Inside HIV: The genetic story of the AIDS epidemic
Image credit: David S. Goodsell, The Scripps Research Institute, Wellcome Collection
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The beginning
April 1981. Our story starts in Room 161 of the Centre for Disease Control’s Building 6 in Atlanta, Georgia. A drug technician by the name of Sandy Ford writes a memo to her superior about five unusual pneumonia cases, all occurring in young gay men and all caused by a rare yeast-like fungus only ever seen in immunosuppressed patients. By the time the CDC publicly acknowledges this unusual coincidence, 3 of the 5 patients have died. And so begins the global AIDS epidemic.
Meanwhile, dermatologists across the US are noticing an increasing number of people with an aggressive and uncommon skin cancer called Kaposi Sarcoma. Once again, all the patients are homosexual men - and in the few patients who had their immune system tested, all are found to be severely immunosuppressed.
By August 1981, the CDC has received reports of well over a hundred cases of Kaposi Sarcoma or fungal pneumonia, sometimes both at the same time, and almost always in previously healthy gay men. By the end of the summer, nearly half of them have died.
As the new year rolls in, the epidemic of strange, deadly symptoms grows ever larger, and fear and stigma spread across the population. Newspapers label the disease GRID, for Gay-Related ImmunoDeficiency. The term “gay cancer” enters the lexicon as a synonym for Kaposi Sarcoma, and young men begin to dread the appearance of the telltale purple skin lesions that invariably marks them for a rapid death.
But by now, the strange syndrome has already spread outside of the gay community. Reports of a similar illness are emerging in intravenous drug users, haemophiliacs, sex workers and their respective partners. And it’s no longer confined to the US either, as cases are found in Australia, Europe and South America. Meanwhile the list of symptoms grows with every new patient, and soon includes seizures, rapid weight loss, fevers and other types of cancers. But no matter the symptoms, it is, without exception, fatal.
It’s now August 1982, and for the first time, the CDC uses the term Acquired ImmunoDeficiency Syndrome (or AIDS) to describe this new illness, defining it as a “disease at least moderately predictive of a defect in cell-mediated immunity, occurring in a person with no known cause for diminished resistance to that disease”. The CDC also puts forward the hypothesis that this immunodeficiency syndrome may be caused by an “infectious agent not yet identified”. The hunt for the killer behind AIDS is finally on…
April 1983. Two years have now elapsed since Sandy Ford’s fateful memo to her CDC boss, the global toll of AIDS is growing ever higher, and the culprit behind the epidemic remains elusive.
At last, Françoise Barré-Sinoussi and Luc Montagnier from the Pasteur Institute in Paris report that they have isolated a new virus from the lymph nodes of a homosexual man displaying symptoms known often to precede AIDS. They publish an electron micrograph showing irregular-shaped circular virus particles, or virions, budding from the surface of immune cells taken from the patient. The now infamous black and white image is the first ever picture of the Human Immunodeficiency Virus, or HIV.
Barré-Sinoussi and Montagnier stop short of identifying this new virus as the cause of AIDS, though they do put the idea forward. However, they correctly identify this infectious agent as belonging to a family of viruses called retroviruses. As it so happens, the first human retroviruses were identified only a few years earlier by Robert Gallo at the National Institute of Health, or NIH, in the US.
With both the French and the American groups working on the same disease, they’re in regular contact, and some time in the summer of ‘83, the scientists from Pasteur send Robert Gallo in the States a sample of HIV. But this seemingly ordinary act of scientific collaboration would soon have consequences neither groups could ever have predicted.
Across the Atlantic, Gallo’s group has also been investigating the cause of AIDS since the early days of the epidemic. Finally, in 1984, he and his colleagues publish their findings. They’ve isolated the retrovirus from 47 patients diagnosed with AIDS or pre-AIDS, as well as from one clinically healthy gay man who goes on to develop AIDS shortly later. But - and very importantly - the team were unable to find this virus in over 100 healthy, heterosexual donors.
