A lot of progress towards combatting HIV/AIDS has been made possible by female scientists, but they’ve often been overshadowed. Yesterday I told you the story of one such woman, Flossie Wong-Staal who, among other achievements, was the first person to clone HIV & determine its genetic sequence. If you missed that story don’t worry, I recap it here. And I also tell you the story of 6 other female scientists who’ve been instrumental in the fight against Acquired ImmunoDefficiency Syndrome (AIDS) & the virus that causes it Human Immunodeficiency Virus (HIV): French virologist Françoise Barré-Sinoussi , who co-discovered HIV; Janet Lister Rideout, an organic chemist and one of the scientists who discovered that azidothymidine (AZT) could be used to treat HIV; Mathilde Krim, biologist and HIV/AIDS crusader who founded the nonprofit that became the Foundation for AIDS Research (amfAR); Daria Hazuda who opened up a whole new class of antivirals for treating HIV, Integrase Strand Transfer Inhibitors (InSTIs), Namandjé N. Bumpus, a pharmacologist who studies the effects of antiretroviral drugs; and Theodora Hatziioannou, who “broke the species barrier” and became the first person to develop a non-human or chimp AIDS model in 2014. Note – there are a lot of other amazing women who have done/are doing HIV/AIDS research, but these are just a handful that I’ve covered in the past. ⠀
note: this is an updated and extended version of a post from last October
Some opening remarks…
These are just a few of the MANY people doing research on HIV/AIDS, even before studying viruses was in fashion. They’ve devoted their lives to studying a disease that many have tried to ignore, committed themselves to helping those who have often been ostracized and/or “other”-ized. I hope that the current pandemic has helped show that no one is safe from a virus until the least-resourced, most-vulnerable, populations are safe. In our race to vaccinate against the coronavirus, we must not let under-resourced countries go vaccine-less. And, in our laser focus on this latest virus, we must not forget that HIV/AIDS remains a global scourge. SOOOO much of the research on the coronavirus has been made possible by years of research on HIV. I sincerely hope that some of the findings from coronavirus research can similarly give a boost to HIV research. HIV is in many ways a much more difficult virus to combat than the coronavirus (due to HIV’s high mutation rate, the cell types it infects, etc.) but it’s hard not to look at all the amazing progress that’s been made on the coronavirus, fueled by huge influxes of cash, and not wonder how much more we might be able to accomplish if we invested that much in HIV…
But I don’t mean to set a pessimistic tone. Even without all the financial investment and popular support research into this virus deserves, scientists, many of whom are female, have made tremendous progress in uncovering HIV’s secrets and exploiting its Achilles’ heels. And here are a few of their stories.
When the AIDS crisis struck, some tried to isolate themselves or ignore the problem – not this woman! French virologist Françoise Barré-Sinoussi co-discovered the cause of AIDS, HIV. Before this cause known, gay men and other populations hit hard by AIDS faced strong discrimination and stigma. Unfortunately many of those groups still face discrimination for other reasons…. but this discovery was a crucial step in understanding how AIDS spreads, helping to combat both the disease and the climate of fear that surrounded it.⠀
Barré-Sinoussi made the discovery in 1983 while working at Paris’ Pasteur Institute (where she started as a volunteer). In recognition of her work, she and her former mentor Luc Montagnier were awarded the Nobel Prize in Physiology or Medicine in 2008. Barré-Sinoussi started her own lab at the Pasteur in 1988, where she continued research on HIV: basic research including factors that affect its transmission as well as more translational explorations into potential treatment and prevention measures. She has also been actively involved in international AIDS organizations including UNAIDS-HIV and the International Aids Society (where she served as president from 2012 to 2014) and has trained many of the “next generation” of AIDS researchers.⠀
Additionally, Barré-Sinoussi has been a strong advocate for women in science. I was personally inspired by her when I had the great honor of hearing her speak at a special meeting at Cold Spring Harbor Laboratory: HIV/AIDS Research: Its History & Future. ⠀
photo credit: U. Montan⠀
