and the AIDS Epidemic tell stories of those in the midst of the new AIDS epidemic. Shilts died of AIDS, and in a NY Times interview said:
“H.I.V. is certainly character-building, it’s made me see all of the shallow things we cling to, like ego and vanity. Of course, I’d rather have a few more T-cells and a little less character.” -Randy Shilts [1]
HBO made a movie in 1993 based on Shilts’ book, also called And the Band Played On. I watched it, with pretty low expectations (a made-for-TV book adaptation from the nineties, right?). Turns out, it is a great movie, and I highly recommend it. What impressed me the most about the film was the feeling of unknown. It made me think about what it must have been like for people at that time, not knowing anything about the disease that they were fighting. Was it coming from “poppers?” Bathhouses? Was it sexually-transmitted? Could only gay men get it? And that was just the epidemiology side. As a virologist, I wouldn’t even know where to start with the tools and science of that time. That struck me violently: it’s easy now to take for granted our accumulated knowledge and today’s technology. The heavy-lifting that was done in 1983 to discover HIV in the laboratories of Dr. Françoise Barré-Sinoussi and Dr. Luc Montagnier at the Pasteur Institute, Dr. Robert Gallo at the NCI, and Dr. Jay Levy at UCSF is awe-inspiring, and that was just the start.
After reading and watching And the Band Played On, I wanted to learn more about the HIV/AIDS epidemic. The library at the University of California, San Francisco (UCSF) has an Archives & Special Collections department, which is run by Polina Ilieva. Part of the Archives is the AIDS History Project, and Polina was kind enough to talk to me about this collection. We started our conversation with why the AIDS History Project is part of the Archives, and Polina said it was important to “preserve the past for the future; you can’t move forward without knowing your past and learning from it.” As a virologist, it struck me when she warned “[AIDS] was one epidemic, but we as a society will have more epidemics, and it can serve as something we can learn from.” She then quoted Shakespeare “The past is prologue…”
“[AIDS] was one epidemic, but we as a society will have more epidemics, and it can serve as something we can learn from.” -Polina Ilieva
Polina then took me on a tour of the Archives. Contained in a secure room (that has Halon fire suppression — how cool is that? Polina tells me it’s getting replaced soon with something less dangerous) are rows of books, papers, and folios, many of which are the only copy in the world and only a small portion are digitized. The room has a special climate control and the air is chilly and dry. The smell of the books is intoxicating, and I can’t help by feel like I’m in a holy sanctum where I can only whisper. Polina opens a copy of 1984 The Year of the Plague special issue from the SF Chronicle (most pieces written by Randy Shilts) and tells me to look through it. I tell her I’m afraid to touch it, and ask her to page through it for me. Why can’t I wear gloves? She says you’re more likely to tear the pages with gloves.
We then go to another room of the Archives, where indexed boxes of the collections are kept. High on a shelf is an old, beaten, brown leather briefcase. Polina tells me this is the briefcase that Don Francis used during his work for the Centers for Disease Control and Prevention (CDC) researching AIDS. She says that before coming to San Francisco, Don used the same briefcase in Zaire during the 1976 Ebola outbreak. I immediately thought about how reading Richard Preston’s book about Ebola, Hot Zone, when I was 12-years-old inspired me to become a scientist. I want to touch the briefcase, but I don’t ask. She tells me that HBO used it in the movie. It’s all part of a collection that Don, a Bay Area native and resident, donated to the Archives.
Deeper in the room are secure boxes with patient information, and others that are public and include notes, letters, pictures, and ephemera. Among these are three collections that Polina and Kelsi Evans (who is also an archivist) selected to show me.