Robert Gallo and his colleagues reach the obvious conclusion: this retrovirus must be the mysterious “infectious agent” behind the AIDS epidemic. And it is probably the same retrovirus that the scientists from the Pasteur Institute had isolated and photographed the previous year. But Gallo’s groundbreaking findings don’t just stop there: his team also figures out how to grow large quantities of the virus in the lab, paving the way for the development of a patented HIV blood test still used to this day.
This should have been the world-changing breakthrough that forever cemented Gallo’s name in the scientific hall of fame. Unfortunately, Gallo’s contribution is often overshadowed by the events that followed.
Although Gallo and his colleagues had successfully isolated and grown HIV from a number of patients, the viral strain they used to develop their patented blood test turned out to be none other than the very same strain sent over by the French research group in the summer of 1983. As you can imagine, this revelation did not go down too well in France.
A major dispute erupted between the Pasteur Institute and the NIH - with the French accusing the Americans of taking credit for their research. The misconduct accusations swelled into international lawsuits and escalated to the top levels of government, culminating in US President Ronald Reagan and French Prime Minister Jacques Chirac meeting in person to settle the dispute.
Throughout the affair, Gallo maintained that his use of the viral isolate from the Pasteur Institute had been purely accidental. Although he would eventually be cleared of malpractice, the controversy fall-out would follow him throughout his career. In 2008, the Nobel Prize for Medicine was awarded for the discovery of HIV. While the Nobel committee is allowed to celebrate up to three winners, only Françoise Barré-Sinoussi and Luc Montagnier were named, while Robert Gallo was passed over…
The life of HIV
As AIDS continued to sow devastation through the 1980s and into the 1990s, the culprit behind this epidemic finally had a name: the Human Immunodeficiency Virus. But the identification of HIV raised as many questions as it answers. Where did the virus come from? How could it cause such an array of symptoms? And why would it take months, or even years, for these symptoms to appear following infection?
A little aside here before I go any further: the term HIV is slightly misleading. We now know that HIV refers to not one but two distinct viruses: HIV-1, and the much less common HIV-2. Both viruses are the result of similar retroviruses naturally found in African primates jumping across species into humans, likely as a result of bushmeat hunting. But for the sake of simplicity, I will continue to use HIV to refer to both subtypes as a whole.
Now as a listener of genetics podcasts, you may have heard of the so-called “central dogma of molecular biology”. Put forward by Watson & Crick in the early days of their research, the dogma states that “genetic information flows only in one direction”, from DNA to RNA during transcription, and from RNA to protein during translation.
In case you need a quick refresher: DNA is the long, double-stranded molecule and the master copy of our genetic information, while RNA is a single-stranded “photocopy” of a section of DNA. A transcriptase enzyme makes these RNA photocopies in the nucleus of a cell before it’s transported to the cytoplasm and read by ribosomes that translate the code into proteins.
Now we're all clear on the laws of molecular biology, I've got some bad news for you. HIV doesn't play by the rules. It turns the whole central dogma on its head, because as the name suggests, retroviruses do things a bit backwards.
If you zoom in on an HIV virion, it looks like a tiny ball surrounded by a membrane and decorated with proteins pointing outwards, and with strands of RNA and a few well-chosen proteins on the inside. If you picture SARS-CoV2, the virus behind COVID-19, HIV looks pretty similar. But that's where the similarities between the two viruses end. Despite both being RNA viruses, their ‘life cycles’ for lack of a better word, look nothing alike.
An HIV infection starts with an initial exposure from an infected individual. As the virus is found in bodily fluids, it is usually transmitted by blood contact, such as needle sharing or blood transfusion, unprotected sexual intercourse or from a pregnant mother to her developing foetus. Once inside the body, the virus attaches itself to a specific type of immune cells called CD4 cells, a type of helper T cell.
Immunology is wonderfully complicated, but all you need to know is that these helper cells are absolutely essential to the proper functioning of our immune system. As their name suggests, helper cells don’t attack pathogens directly but rather help instruct other immune cells into action. Think of them as army generals who don’t do any fighting themselves but command their soldiers into battle. Except in the case of HIV, it’s the generals that are under direct attack from the enemy.
