ME/CFS and HIV/AIDS: A tale of two illnesses

How did the trajectories of HIV/AIDS and ME/CFS diverge so radically?

In the 1970s and early 1980s, two terrible diseases silently, and almost entirely unnoticed, became epidemics. These two were strange twins; with similarities in history, form, and function. They brought ruination to lives of untold millions of people; previously healthy people were struck down, sometimes in the prime of their lives, with no idea what was happening, or why. Baffled doctors had no answers. Many patients were dismissed, their suffering seen as reflecting intrinsic moral or personal failings – a punishment from God for laziness or sin. The two illnesses were not identical, however, and it was those crucial differences that would ultimately send them, and all the unlucky people whose lives they touched, down very different paths.

These two diseases were HIV (the human immunodeficiency virus), and ME/CFS (known variously as mylagic encephalomyelitis or chronic fatigue syndrome).

Everyone knows what HIV is and has heard of its brutal final stage: AIDS (acquired immunodeficiency syndrome). Teenagers learn about it sex ed class, and colleges all over the country teach courses in the history of the disease. Since the 1980s, the engineering problem of solving HIV has garnered billions of dollars in government and philanthropic funding, and every year, new groundbreaking discoveries are announced. The treatments for HIV are so well-developed that a virus that was once a painful death sentence can be managed with a few pills a day. Experimental total cures are being developed, and an HIV vaccine is almost on the horizon. In the 40 years that HIV has assailed humanity, scientists, doctors, and engineers have mounted a valiant defense, turned the tide of battle, and seem poised to claim victory in what would be one of the greatest triumphs of scientific spirit in human history.

In contrast, almost no one knows what ME/CFS is. Children don’t learn about it in health class. Many doctors don’t even acknowledge that it exists, instead writing patients off as neurotic, hysterical, or as suffering from some kind of “psychosomatic illness” or a “phobia of exertion” (best treated with cognitive-behavioral therapy). In the US and UK, ME/CFS care was dominated by a cabal of psychologists who insisted that the disease was “all in the heads” of sufferers and prescribed what was essentially a course in “pulling-yourself-up-by-your-bootstraps” (called “graded-exercise therapy”), which ultimately proved to be a catastrophic misjudgment that left patients even worse off. When this “tough love” approach failed to help, one caregiver infamously exclaimed “the bastards don’t want to get better”! Funding for research into ME/CFS remains almost non-existent (one year, the National Institute of Health allegedly wanted to allocate more money to male-pattern baldness than ME/CFS), and there are no FDA-approved therapies or treatments. While people with HIV are now able to live full and essentially normal lives thanks to the miracles of modern medicine, millions of people with severe ME/CFS remained confined to darkened bedrooms, unable to move, speak, or tolerate sensory stimulation. Lying in bed with earplugs and eyeshades on, living in a state evocatively called a “conscious coma.”

How did this happen? What led HIV and ME/CFS, twin children of 1980s that started off with so many similarities, to such strikingly different endpoints half a century later?

Early overlap

While the 1980s are generally the decade when both HIV and ME/CFS are thought to have “gone viral”, as it were, both illnesses have a much longer, if murkier history. HIV is thought to have spilled over from primates to humans sometime in the early 20^th century in sub-Saharan Africa – probably when a hunter collecting bushmeat (which can include great apes such as chimpanzees) became contaminated with infected animal blood that carried the virus that would become HIV (simian immunodeficiency virus) . From this initial spillover, the virus spread, propelled by the rapid urbanization and colonization of Equatorial Africa in the 20^th century. It spread human-to-human, transmitted by sex workers and by colonial doctors who re-used needles on hundreds of laborers without proper sterilization. These dynamics laid the ground for the African AIDS Epidemic, which continues to burn to this day. By the 1950s, HIV had made it out of Africa, and by the 1970s, cases were appearing with alarming regularity. HIV jumped from central Africa, to Haiti, and from Haiti to New York City and the West Coast of the United States, at which point, a global pandemic was well and truly under way. HIV’s spread is cryptic, however; it takes years for an infection to produce visible symptoms of AIDS, and it would be for another decade before anyone knew what was happening, at which point it was far too late to stop.