Virologist and molecular biologist Dr. Flossie Wong-Staal was the first person to clone and sequence a virus of the type that causes HIV (a pathogenic human retrovirus), and later she was the first to clone HIV itself, a breakthrough that helped her and her team figure out the function of the HIV virus’ different parts.⠀
She was born Yee Ching Wong in China in 1947 and her family fled to Hong Kong in 1952. The first woman in her family to work outside the home or pursue an advanced education, she left Hong Kong as a teenager to attend UCLA, where she earned a BS in bacteriology followed by a PhD in molecular biology.⠀
She moved to the NIH’s National Cancer Institute (NCI) in 1973 to work with Dr. Robert Gallo studying retroviruses, a type of virus that inserts itself into a host cell’s DNA. There, she was part of a team that co-discovered the retrovirus that causes AIDS, HIV (a second team, at the Pasteur Institute in Paris, including Françoise Barré-Sinoussi (another amazing female scientist we’ve profiled) also made this discovery). This breakthrough was only one (important) step in scientists’ contribution to the fight against AIDS. They still needed to figure out how this virus was able to cause the devastating disease, and in order to do that they needed to see what it contained. ⠀
Wong-Staal was able to clone and genetically map the HIV virus. Knowing the sequence helped in the development of blood tests for the virus and having the map helped them figure out the function of the HIV virus’ different parts, identifying several of its key components. Her team was also able to show that the virus depleted the immune system’s T cells, helping definitively pin down HIV as the cause of AIDS.⠀
In 1990, she moved to the University of California, San Diego (UCSD), where she continued to study HIV as the Florence Riford Chair in AIDS Research. In 1994, she was chosen to lead UCSD’s Center for AIDS Research, the same year she was elected to the National Academies’’ Institute of Medicine. She retired in 2002 as Professor Emerita but continued a career in biotechnology, co-founding and serving as the Chief Scientific Officer of iTherX Pharmaceuticals, which researches treatments for another deadly virus, hepatitis C. Sadly, Flossie did July 8, 2020. more: https://bit.ly/flossiewongstaal ⠀
photo credit: National Institutes of Health (NIH)
Mathilde Krim (1926-2018)⠀
Among her other accomplishments, biologist and HIV/AIDS crusader Mathilde Krim founded the nonprofit that became the Foundation for AIDS Research (amfAR). Krim was born in Italy in 1926 and raised in Switzerland, where she received degrees in genetics from the University of Geneva. She worked for a time at the Weizmann Institute of Science in Israel before moving to New York, where she took a position at Cornell University Medical School and, later, Memorial Sloan Kettering Cancer Center. ⠀
She was deeply involved in research on the use of the drug interferon to treat leukemia when a physician friend drew her attention to mysterious disease clusters we now know to be caused by HIV/AIDS. Showing her characteristic flexibility in techniques and pathways, but never morals, she switched her research focus to HIV. Quickly becoming deeply involved in the HIV/AIDS community, she was deeply troubled by the stigma surrounding the disease, stigma she began to work tirelessly to dispel, in part through helping explain the science behind it. ⠀
Krim knew that she was in a unique position to address the AIDS crisis – she had a strong scientific background as well as connections to people in power (and sources of money) through her movie mogul husband, Arthur Krim. Utilizing these resources, she co-founded what would become amfAR in 1983. She served as amfAR’s chairman for over a decade, helping introduce legislation for increased research into AIDS as well as improved access to AIDS treatment. In addition to working through scientific and political channels, she recruited prominent celebrities to her cause – through fundraisers and events they raised millions of dollars while also helping with destigmatization.⠀
Mathilde Krim has been described as a “scientist turned activist,” but these roles are not mutually exclusive – Krim was a scientist AND activist. After decades of research, she eventually left academia to focus on advocacy; but when she left the lab, she didn’t leave science, she merely contributed from new angles. Furthermore, Krim was an advocate all her life, active in numerous civil and human rights movements around the world. No, Krim was not a scientist TURNED activist, she was a scientist AND activist who was able to unite these two roles to great effect. ⠀
Photo credit: amfAR⠀
Janet Rideout ⠀