When HIV locks onto a helper cell, it injects a mix of viral RNA and enzymes into the cell. Amongst these is an enzyme called reverse transcriptase. If you remember from the central dogma, normal transcriptase enzymes make RNA photocopies from the DNA master copy. Reverse transcriptase, on the other hand, has the unique ability to make DNA from RNA. In other words, this reverses the flow of the central dogma.
Inside the infected cell, the reverse transcriptase takes the viral RNA and makes double stranded DNA copies. These are then transported into the nucleus of the cell where a second HIV enzyme, called integrase, integrates or stitches it into the helper cell’s chromosomes.
That’s right - the HIV genes actually become part of the human genome, sitting side by side with all the other genes that make you human. And because the virus has managed to edit the genetic master copy, any time the helper cell splits in two to make new helper cells, those HIV genes get copied over with the chromosomes into the new cells too. This leads to the most challenging aspect of HIV and AIDS: once you’re infected, you’ll be HIV-positive for the rest of your life, because our body doesn’t have a way of finding and removing viruses hidden in our own genomes.
It’s not just HIV that does this by the way. Our genomes are riddled with the traces of ancient retroviruses; long extinct infections that now make up up to 8% of our genome. In Season 5 Episode 7 of this podcast, Face to Face, Kat found out how some of these endogenous retroviruses are actually responsible for making us look human, and we’ll put a link to that episode in our show notes.
Back inside our infected helper cell, these viral genes contain all the necessary information to make more HIV proteins like reverse transcriptases and integrases. From then on, the infected cell transcribes the viral DNA as if it was its own, producing more and more HIV RNA & proteins.
These viral products eventually assemble into new virions that bud off from the cell, stealing a little bit of the cell membrane as they do so to form their outer layer. They’re released into the body, ready to infiltrate more helper T cells, and the cycle continues. The infected cell, meanwhile, does not survive this hijacking of its genetic machinery and dies.
In some cases, this replication cycle hits a few snags - but these benefit the virus. First of all, once inserted into the host genome, retroviral DNA can stay hidden for long periods of time. This DNA is said to be ‘latent’: it is not transcribed and no viruses are produced. These sleeper agents provide HIV with a safety reservoir: even if all of the actively producing cells were to die, some viral DNA would still be present in latent cells, ready to re-activate as and when necessary.
Secondly, the HIV reverse transcriptase is notoriously error-prone and introduces a ton of spelling mistakes when copying RNA into DNA. As a result, an infected cell may accumulate incomplete, error-filled DNA fragments in their cytoplasm that never end up integrated into the genome. The cell recognises this as a sign that something is going wrong. In response, it dramatically self-destructs, hoping to nip the ongoing infection in the bud, and in its dying breath, sends alert signals to the rest of the immune system.
Unfortunately, this noble sacrifice backfires spectacularly. Alerted by the dying cell, more immune cells rush to the site of infection to battle, and under normal circumstances, they would neutralise and destroy whatever danger they found waiting for them. But HIV is a disease of the immune system. It targets and infects immune cells. So instead of summoning an influx of soldiers, the dying cell has attracted the virus’ next victims.
As the HIV infection progresses, helper cells die in droves. The body can’t replace them fast enough, as each new cell is merely a new target for the virus to subvert. Eventually, helper cell numbers fall so low that the immune system collapses: all the generals have succumbed, the soldiers do not know what to do, and the army falls into complete disarray. The patient develops full-blown AIDS, as infections and cancers take over their body, left unchecked by a crumbling immune system.
The fight
Some 40 million people have died of AIDS or AIDS-related illness since the start of the epidemic, while another 40 million are living with HIV today. But much has changed over the past four decades.
In the early days of the epidemic, HIV was invariably fatal with no long-term treatment, and patients died within two short years of an AIDS diagnosis. In 1987, the first ever HIV drug was approved in the US, but the virus rapidly developed resistance against the treatment, making it ineffective. HIV was still considered pretty much untreatable well into the 1990s, until new drugs targeting reverse transcriptase, integrase and other cogs in the viral replication cycle finally became widely available.
When used in combination, these drugs control an HIV infection by preventing the virus from making copies and either delay or altogether prevent the immune system collapse that marks the development of AIDS. This mixed treatment regimen is still used to this day and, when taken consistently, grants HIV-positive patients a near-normal life expectancy. Once a death sentence, HIV infection is now a lifelong, manageable condition.