ME/CFS, similarly has an often-unappreciated early history. In 1934, at a hospital in Los Angeles, there was an outbreak of an unknown disease: 198 staff at the Los Angeles County General Hospital came down with an unknown virus (described as “atypical polio”) that left them debilitated for years, with now-recognizable symptoms of fatigue, exercise intolerance, sensory sensitivity, widespread pain, sleep disturbances, and cognitive disturbances. Twenty years later, a study of twenty one survivors found persistent pain, fatigue, and cognitive difficulties. Since this first cluster, “outbreak clusters” of what we now recognize as ME/CFS have been reported throughout the world, including Akureyri, Iceland (1948), Adelaide, Australia (1949), Maryland, USA (1953), Johannesburg, South Africa (1954), London, England (1955), and New York, USA (1961). Many of these outbreaks were written off as medical curiosities and little work connecting these seemingly disparate cases was done, although follow-up studies report that many patients remained ill for years after the fact. If these early stirrings of ME/CFS are analogous to the early, underground spread of HIV, then the Incline Village Outbreak in 1984 is analogous to the now-famous CDC report of five deaths in 1981 that brought the HIV crisis to light.

The Incline Village Outbreak described a cluster of at least 175 people who came down with a “chronic, flu-like illness” in the winter of 1984/85, in and around the Lake Tahoe region of California. So severe was the illness that ultimately the Center for Disease Control was called in. Inexplicably, however, the CDC investigators declined to physically examine any patients, and the final report said little beyond that the cause of the illness was “probably” not Epstein-Barr virus and that doctors should focus on “more definable, and possibly treatable, conditions”. The Incline Village patients were essentially abandoned – written off as “untreatable” and left to rot. This lack of interest from medical institutions set the tone for what would become the next forty years of ME/CFS research – a deliberate and nearly complete radio silence.

In outbreak round Lake Tahoe was just one part of a global wave, however. In the 1980s, for reasons that remain unknown, there was an estimated five to eight-fold increase in the number of ME/CFS cases around the globe.

In her history of ME/CFS, Osler’s Web, journalist Hilary Johnson reported:

“In April l994, however, one of the nation’s largest private providers of disability insurance, the UNUM Corporation, issued a press release revealing chronic fatigue syndrome claims to be the fastest-growing sector of their business. According to UNUM, claims for disability caused by CFS had increased 500 percent from 1989 to 1993, a bigger increase than any other category of disability.”

And so, by the end of the 1980s, the world appeared to be in the grip of two, competing pandemics. HIV/AIDS, which was burning through Africa and gay communities in the West, and ME/CFS, which was much more quietly diffusing around the globe. By 1990, both illnesses had been recognized for what they were: globe-spanning public health crises.

H owever, this is where the stories of HIV and ME/CFS diverge. In the intervening three decades, HIV became a public health priority: with US federal funding ballooning from just a few hundred thousand dollars in 1982 to over forty billion dollars in 2022 (of which 2.7 billion dollars was allocated for scientific research). These billions of dollars of investment have borne incredible fruit: while access to life-saving medicine is still unequally distributed, miraculous technologies have been developed that have turned what was once a painful death sentence into a manageable, albeit chronic, affliction. Antivirals are so effective at suppressing viral load that HIV becomes undetectable (and by extension, the virus itself is transmittable, even to intimate partners). In contrast, investment in ME/CFS remains appalling low: the SolveME initiative (a nonprofit that advocates for the illness) estimates that NIH funding works out to about $5 per patient: a pathetic amount given the abysmal quality of life suffered by patients. There are currently no FDA-approved therapies, treatments, or cures, and doctors are generally poorly equipped to handle the illness, leaving debilitated patients left to cobble together DIY treatments from supplements and “wellness” plans.

