by Greg Gibson
Unlike most viruses, HIV does its damage indirectly. By disabling the cellular immune system, it allows all manner of opportunistic infections to attack various organ systems. It basically opens the door to the pathogens that cause pneumonia and tuberculosis, diarrhea and colitis, fevers and encephalitis. AIDS is how we would all be without the T-cells that we met in Chapter 4, “Unhealthy Hygiene.”
In fact, there are a dozen or so similar, and thankfully extremely rare, genetic conditions just like this, known collectively as Severe Combined Immune Deficiency. The immune system never develops in infants who have SCID diseases. The A in AIDS signifies that the disease is acquired rather than inherited, though viral transmission might as well be genetic when it is from mother to child, as is the case in a large proportion of HIV infection worldwide.
The probability of becoming infected from a single encounter with an HIV positive individual, either through unprotected intercourse of any type or by sharing of a needle, is actually quite low. But the less than one percent chance per exposure quickly translates into near certainty of infection when the risk is taken 100 times. The virus establishes itself by hanging out in places where the immune system is likely to be needed, notably around cuts and abrasions, where it can latch onto a passing macrophage or T-cell, which is why it is not a good idea to play contact sports when blood is in the offing. I was once refereeing a game of rugby in the early 1990s between a team from northern California and one from a mountain state, and asked a visiting player to leave the field to get bandaged up when he sustained a gash. He complained that this was unnecessary since they do not have AIDS in his town, but hightailed it to the sideline pretty quickly when I pointed out that they sure as heck did in San Francisco.
In the second month after a person becomes infected, the virus spreads through the immune system, seeding the roots of demise of lymphoid organs spread around the body. During this time, the patient may feel acute episodes of nausea, headache, rashes and sores, malaise, and weight loss, but it can take three to six months before infection is even detectable using biochemical tests. By then, HIV has gone into hiding inside the so-called CD4+ T-cell population. There it bides its time for maybe a decade or so, gradually eroding the numbers of these cells until they drop below 200 per microliter of blood, down from about 1,200 in healthy people. Only then is AIDS diagnosed, as occasional respiratory and genital infections give way to the typical course of immune deficiency.
So unusual is this pattern of disease progression that a few prominent virologists denied that HIV could be the cause of AIDS when the virus was first isolated and shown to have infected hundreds of patients. Peter Duesberg ran afoul of the establishment for many years with his claims that the gold standard for establishing that a pathogen causes a disease, Koch’s postulates, had not been fulfilled. We now know that HIV really is detectable in more than 95 percent of AIDS patients; the virus has been cultured and shown to infect and inactivate T-cells; and extraordinary cases, such as accidentally infected nurses with no other risk factors, establish beyond a shadow of a doubt that HIV is responsible. No one denies that other factors that affect the competence of a person’s immune system also impact the progression of disease, but denying HIV’s role is like denying that computer viruses cause software to crash. Unprotected downloads usher in cyber disease, but unless they bring in a virus, they won’t bring down your system.
Without antiviral therapy, progression to AIDS is inevitable. A typical telltale sign is the experience of a month or more of chronic diarrhea brought on by bacterial infection of the gut. Thereafter upper respiratory infections assert themselves, the most common of which are PCP, short for pneumocystic pneumonia, and tuberculosis. Together these account for the majority of AIDS mortality, although drug treatments are used to control these, at least in Western countries. Inflammation of the esophagus is often due to infection with fungi or common sexually transmitted viruses such as herpes and cytomegalovirus. Further down the intestinal tract, a lot of bacteria that commonly live with humans without causing too much harm cause gastric diseases and eventually interfere with digestion, leading to characteristic wasting. In up to ten percent of patients, still other stray infections with parasites, bacteria, and viruses can attack the brain, perhaps leading to chronic headaches, fever, and fatigue, if not AIDS dementia.
Cancer is another common cause of death in long-term AIDS patients. Viral infection only rarely causes cancer in the general population, but coinfection with three common cancer-promoting viruses poses a constant threat to HIV positive people. Kaposi’s sarcoma is caused by a herpes virus that starts by infecting the skin and mouth but may later populate the lungs and intestines. Epstein-Barr virus will activate a particular class of lymphomas, knocking out the B-cell arm of the immune system just when HIV has debilitated the T-cell arm. And women, who are particularly susceptible to coinfection with all sorts of sexually transmitted diseases, are prone to cervical cancer due to human papillomavirus (HPV). In fact, HPV is the target of a vaccine known as Gardasil that has recently become widely used by teenage girls. HPV is well known for its role in genital warts, but some strains are much more capable of promoting cancer of the cervix, particularly in immunologically compromised patients.