The past 40 years have also seen tremendous progress towards reducing global HIV transmission and preventing infections from occurring in the first place. Antiretroviral treatment taken during pregnancy minimises the risk of transmission from an HIV-positive mother to her unborn child. In the UK, PrEP - or pre-exposure prophylaxis - has been freely available on the NHS since 2020 to people at high risk of exposure to the virus because they are intravenous drug users or have sex with high-risk partners.
PrEP greatly reduces the chance of new infections in HIV-negative individuals, and if taken consistently, reduces the rate of sexually transmitted infection by 99%. Meanwhile, initiatives such as World AIDS Day and the UNAIDS programme continue the essential work of increasing public awareness, reducing stigma, promoting prevention practices and testing across the globe.
However, access to healthcare and the cost of a lifetime regimen of treatments remains a barrier in many low and middle-income countries - the same countries most affected by AIDS. Today, half of all HIV-positive individuals live in Eastern and Southern Africa. Infections are no longer restricted to historically “at risk” groups either: over half of all people living with HIV in the world today are women and girls.
And in spite of the remarkable medical advances of the last four decades, AIDS still claimed one life every minute in 2022. So how can we end this epidemic for good?
The end of HIV - or not?
“[...] Given the fact that we now have the virus in our hands, it is quite possible, in fact it's invariable, that we will develop a vaccine for AIDS. The question that remains to be answered is will that vaccine be effective in protecting individuals against infection with the virus? And we don’t know that [...] but hopefully our recent advances of being able to isolate, identify, and characterize the agent,will allow us over the next year to come back to you and tell you that we now not only have hope and hypothesis, but that we have a real prevention and indeed a real cure…”
This is Dr Anthony Fauci, speaking at the NIH in 1984. Sadly, his hope that a vaccine or cure would be found within a year of that speech never materialised.
The rapid demonstration of the potential of mRNA vaccines was one of the very, very few good things to come out of the recent COVID-19 pandemic. So you may well be wondering why, after decades of concerted effort, there’s still no sign of a promising HIV vaccine, when the first COVID-19 jab was administered barely a year after the SARS-CoV-2 virus was identified.
It’s not been for lack of trying. There have been more than 250 vaccine trials to date, abandoned one after another due to disappointing results. Why? Well because HIV is a uniquely challenging virus.
First of all, it is notorious for its rapid mutation rate. I mentioned earlier in the episode that the HIV reverse transcriptase enzyme was very error-prone and introduces mutations in the DNA it synthesises. What I didn’t emphasise was just how error-prone the enzyme really is…
The HIV genome ends up being mutated 100,000 times faster than our own genome, and up to a hundred times faster than the influenza virus, which mutates so quickly you need a new flu jab every year. In fact, HIV has the highest reported mutation rate of any known biological entity. This means the virus can adapt and evolve extraordinarily quickly, and acquires drug resistance at an alarming speed. It also means it’s extremely difficult to develop a vaccine against this constantly shape-shifting target.
What’s more, HIV infects the immune system, throwing yet another spanner in the works. The virus hides in the very cells responsible for clearing the infection. As you can imagine, teaching the immune system to mount a response against itself is far from straight-forward.
Taken together, it’s not surprising that the quest for a HIV vaccine has consistently hit roadblock after roadblock. So while scientists grapple with a way to prevent new infections, what about the other part of the puzzle, not just treating but curing existing HIV infections?
In order to enter and infect a target cell, HIV grabs onto two receptors on the helper cell surface: the CD4 receptor - which incidentally, gives the cell type its full name - and the CCR5 receptor. And it needs to grab onto both receptors at once.
But some people carry a mutated version of the CCR5 gene called delta32, meaning that it’s missing 32 crucial base pairs of DNA. This mutation prevents the receptor from being expressed on the cell surface and is surprisingly common. Up to one in five people of European ancestry have one copy of the CCR5-delta32 gene, while one in a hundred people have two copies. These double, or homozygous, carriers have no CCR5 receptors on the surface of their immune cells, effectively locking HIV out and protecting them from infection. Heterozygous carriers, who carry one full-length CCR5 gene copy and one mutated copy, aren’t fully protected from infection but their disease progression is slower.