What explains this divergence? One commonly cited issue is that ME/CFS affects women about twice as often as men, and in general, diseases that preferentially impact women do get less research funding and medical support. This, combined with the deep-seated tendency for doctors to write off women’s medical issues as “psychological” (or perhaps just a consequence of needing to lose weight), unquestionably stacks the deck against ME/CFS sufferers (both male and female). However, it’s hard to believe that this is the whole story: for one, HIV/AIDS is most well-known for infecting gay men and intravenous drug users, two populations that have been historically marginalized themselves (especially in the Reaganite 80s and 90s). Furthermore, while under-investment in female-dominated illnesses is a real issue, it is apparently not an insurmountable one: multiple sclerosis affects women about four times as often as men, however, there are over 20 different FDA-approved drugs for the treatment and management of MS. Similarly, rheumatoid arthritis (another painful, autoinflammatory illnesses) impacts women at a ratio of three to one and also has a large number of existing treatments available. Even fibromyalgia, a close cousin of ME/CFS with a similarly disparate impact on women and which is also highly stigmatized has three approved treatments. ME/CFS is unique, even among illnesses that predominately impact women, in terms of the total lack of options available to patients.

The existence of these drugs also flies in the face of a different common explanation: HIV kills people, while ME/CFS “just” disables people. Neither multiple sclerosis, nor rheumatoid arthritis are commonly fatal either, however, but the medications still exist. So that tells me that neither the gender bias, nor the fatality is sufficient to explain the difference.

Another popular explanation puts the blame on a small cabal of neurologists and psychologists (the so-called “Wessely School”, named after English psychiatrist Dr. Simon Wessely), who spent decades arguing that ME/CFS was best understood as a psychosomatic phenomenon, rather than a biomedical one. Instead of a physical cause of the illness, they claim that “dysfunctional illness beliefs”, “fear of exertion”, and “secondary gain” are the best explanations for the debilitating symptoms patients report. While the psychosomatic theory of ME/CFS has been essentially entirely debunked at this point, the damage has been done. The Wessely School has been influential in the UK for decades, and has seeded acolytes across the pond in the US (most notably Dr. Brian Wallit, who is the lead of the NIH Post-infectious ME/CFS study, and who controversially described ME/CFS and fibromyalgia as “somatoform” disorders).

Even if we accept the consequences of the Wessely school as fundamental issues though, this just prompts a rephrasing of the original question: how were psychiatrists and ME/CFS skeptics able to dominate the field and deliberately obstruct decades of potentially productive research, but attempts to write off HIV/AIDS as “psychological” or “behavioral” manifestly failed? While AIDS denialism, which puts the blame on the malignancies of the so-called “gay lifestyle” persist in conspiracy-crank circles (as well as in the worm-riddled brain of Health and Human Services Secretary RFK Jr.), it clearly was not able to derail the progress that HIV/AIDS research was able to make over the last several decades the way ME/CFS skeptics were.

At the risk of being glib, I think the fundamental answer is that ME/CFS is just a much harder scientific problem than HIV/AIDS. Not only is it a harder problem, but it is hard in ways that the modern academic-industrial-scientific system is particularly vulnerable to. HIV is, in some sense “simple”, while ME/CFS truly is a “complex” chronic illness. I realize that some might bristle at that claim, feeling that I am minimizing the damage that the AIDS pandemic has done to people around the world. I am not. Instead, the distinction I want to draw is that AIDS has a singular, identifiable “root cause” that is common to all patients, while no such fundamental commonality appears to exist for ME/CFS.

Simplicity and complexity in root causes.

While the term “root cause” itself has become considerably tarnished by association with less-than-scrupulous alternative medicine practitioners, the basic idea is fundamental to medical science. Every medical student learns about Koch’s famous postulates, which were an early attempt at a kind of scientific causal inference, aimed at teasing out the primary drivers of diseases. In some cases the root cause of an illness so obvious that we don’t even think about it, for example every case of the flu has a common source: the influenza virus. If we can either inhibit those flu virions (with an antiviral), or stop the initial infection (with a vaccine), then the disease will stop. HIV/AIDS is a typical example of a disease with a single root cause:

1) The HIV virus infects a host – transmitted by exposure to infected bodily fluids.