Bobbi Campbell: Person With AIDS
Bobbi Campbell was a nurse from San Francisco and was among the first to be diagnosed with KS. He lived publicly with AIDS and spent his few years of life after being diagnosed trying to raise awareness of the disease. One of his first public actions was to post a picture of his KS lesions with the title “Gay Cancer” in the Castro — the first AIDS poster — to urge people to get treatment if they had similar symptoms. His vociferous fight for public awareness of the new plague is captured in his self-proclaimed title of “AIDS Poster Boy.” Along with awareness, Bobbi fought stigma associated with AIDS. He refused to be labeled an “AIDS victim,” and co-authored the “Denver Principles” which opens with:
“We condemn attempts to label us as ‘victims,’ a term which implies defeat, and we are only occasionally ‘patients,’ a term which implies passivity, helplessness, and dependence upon the care of others. We are ‘People With AIDS.’” -Denver Principles [2]
In the Archives is Bobbi’s diary from 1983–1984. Kelsi handed me a blue journal that is handwritten in a simple, slanted print. From the casual style of his penmanship and his candor, I get the impression that Bobbi was writing for himself: the private thoughts of this public person. Bobbi writes about his diagnosis, his personal feelings, and his struggles with intimacy in his relationship with his boyfriend. One whole page is reserved for large letters in red pen that say “October 26, ’83 KS Diagnosis — 2 years”.* He wouldn’t live another year after writing that. Bobbi Campbell died August 15th, 1984. An obituary written by Allen White in the Bay Area Reporter tells of an emotional candlelight memorial on a closed Castro Street. The obituary ends with a quote from Bobbi’s last speech:
“We are not victims! And there is no need to panic.” -Bobbi Campbell
*Diary, Finding Aid to the Bobbi Campbell Diary 1983–1984, MSS 96–33. Archives and Special Collections, University of California, San Francisco.
San Francisco General Hospital
A constant bulwark in the medical response to the AIDS crisis, San Francisco General Hospital (SFGH) established the first AIDS Clinic, Ward 86 (outpatient) and Ward 5B (inpatient). It continues to lead the world with the “San Francisco Model” of HIV care [3,4,5].
The San Francisco Model centered around compassionate treatment and patient education, emphasizing retention in care. That’s a term used in medicine that means the patient continues to engage with their doctors, including regular follow-up appointments and sticking to a treatment regimen. There were many people at SFGH that led the development of this model. To notable figures are Dr. Merle Sande and Dr. Paul Volberding.
Merle was the new Chief of Medicine at SFGH, and he hired Dr. Paul Volberding as chief of a new oncology division. In a cruel irony, Paul had just finished a fellowship in Jay Levy’s laboratory at UCSF, where he studied retroviruses. As Paul said, “I walked from a retrovirus lab into a retrovirus epidemic literally my first day.” [6]
And what an epidemic it became. Paul and Dr. Marcus Conant (who diagnosed Bobbi Campbell) saw a wave of KS patients in the oncology clinic — all gay males. Merle described how the connection was made that they were facing something new:
“The first patient I saw — my dates are always sort of suspect these days — in the spring of ’81, was a patient on the fourth floor with three brain lesions — a young gay male. We had biopsied him three times, and we couldn’t figure out what it was. Finally, somebody thought they saw toxoplasmosis. We sent the specimen down to Jack Remington at Stanford, and he confirmed that it was toxoplasmosis… That [case] was really bizarre; it didn’t make any sense, but we see a lot of bizarre things. I didn’t think too much of it. Then Paul… told us about some of the KS patients that he was seeing with Marcus Conant in the Kaposi’s clinic at UC. Then, I remember a rumor came from the CDC that they had seen a cluster of gay male patients with an unusual pneumonia in Los Angeles. The report by Mike Gottlieb at UCLA came out in the [Morbidity and Mortality Weekly Report] that summer of a cluster of five patients with this weird pneumonia called Pneumocystis. At about the same time, we started seeing patients here with Pneumocystis pneumonia and we were off and running… We were seeing the Pneumocystis pneumonia cases, but they didn’t make any sense. They were all in gay men. The toxoplasmosis patient was gay. The patients with Kaposi’s sarcoma were gay. But it was the click from the Gottlieb observations that, ‘Gee, there’s something really bizarre going on here.’” -Merle Sande [7]
After realizing these patients were connected, Merle charged Paul with heading the world’s first AIDS Clinic at SFGH. However, there was little they could do at first, other than battle the opportunistic infections that were ravaging these men with depleted immune systems. They could see that their patients were losing T cells, but they had no idea why.