Nobody knows for sure why this mutation is so common in people of European descent while it is virtually absent from African and Asian populations. Some scientists suspect that individuals carrying the CCR5-delta32 version in the past may have been protected against the Plague or some other deadly infectious disease - that swept through Europe in the Middle Ages. Those survivors passed on their mutated genes to the next generation: evolution in action. But whatever disease delta32 protected against back then, it is certainly protecting against HIV now. And it could even hold the key to a HIV cure…
The discovery of CCR5-delta32 gave scientists a daring idea. What if you could replace all the helper T cells of a HIV-positive patient with cells carrying the protective version of the CCR5 gene so the virus wouldn’t be able to grab on and infect them? Switching an entire blood system out is easier said than done - but not unheard of: it’s exactly what happens during stem cell transplants.
So when in 2007, HIV-positive Timothy Brown needed a stem cell transplant to treat his aggressive leukaemia, his medical team had a thought. They were already replacing all of his blood with that of a donor, so why not choose a donor who happened to carry the CCR5-delta32 mutation? The team genetically tested dozens of potential donors, and on the 61st attempt, they finally struck gold with a CCR5-delta32 homozygous donor who was also a good match for the transplant.
Timothy underwent chemotherapy to wipe out his blood cells, including any cancerous or virus-infected cells, before receiving new cells from the donor. On the day of his transplant, he stopped his HIV medication for the very first time since his HIV diagnosis. Remarkably, his HIV infection never came back and Timothy Brown became the first individual ever to be cured of the virus.
To date, five people have been cured of HIV using this approach, but the procedure is not without risk. Stem cell transplants can go badly wrong and are normally reserved as a treatment of last resort. Timothy’s case is often cited in the press as an exciting success story but the reality wasn’t as simple as the papers made out. Shortly after his first treatment, his leukaemia came back, requiring him to undergo a second transplant from the same donor. This time, he nearly went blind, lost the ability to walk, and took six years to fully recover from the procedure.
So even though this treatment approach is exciting, and can be a cure, it is clearly not applicable for widespread use. And why subject someone to a life-threatening procedure when antiretroviral drugs can effectively suppress HIV anyway?
Nevertheless, the prospect of a gene-based cure has not been abandoned. In 2018, CCR5 found itself in the news once more, albeit this time mired in controversy. Chinese geneticist He Jiankui stunned the world when he announced he had used CRISPR-Cas9 to genetically modify two human embryos. The twin girls born as a result of his “experiment” - for lack of a better word - reportedly carried a modified version of the CCR5 gene, making them (at least in principle) resistant to HIV .
The news received tremendous backlash from the scientific community and He Jian-Kui was sentenced to three years in prison for illegal medical practices. If you want to hear more about this story, Sally and Kat covered the controversy in more detail in our CRISPR in the Clinic episode from 2021, and our GMO or GMO NO? episode from earlier this year.
The ending of the HIV story has yet to be written but scientists haven’t stopped coming up with new ways to tackle the virus. Daily pills are already being replaced with monthly injections to help patients that often forget to take their medication, and earlier this year, doctors began trialling a new CRISPR-based cure in humans, injecting adults with gene-editing molecules that seek out and excise the HIV DNA from the genome. Given how far we’ve come from Sandy Ford’s memo in 1981, who knows where we’ll be, four decades from now.
References:
Current Trends Update on Acquired Immune Deficiency Syndrome (AIDS) --United States September 1982
Hemophilia: An Amazing 35-Year Journey from the Depths of HIV to the Threshold of Cure
A historical reflection on the discovery of human retroviruses
Abortive HIV Infection Mediates CD4 T-Cell Depletion and Inflammation in Human Lymphoid Tissue
Molecular biology of the gene - 1st Edition - Watson (1965)
60 years ago, Francis Crick changed the logic of biology - PLoS Biology
HIV-1 Infection in Persons Homozygous for CCR5-Δ32 Allele: The Next Case and the Review