Janet Rideout is an organic chemist and one of the scientists who discovered that azidothymidine (AZT) could be used to treat Human Immunodeficiency Virus (HIV). She also played a key role in the development of acyclovir, the first effective treatment for herpes viruses.⠀
Rideout was born Janet Litster January 6, 1939 in Bennington, Vermont. She received bachelor’s and master’s degrees in chemistry from Mount Holyoke College followed by a PhD in organic chemistry from State University of New York, Buffalo (UB) in 1968. Shortly before graduating from UB, Rideout was hired by chemist and future Nobel laureate Gertrude Elion to work at a small US subsidiary of the British pharmaceutical company Burroughs Wellcome Company (now GlaxoSmithKline).⠀
In June 1984, Burroughs Wellcome initiated a program to identify chemical compounds that might be effective against HIV, and they put Rideout in charge of choosing which compounds to test. There was limited knowledge about HIV at the time, but Rider’s search was aided by the finding that HIV was a retrovirus, a type of virus that transfers between cells with its genome encoded in RNA but, once it infects a host cell, reverse transcribes its RNA genome into a DNA copy which it then inserts into the host cell’s DNA, so that the cell and all its progeny are perpetually infected. Knowing that HIV was a retrovirus, Rideout searched for compounds with antiretroviral activity.⠀
One of the compounds she chose to test was azidothymidine (AZT), a structural mimic (analog) of the canonical nucleoside thymidine, one of the building blocks of DNA. Unlike thymidine, AZT doesn’t have the chemical group needed to link nucleotides together, so it could potentially act as a chain terminator (when the virus tried to reverse transcribe its RNA, it would incorporate the analog and get stuck since additional nucleotides couldn’t link to it).⠀
Colleague Marty St. Clair tested it against two animal retroviruses, and found it to be highly effective. To see if it was also active against HIV, they collaborated with scientists at the National Cancer Institute (NCI), including Samuel Broder and Hiroaka Mitsuya, who found AZT to be highly effective against HIV in human cells, and it went on to become the first FDA-approved treatment for HIV. Rideout is listed as the first co-inventor on the patent for the use of AZT to treat HIV (one of more than 40 U.S. patents she now holds).⠀
The rollout of AZT, given the chemical name zidovudine and the proprietary name Retrovir, was contentious, as the product was rushed to market and approved at doses later shown to be toxic. Additionally, many protested the high price of the treatment. Today, AZT is given at lower doses and as part of a combined antiretroviral therapy for AIDS. It is also important for preventing the transmission of HIV from mother to unborn child. It is on the WHO list of essential medicines.⠀
As Flossie Wong-Staal showed, HIV mutates really quickly, so it’s often able to develop resistance to single drug treatment regimens (monotherapies). For that reason, patients with HIV are usually treated with multi-drug “cocktails” containing several different drugs. Often, one of these drugs is a drug that Hazuda led the development of, Raltegravir, or a related “second generation” Integrase Strand Transfer Inhibitor (InSTI). But, in the first decades of HIV treatment, before Hazuda’s groundbreaking work, anti-HIV drugs went after the HIV reverse transcriptase (the enzyme HIV uses to make a DNA copy of its RNA) or the HIV proteases (protein cutters that HIV uses to process its proteins). They’d work for a time, but resistance would occur. Scientists realized they should look for another target to add into the mix. So some of them, including Haruda, turned to a different viral protein, an enzyme (reaction mediator/speed-upper) called integrase, which is responsible for sneaking HIV DNA into a cell’s DNA.
Integrase allows HIV’s genome to get permanently embedded in that cell, so all the cells that are made from it will inherit that viral genome (note that these aren’t germline cells (egg & sperm cells) so HIV doesn’t get inherited in that sense). So all those cells will have the capacity to infect more cells, and the person will have the capacity to infect more people.
Therefore, if you could inhibit integrase, you could prevent the virus from infecting cells and/or people. Problem was, most people didn’t think you *could* inhibit integrase. Hazuda wasn’t the only person to try it. People at all the other pharma companies were trying as well. But, after lots of failure, they deemed it “undruggable.” Hazuda didn’t. She kept going, although she faced skepticism and pushback at almost every step along the way.