2) The HIV virus persists in their body, resisting immune clearance and writing itself into the DNA of infected cells.

3) Persistent HIV causes catastrophic damage to the immune system, causing immunodeficiency.

4) Opportunistic infections take advantage of the immunodeficiency and kill the patient.

As early as the 1990s, scientists had isolated the HIV virus from multiple patients, identifying it as a common agent shared across individuals. In a triumph of scientific ingenuity the puzzle of AIDS was already starting to transform from a scientific problem into an engineering one. If any of these steps could be halted, then AIDS would not occur: the causal chain is essentially one-dimensional. Step one leads to step two and so on. The technical details of each one of these steps is incredibly complicated, and it has taken nearly half a century of work by brilliant minds to work out the various mechanisms, but the ten-thousand foot view was understood very early on. We knew where we had to go – we just had to figure out the best way to get there.

In contrast, no such causal map exists for ME/CFS. In fact, I am not convinced that such a map would be even theoretically possible, as I’m not sure there is a common “root cause” shared by all people who have ME/CFS diagnoses. While HIV/AIDS has a single identifiable root cause, ME/CFS (and other similar conditions) are a rats nest of feedback loops, individual differences, and apparently unknown processes all playing out simultaneously.

Consider the staggering amount of heterogeneity among ME/CFS patients. While most people become ill after an acute infection (which can be viral, bacterial, or fungal), some develop it after traumatic injury, or a even a period of severe stress. Some drop immediately into the most severe depths, while others slowly degenerate over months or years. Some (lucky, rare) people recover. Many never do. There are different responses to medications: some people respond very well to rapamycin (perhaps suggesting impairment of autophagy), others show no benefit. Others find low-dose naltrexone to be a game-changer (implying neuro-inflammation as a fundamental issue), while others don’t. Compare this uncertainty to HIV, where a small number of well-designed antivirals work essentially for everyone.

Among those lucky people with ME/CFS who have found effective treatments, the variety of interventions is bizarre. Two well-known case-studies describe patients who discovered that their ME/CFS was caused by mechanical compression of the brainstem, which reversed following surgery for cranio-cervical instability. One woman seemed to recover from post-COVID ME/CFS following a course of Japanese encephalitis vaccines. One person on Reddit discovered that they had Very Long Chain Acyl CoA Dehydrogenase Deficiency, a very rare metabolic disorder typically identified in infancy. Another subset of people seem to respond well to anhydrous oxaloacetate – a supplement that costs hundreds of dollars per bottle. This leaves desperate patients chasing seemingly random success stories, hoping that maybe they’ll get lucky the same way.

The scientific landscape isn’t much better. Rather than converging on a single hypothesis, the number of possible explanations that have been floated is dizzying: is it viral persistence, or reactivation of latent herpesviruses? Could it be new-onset autoimmune conditions, gut dysbiosis, or biofilms of stubborn bacteria like Borrelia burgdorferi in hard-to-reach places? Exposure to environmental pollutants may play a role. Maybe it’s all of those things converging in the body of one unlucky person – possibly due to genetic vulnerability, or just the phase of the moon. Who knows.

Further complicating this already-complex picture is the fact that we have almost no way of knowing what is a “root cause” versus a second order effect. And second order effects themselves can feedback in non-trivial ways: consider someone who contracts a severe case of COVID-19 which leads to ME/CFS. This person then later discovers that, since contracting COVID, latent Epstein-Barr viruses (which lie dormant in the vast majority of adults, following routine exposure in childhood) have reactivated. Those reactivated EBV virions almost certainly cause inflammation, and chronic inflammation does its own on-going damage. But does that reactivated EBV explain symptoms like post-exertional malaise? Would our hypothetical patient have gotten ME/CFS if they hadn’t had prior exposure to EBV earlier in life? Some patients with ME respond well to anti-herpes drugs like Valtrex. Others have no response at all.