The courage shown by the healthcare workers at SFGH in the face of this deadly unknown disease was tremendous. How deadly? According to Paul, “The fatality rate was 100 percent. Everybody who got it died.” [8] And since they didn’t know how this new disease spread, they worried about not just themselves, but also their families. Paul recalls, “My recurring nightmare was not so much that I had AIDS but that I had given it to my kids because we didn’t know how it was transmitted, an important part of the memory for people… is how terrified they were.”[8]
“I was the one responsible. I had more [AIDS] patients than anybody in the world. I had a faculty, nurses, students, housestaff, that were incredibly exposed. And that scared the hell out of me. It really scared me.” -Merle Sande [7]
But despite the anxiety of an unknown plague, they resolved to care for their patients above all. Merle recalled, “We said that if you’re a physician and you’re in this setting, and somebody comes in who’s sick with HIV, then it’s your obligation to care for him.” [7]
Guerrilla Clinic
The fight against AIDS was not limited to traditional approaches of medical practice. It took on a grassroots, no-holds-barred form — a community banded together to fight with nothing less than the desperate fervor of survival in the face of an existential threat.
One approach in the community of People With AIDS (PWAs) was the formation of “buyers clubs” that distributed unapproved drugs in an attempt to treat AIDS and related opportunistic infections. This was recently highlighted in the biographical film Dallas Buyers Club, which told the story of Ron Woodroof. These buyers clubs grew out of desperate frustration with the lack of treatment for AIDS. Mary Franklin, who worked at the actual Dallas Buyers Club, recalled, “I know it made them feel more powerful about their disease… That they had a fighting chance, which is something the government was not offering."[10] Ron Woodroof, who died of AIDS in 1992, said, “Well, instead of letting these guys kill me, let me try anything I can get my hands on. Because if it kills me, at least I died trying.”
In San Francisco, the Guerrilla Clinic was formed by Blaine Elswood, focusing on his use and advocacy of dinitrochlorobenzene (DNCB) as a treatment for KS and AIDS. DNCB causes inflammation when applied to the skin, called contact hypersensitivity, in a similar manner to poison ivy. The chemical binds to proteins, causing the immune system to activate. Blaine had KS as a symptom of AIDS, and he kept meticulous records of his self-medication with DNCB, which he donated to the UCSF Archives. Reading over his medical records and letters that he hand annotated on yellow sticky-notes, I could sense his frustration — he perceived that he was being ignored by the medical community at large. “At last” he exclaims in a sticky note attached to a letter from Dr. Volberding. In an interview with the Associated Press, Blaine said he believed, “[DNCB] normalize[s] the immune function in skin… The doctors should be doing this… We’re doing this out of a sense of desperation.’’ [11]
Blaine worked hard to advocate for DNCB, and he co-authored an application to the Federal Drug Administration (FDA) to conduct a trial, which was approved for study in 1988. He published multiple papers about results that showed some promise, but didn’t block development of AIDS.
A more effective drug, AZT (see below), was already fast-tracked through the FDA, and a new era of hope was finally on the horizon.
You can see more details on these and other collections of the AIDS History Project at the UCSF Library website: https://www.library.ucsf.edu/collections/archives/manuscripts/aids/guides
Many of the quotes above come from the AIDS Oral History Project: https://www.library.ucsf.edu/collections/archives/manuscripts/aids/oh
A Glimmer of Hope
With modern antiretroviral therapy (ART), it’s easy to underestimate the deadliness of HIV, but we are incredibly lucky to have that perspective. Before the most recent strain of Ebola, HIV was the deadliest virus a human being could contract, if untreated. Without ART, HIV kills about 85% of the people who become infected.
ART works by blocking processes that HIV uses to replicate. What are those? HIV is a retrovirus, which means that the virus carries its genetic information as RNA and integrates into the hosts genomic DNA. To do this, the viral RNA must transform into DNA, and this RNA→DNA conversion happens with help from a viral protein called reverse transcriptase (RT). RT takes DNA building blocks (remember A,C,T,G?) from the cell and assembles them to match the viral RNA. It is this process that the earliest ART strategy targeted.
AZT (azidothymidine, a.k.a. Retrovir, Zidovudine) is mistaken for thymidine (the “T” of A,C,T,G) by reverse transcriptase, and this mistake can block the replication of the virus. AZT was first developed as a cancer drug, but was unsuccessful, because when human cells replicate, they are more likely to select real thymidine and ignore AZT. An important clue for HIV was that AZT had previously worked to inhibit a mouse retrovirus [13]. In 1985, scientists at Burroughs Wellcome Company (now GlaxoSmithKline) and the National Cancer Institute made the critical connection that AZT also worked to inhibit HIV in human T cells [14].