People thought it would be impossible to inhibit integrase for a couple of reasons. First off, the integration reaction carried out by integrase is “irreversible” in that integrase won’t just change its mind and pop that viral DNA back out. However, the integrase inhibitors they were testing were reversible in terms of their binding – they can bind and unbind and bind and unbind and bind…
The thought of many skeptics was that such reversible binders would be useless because all the unbindings would allow integrase to quickly do its thing. But Hazuda found that, although the drugs’ binding was reversible, it was “functionally irreversible.” Binding of the drug prevented the viral DNA from getting in long enough that the cell caught wind of that foreign piece of DNA hanging out and degraded it and/or turned it into circular non-functional viral. Therefore, the drug wouldn’t need to constantly be guarding every copy of viral DNA. Instead, it would only have to stall things long enough for backup to arrive.
And she and her team discovered a drug that could do just that, raltegravir (Issentress), which was FDA-approved in 2007 and is now a staple of combination HIV therapies, included in the WHO’s listing of essential medicines. Hazuda didn’t stop there. She continued climbing up the ladder at Merck and currently serves as Vice President for Infectious Diseases Discovery for Merck and Chief Scientific Officer of their MRL Cambridge Exploratory Science Center.
Hazuda was raised in Hillsborough, New Jersey. Her father was an engineer and her mother worked in the regulatory-compliance division of Janssen Pharmaceutica (now a part of Johnson & Johnson) She initially pursued a premedical degree at Georgetown University, but fell in love with research during a part-time job in a lab and decided to go into drug discovery. She earned got a B.S. from Rutgers University, followed by a PhD in biochemistry from the State University of New York at Stony Brook, where she trained with Dr. Cheng-Wen Wu. She then did a post-doctoral research fellowship at Smith, Kline, and French in the department of Molecular Genetics.
Hazuda joined Merck in 1989, where she started as a Senior Research Biochemist in the antiviral research group. She was initially assigned to work on influenza, but she asked to be switched to HIV research. She continues to oversee Merck’s HIV research, which includes the development of long-acting antiretrovirals. She has also been instrumental in the development of antiviral treatments for Hepatitis C Virus (HCV), leading the development of antivirals for Hepatitis C Virus (HCV) including Elbasvir and Grazoprevir. Additionally, as Chief Scientific Officer of the Merck Research Laboratory Cambridge Exploratory Science Center she oversees research on interactions between the human microbiome and immunity. She previously served as Global Director of Scientific Affairs for Antivirals in Merck’s division of Global Human Health, as well as co-site head of basic research for the Merck West Point research facility.
photo credit: Merck & Co.
Namandjé N. Bumpus⠀
Many life-saving drugs, including those used to treat HIV & hepatitis, can have side effects that themselves can be life-threatening. Often these side effects come from breakdown of the drug into toxic compounds. Pharmacologist Namandjé N. Bumpus uses mass spectrometry and molecular pharmacology to figure out what toxic compounds are produced from these drugs, why they’re toxic, and how their toxic effects can be prevented. ⠀
In addition to carrying out this critical research as a Professor of Medicine and Pharmacology at John Hopkins University, in 2020 she was named Director of the Department of Pharmacology and Molecular Sciences! This made her the first Black woman to become a department director at Hopkins Medicine and the ONLY Black woman chairing a pharmacology department at any medical school – in the entire United States.⠀
Bumpus studies anti-HIV drug metabolism – metabowhatta? Metabolism is just a term we use to describe the chemical changes our body makes to molecules, and metabolite’s what we call the changed version. When you ingest a chemical that’s in one form, that’s not necessarily the form it stays in as it travels throughout your body and “does its thing.” You take some drug, your liver does something to it and, bam – it’s a metabolite.⠀
Just like the food you eat gets processed, the pharmaceutical drugs you take do too. They’re already pretty small (much smaller than that bite of sandwich) but they can still get broken down further. And they don’t just get broken down, they can also get added onto or just tweaked a bit. All of these changes fall under “metabolism” and it’s a big focus for pharmacologists, because these changes can affect the drugs’ activity – either positively or negatively. Different people can have different variants of the the proteins that do this metabolism stuff (including the cytochromes, aka CYP proteins), so different people sometimes metabolize drugs differently.⠀