In the simple Newtonian world, cause and effect are easily distinguishable: a thrown baseball hits a window and the glass shatters. Students of causal inferenc will often use “counterfactual criteria” to try and tease out cases. If the ball hadn’t hit the window, then the glass wouldn’t have shattered. If the person hadn’t contracted HIV, then they wouldn’t have developed AIDS. Does this work in ME/CFS? If the person hadn’t gotten COVID, would they have still gotten ME/CFS? What if they had gotten COVID, but didn’t have latent EBV in their immune cells? Maybe it’s the synergistic conjunction of both (COVID and EBV). Maybe genetic risks mean that either one alone would have done it eventually.

ME/CFS transcends the simple, Newtonian world of linear causality into the complex world of synergistic causality: multiple factors come together in ways that are almost impossible to untangle.

Why medical science fails in the face of complexity.

So is that it? HIV/AIDS made progress because it was causally “simple” while ME/CFS has held out because it is too “complex”? While this is absolutely is a huge part of it (I wouldn’t have written this essay otherwise), it provides only a partial answer to the original question. Even if ME/CFS is a thorny problem, why did so few people even try? Why were scientists, doctors, and government agencies so ready to default to the “it’s all in their heads” position, even while huge mysteries remained?

The fundamental problem isn’t just the complexity of the puzzle, it’s that the modern edifice of biomedical research is set up to punish interdisciplinary research at every turn. This puts it fundamentally at odds with the complexity of ME/CFS (and other neglected illnesses like fibromyalgia), which inherently require thinking through complex interactions. Look at the symptoms required by the Canadian Consensus Criteria for a diagnoses of ME/CFS. Patients must have: severe fatigue, post-exertional malaise, sleep dysfunction, chronic pain, neuro-cognitive issues, issues with heart-rate or orthostatic intolerance, immune dysfunction, and more. ME/CFS is an illness that necessarily touches every major physiological system: the central nervous system (for the cognitive issues), cellular energy production (fatigue), arousal (sleep issues), the somatosensory system (pain), and the immune system. This is not a problem that will be solved by just cardiology, or immunology, or neurology: it is one that sits at the intersection of all of them, and unfortunately that is the exact opposite of how medical science operates.

Patients who have struggled to coordinate care between multiple specialists will intuitively know what I’m talking about: science, and medical science in particular, is fractured into different disciplines that have almost no cross-talk. In medical school, students gain a high-level, cursory education of the major physiological systems, but then specialize in one subfield with monomaniacal precision. You can be a cardiologist, or a rheumatologist, or a neurologist, but it is vanishingly rare to find someone who can operate at the intersection of any two fields, let alone the intersection of all of them. This is true in academia as well: doctoral training for scientists follows the same model of hyper-specialization. There are very few journals open to truly interdisciplinary research (most journals focus on a single subject), and the same is true for conferences. Journals that are explicitly transdisciplinary tend to be lower-impact and less prestigious than their big-name counterparts.

And the problems don’t end there. It’s not enough that the structure of scientific and medical training tends towards disciplinary siloing; anyone who attempts to buck that trend pays a significant career price for it. Especially young scientists still trying to form their careers. Early career researchers who embrace interdisciplinary research face a host of career challenges, including washing out of academia faster, and are less likely to be hired for competitive research positions, which is a significant issue, as a prestigious institute can make getting grants more likely. Interdisciplinary research is consistently funded less, and PhDs who wrote interdisciplinary theses earn lower salaries than their orthodox counterparts. The result is that the people who might be most inclined to do the interdisciplinary science that ME/CFS and other post-acute infectious syndromes need are either being forced into silos that will make the necessary work impossible, or they’re being pushed out of the field altogether. Every piece of the Academic/scientific establishment, from grant review committees, to peer reviewed journals, to hiring, tenure, and promotion committees seems to be converging in such a way as to make it harder, not easier, to tackle the thorniest problems in biomedical science.

Looking forward, looking back.

And so here we stand, half a century after HIV/AIDS and ME/CFS took off, and almost a full century after the first stirrings of both diseases. Despite their similar early years, the trajectory of these two illnesses could not have been more different. Technological miracles have turned HIV/AIDS from a brutal, protracted death sentence to a manageable chronic illness (if you are lucky enough to have access to medication, that is), but ME/CFS remain as intractable as ever.