Science had given medicine its first weapon to fight HIV, and now it was time to see if it would work. In a historic clinical trial in 1987, which included patients from SFGH and work by Paul Volberding, AZT was found to be effective at treating AIDS [15]. The result was FDA approval in record fashion, just over 2 years from the first description of activity against HIV. Controversy whirled. AZT was far from perfect, but it was something — it was hope.
In a review article about the history of antiretroviral therapy, Samuel Broder, who led the discovery of AZT, said:
We also strongly believed then, as we do now, in Voltaire’s maxim: “Le mieux est l’ennemi du bien,” which translated for the AIDS pandemic means, “The perfect is the enemy of the good.” Rather than wait for the perfect antiretroviral drug to be developed, we decided to proceed with what we had in hand as rapidly as possible. -Samuel Broder [16]
Knowing the Enemy: the Basic Science of HIV and Foundation of the Gladstone Institute of Virology and Immunology
In science, we often talk about research as basic or clinical. Basic research focuses on the fundamental processes and mechanisms of biology, like the discovery of AZT. Clinical research assesses the response of patients to therapies, like the trial showing AZT could work. If basic research makes new weapons, clinical research deploys them on the battlefield. The process is best when the two components inform each other; we call this translation.
AZT gave hope, because it showed a vulnerability in the enemy. If they could just target key viral programs with drugs, perhaps the fight could be won. But what viral programs and what drugs? Merle Sande was confident in the clinical team at SFGH, but he thought that a basic research department needed to be created with a mission to study HIV and the hope that new treatments and a cure could be developed.
Merle joined forces with the Gladstone Institutes (at the time a leading center for cardiovascular and neuroscience research), UCSF, and the City of San Francisco (SFGH) to form the Gladstone Institute of Virology and Immunology. He recruited Dr. Warner Greene from Duke University to lead this new basic science institute. Merle thought that Warner was “probably one of the best basic science investigators in AIDS in the world right now.” [7]
Warner has led the Gladstone Institute of Virology & Immunology from its inception to today. Over the years his laboratory and others in the Institute have made major discoveries propelling our basic understanding of HIV and the immune system.
I joined Warner’s lab because of a recent discovery led by him and Gilad Doitsh. They found a missing piece in the puzzle of how T cells die from HIV. Since the beginning of HIV research, scientists have focused studies on T cells that have been activated. If you don’t activate T cells, very few become infected with HIV. So they activate them, infect them, and watch them die.
The problem is that in a person infected with HIV, only a minority of T cells are activated, and just a small fraction are actually infected. Yet, most of the individual’s T cells die. The numbers don’t add up.
Gilad and Warner made the observation that these uninfected cells (called bystander cells) were actually being abortively infected by HIV. Put simply, HIV would enter the cell, start the process of infection, and stop.
The halted infection should be good news for the cell; but it comes too late. The newly-formed HIV DNA triggers the cell’s innate defense against viral infection and the cell commits suicide. But it isn’t the quiet cell death that is normally used: it’s a fiery, inflammatory death called pyroptosis. Suddenly, with this discovery, the pieces fit. Here was a mechanism that linked the disappearance of T cells and the inflammation that HIV patients suffer.
Today, I’m trying to figure out if this inflammation forms the foundation of the HIV reservoir — but that is just one project. We’re also looking for ways to block pyroptosis, preventing T cell loss and inflammation.
I chose to study HIV because it seemed like a challenge, and because HIV continues to be a global epidemic. Today, I choose to research HIV because of the incredible dedication and sacrifice of the people who have led the charge in this fight against a plague. The people infected with HIV, the healthcare workers, and the scientists. Like Bobbi said: “I have a message for the person with AIDS…Keep the faith, baby, I love you.”
I had to stop this article here, it’s already probably too long. Some sections I left out that I hope to write in a series:
AIDS in the ART Age: The Plague Isn’t Gone (Africa)
We have new answers in prevention (PrEP)
Hope for future (Vaccines & Cure)