Bumpus researches what metabolites form when patients take anti-HIV drugs, how they form, where they go, how they cause problems, how we can tell they’re causing problems before things get too bad, and whether we can keep them from causing problems. ⠀
Among other accomplishments, Bumpus worked out the pathway of metabolism of several anti-HIV drugs including tenofivir & Riplivirine (RPV). She found that genetic variants in CYPs can make them more or less active at metabolizing some of these drugs. So some patients might have drugs buildup while others need higher doses. This sort of thing is the realm of “pharmacogenetics” – the idea is that, for drugs where there is a known difference based on what version of a specific gene you have (the genotype) doctors should take that into account when prescribing a dosage – or maybe they need to prescribe a different drug altogether. ⠀
But often the dosages are set based on studies done just white people, which means that people of color, who are more likely to inherit certain genetic variants, can end up receiving ineffective doses. Bumpus found that one such variant, CYP3A5*1, which is rare among white people, but common among African Americans (almost 1/2 of African Americans have 2 copies of it), makes their bodies better at “detoxing” an HIV treatment & pre-exposure prophylaxis drug called maraviroc (trade name Selzentry). https://bit.ly/2VpoM06 ⠀
This might sound good, but “detoxing” the drug means their livers chemically modify the maraviroc into a form which, instead of preventing or treating HIV infection by blocking HIV from getting into cells, just gets removed from the body. Basically, their cells are “too good” at getting rid of the drug, so they can end up being underdosed. Bumpus published her findings and pushed the drug makers into doing follow-up studies. And she continues to advocate for diversity in medical research.
She recently published an article in Science calling for diversifying clinical trials and offering concrete steps that can be taken to make that a reality: https://science.sciencemag.org/content/371/6529/570
Bumpus earned a bachelor’s degree in biology from Los Angeles’ Occidental College, followed by a Ph.D. in pharmacology from the University of Michigan-Ann Arbor. She then did a postdoctoral fellowship at the Scripps Research Institute. Her many honors include one from a president himself – President Obama awarded her a Presidential Early Career Award for Scientists and Engineers. She also received 2014 Tanabe Young Investigator Award from the American College of Clinical Pharmacology and ASPET’s 2015 Drug Metabolism Early Career Achievement Award.⠀
Bumpus is one of far too few Black female professors in the biomedical field and she’s working to change this. She served as Hopkins’ first associate dean of institutional and student equity and instituted mentoring programs to expand access to resources and opportunities. more: https://bit.ly/diversitybumpus ⠀
Photo credit: John Hopkins University⠀
I first heard of Theodora Hatziioannou in the context of coronavirus research. As an Associate Research Professor at the Rockefeller University in NYC, she was at an early epicenter of the COVID-19 pandemic and she quickly sprang into action to develop and put to use ways to test the ability of antibodies present in recovered patients’ blood to block coronavirus infection (and the ability of the virus to escape). But before that she put in years of work studying how *HIV* is able to escape species-specific cellular defenses called “restriction factors.” ⠀
One of the things that’s made AIDS hard to study has been a lack of good animal models, in part because it’s been hard to get HIV to infect non-hominids (not humans or chimps). In studying *why* it was so hard to infect them, Hatziioannou (and other groups) discovered a number of cellular defenses called “restriction factors.” Unlike antibodies, which are a form of adaptive immunity (your body learns to make them in response to a virus), restriction factors are a form of “innate immunity” – they’re always there (although some only get made in large amounts once they get some form of stimulation (e.g. by the signaling molecule interferon, which is produced in response to a variety of foreign-thing triggers). ⠀
A few important restriction factors for HIV-1 are TRIM5α, which binds to the viral capsid once it enters the cell and leads to its degradation; APOBEC3, which extensively mutates the viral DNA so that it becomes gibberish; and tetherin, which is a membrane protein that tethers new virions on the cell surface as they’re trying to escape. ⠀
But HIV has countermeasures…⠀
cell gives you APOBEC3 – HIV gives you Vif, which binds it, calls in ubiquitin ligases to add a destruction tag and sends it for degradation⠀