I think this divergence was inevitable, baked into the fundamental differences between these two diseases: when scientists finally started to look hard at HIV/AIDS, they found a root cause. They found a guiding light, illuminating a path forward. A long and arduous path, a path that would take decades to walk, with millions falling by the wayside every year, but a path, nevertheless. When they looked at ME/CFS, they saw complexity. They saw non-linearity (even if they didn’t know it). They saw heterogenity, feedback loops, synergistic causes, and great black holes of understanding. Into this void of intractable complexity stepped Wessely et al., promising to erase it all, bring order to the chaos. They did so by entombing ME/CFS within the walls of one discipline: their own. Psychology. In doing so, they provided a great service - not to the patients themselves, but to the doctors, scientists, and funding bodies who suddenly had an out: no longer did they have to face the overwhelming difficulty of understanding a difficult and inscrutable illness. No longer did that have to feel the ego-smarting sting of failing to cure their patients. Now they could offload all of that cognitive work onto the simple solution: they’re making it up!

“The bastards don’t want to get better.”

A simple answer to a complex problem. On to the next patient, get this one out of the door, and let’s allocate whatever research money might have gone to them to designing new boner pills or something.

I’d like to end this article on an optimistic note, and will try my hardest to stick the landing, but it’s difficult. On one hand, the reality of Long COVID (of which as many as 50% of cases may qualify as full-blown ME/CFS) and the recent slew of biomedical findings has essentially made the “it’s all in their heads” position scientifically untenable. I suspect that, by the end of the decade, the “psychosomatic” crowd will be relegated to the same dust bin as AIDS-denialists. It will take a while for the old guard to die out (science, and medicine, advance one funeral at a time, after all), but the movement is undeniable and I don’t think it’s likely to be reversed. So that’s good news. On the other hand, I fear that the machinery of biomedical research remains ill-equipped to deal with the reality of complex chronic illness. Despite lots of lip-service being paid to complex systems, and plenty of fancy visualizations of networks in cutting edge journals, the breakdown of disciplinary silos isn’t going to happen over night – certainly not when the incentive structure hasn’t changed in any meaningful way.

If there is a change, I think it will have to come, at least in part, from outside the ivory tower. While there are plenty of talented and well-meaning scientists tackling the problems of post-acute infectious syndromes, they’re still very much in the minority and still working within a system that is fundamentally misaligned with what needs to happen. Where I think the really exciting stuff is happening is in the world of independent, and often patient-lead research. Citizen scientists, like the Patient-Lead Research Collaborative for Long COVID, or Renegade Research for ME/CFS and other post-acute infectious diseases aren’t constrained by the bureaucratic tangles that academics are, or the same incentive structure that forces narrow specialization. They can think outside of the box. Sometimes that leads to vaguely New Age-y nonsense, but in my experience as a volunteer data scientist for Renegade Research, it can also be pretty remarkable.

At Renegade Research, we just submitted a paper to the journal Medical Hypothesis hypothesizing about the role of mechanical deformation to the brainstem in ME/CF and proposing a research program in that vein. It’s not just hypotheses either: the Internet, and the proliferation of wearable devices, has made it possible for patients all over the world to collect and share their own biometric analyses. Some have even put together rudimentary clinical trials. My favorite of these is the #NicotineTest, where Long COVID and ME/CFS patients have trialed nicotine patches as a possible treatment, and then shared their data with citizen-scientist organizers. One woman has been self-experimenting with transcranial ultrasound, with apparently remarkable results, and is now collecting reports from other patients trying the same DIY intervention. This is work that almost certainly would never be funded by a big institutional player like NIH or NSF, and would probably struggled to get through IRB – but (as the Internet meme goes), a brave patient with resources can “just do things.”

I’m not holding my breath that Academic science is going to change any time soon (except possibly by being further hollowed out by Trump, RFK Jr, and Jay Battacharya), but I remain cautiously optimistic that perhaps the project of science has begun to outgrow the institutional gatekeepers anyway. What happens next, however, remains to be seen.