cell gives you tetherin – HIV gives you Vpu, which binds to tetherin and leads to its degradation.⠀
Your body doesn’t have to “learn” to make restriction factors, but a virus can “learn” to evade them by adapting their counteracting proteins. So, for example, they can change their Vif or Vpu, or change their capsid to evade TRIM5α. This “learning” happens because viruses can replicate rapidly – and make mistakes when they do – so if they make mistakes that make them less susceptible to the restriction factor (but which don’t hurt themselves too much) they’ll be at an advantage. ⠀
Crucially, the virus is going to learn to evade the immune system of its host species, because that’s what it’s feeling the pressure from. So the H in HIV really matters – this virus has adapted to evade human versions of restriction factors. Even though other species have related restriction factors, they’re often different enough that the virus is vulnerable to them. So the virus has a hard time infecting and/or replicating in different species. ⠀
Strains of a related lentivirus (the kind of virus HIV is) called Simian Immunodeficiency Virus (SIV) *can* (and do) infect monkeys and apes, and it’s been used a lot as a model for studying HIV, but it’s really different, and those differences can (and sometimes do) prove critical when it comes to testing out treatments, vaccines, etc. To make the SIV more HIV-like, scientists tried putting some of the HIV genes into SIV to make chimeric viruses called SHIVs, but they still were mostly SIV. Theodora Hatziioannou wanted to try going the other direction – take HIV and make it slightly SIV-like, swap in just enough SIV that it can infect and replicate in a monkey (they used pigtail macaques). After a lot of hard work, much of it in collaboration with her husband and colleague Paul Bieniasz, she was successful in creating the first non-human or chimp AIDS model in 2014.⠀
Biography-wise, Theodora Hatziioannou was born and raised in Rhodes, Greece. She studied biochemistry at the University of Bristol in Britain and then got a Master’s degree in biotechnology from Imperial College, London. She worked as a research technician with Robin Weiss at the Institute of Cancer Research, where she says she fell in love with research and determined she wanted to go on to earn a PhD. She therefore moved to Lyon-France, where she earned a PhD from the University Claude Bernard in 1999. Her PhD research, carried out under François-Loïc Cosset, involved looking at adapting retroviruses to use as tools for gene therapy, seeking to expand their tropism and target them to specific cells by manipulating the retroviral envelope. After earning her PhD, Hatziioannou moved to the United States, where she joined the lab of Stephen Goff at Columbia University as a postdoctoral fellow. She then did further postdoctoral research with Paul Bieniasz at the Rockefeller University and the Aaron Diamond Research Center for AIDS. She became an Assistant Professor at the Rockefeller University in 2006 and was promoted to Associate Professor in 2012.⠀
You can learn more about her here: http://bit.ly/TheodoraHatziioanno
And, thanks to my Greek e-friend Nefeli Boni-Kazantzidou, you can also read the article in Greek! http://bit.ly/theodorahatziioannougreek
photo credit: Rockefeller University
According to UNAIDS, 38 million people around the world are infected with HIV, 1.7 million people became newly affected in 2019, and 690,000 people died from AIDS in 2019. https://bit.ly/2BRQMD5 First reported in 1981, HIV/AIDS clearly remains a huge global problem. However, while there is no cure (yet) for AIDS, decades of research by scientists including the ones I’ve told you about above has turned HIV from a death sentence into a manageable chronic condition. If treatment is accessible, that is. I hope the current coronavirus pandemic has helped point out some of the gross inequities in global health, and that people will start investing more in protecting everyone everywhere, but I worry that societies are just turning their backs on the needy as they’ve done for decades. But, if people do wake up, please help the needy get HIV/AIDS treatment as well while you’re at it. And don’t let a laser focus on the coronavirus drain investment away from more neglected diseases. We all want to put an end to the coronavirus pandemic, but that won’t solve all our problems and we cannot allow ourselves to go back to a state of willful ignorance of global health challenges. In addition to keeping an eye out for “emerging viruses” we must continue to invest in studying and, importantly, treating (*everywhere*) those viruses that have already emerged but which society has tried to keep submerged…
more on topics mentioned (& others) #365DaysOfScience All (with topics listed) 👉 http://bit.ly/2OllAB0⠀