In different parts of the world, different infections dominate the progression of disease. Without a functional immune system, there is little long-term hope, and more often than not death is relatively slow and painful. An ever-present danger is that the pathogens will evolve resistance to drugs that physicians throw at them. Just imagine how it is to live in a society where this disease destroys the lives of more people than suffer from obesity or have blonde hair in our own society.
Why HIV is so Nasty
Ask why HIV is so elusive, and three compelling possibilities present themselves. First, the virus attacks precisely that which would destroy it, namely the immune system. Second, it is an expert at both camouflage and shape shifting, thus adept at avoiding counterattacks. Third, it is new to humans, who have consequently not had time to devise—genetically speaking—an effective strategy for coexistence. We will return to this last point at the end of the chapter, and address the first two reasons here.
It does not take a graduate of Annapolis to realize that destroying the enemy’s defense complex might be a smart military move. Luckily for us, only a handful of pathogens have adopted this approach, HIV being one of them. It is not, though, a guaranteed strategy: Al-Qaeda tried something similar by piloting an airliner into the Pentagon, with spectacularly counterproductive results for hundreds of thousands of Middle Easterners. More successful has been the derived tactic of insurgency—particularly insurgency guided by infiltration of subversives into the police and army units. The human immune system does not have a central command, but it does have hundreds of command posts called the lymph nodes, which are precisely where HIV does its most dangerous work.
To infiltrate the immune system, HIV sneaks into T-cells, macrophages, and other important blood cells through the back door. Actually, it uses the front door as well. The relevant T-cells normally recognize foreign particles by virtue of a molecule called CD4, but each virus particle has a little hook known as gp120 that latches onto CD4 and uses it to open the front door and get inside the cell. At the same time, it must also engage with another molecule normally involved in receiving signals from the cytokines that regulate immune responses. These back-door coreceptors are usually either the CCR5 or CXR4 molecules. The virus uses them to rearrange their own membranes to be part of the target cell, allowing their own genome to empty into it.
The viral genome consists of RNA instead of DNA. Almost always, RNA is the intermediate between genes and proteins, but in this exceptional case, it is both the messenger and the message. HIV is a retrovirus and carries with it an enzyme that reverses the normal flow of information by turning the RNA genome into a DNA copy, which then promptly jumps into one of the host cell’s chromosomes. There it either lies low, or becomes hyperacti
ve, pretending to be a regular gene by having many copies of itself made. The choice is a function of whether the T-cell is already engaged in an active immune response. In other words, HIV is so canny that it uses the fact that the host is already in a battle to ensure that it propagates and establishes the infection.
After the acute phase, when enough cells have been invaded and the immune response dies down, it doesn’t have to do much, being content to sit and wait for the infected person to give it an opportunity to spread to someone else. In fact, it is probably in the virus’s own best interest not to cause too much damage. Really nasty viruses that do kill their hosts in a few days are nowhere near as capable of spreading throughout a population.
So why is it so difficult for the immune system to do what it normally does, namely recognize the virus and kill it before it invades? Similarly, why don’t vaccines work just as they did for polio and smallpox, tricking the immune system into action before a person becomes exposed to the real pathogen?
There is no simple answer, but part of it is that HIV is apparently able to camouflage itself by constantly changing its appearance ever so slightly. For example, at different stages of infection it may switch between which of the two back doors it uses. It can do this, because retroviruses have an unusually high mutation rate. Every one of the 10,000 or so letters in its genome has a better than 1 in 100,000 probability of changing each time the RNA genome is replicated. That does not sound like much, but it means that every tenth new virus particle is different from its parents. So what, you might say, every one of us is different from our parents at dozens of places. True, but there are only one or two of us for every parent, while a billion virus particles may be produced every day in an acutely infected person.
Natural selection among these viruses must be intense. So intense, in fact, that HIV avoids not just the immune system, but also many of the best drugs that humans have designed to deal with it. Early attempts to defeat HIV faltered because the virus just evolved ways around the drugs. The only truly effective strategy, as stated earlier, has been to employ triple cocktails of drugs. Reasoning that the virus is unlikely to simultaneously evolve three separate solutions, each ingredient in the cocktail has been chosen to target a different aspect of the way HIV propagates.
The cocktails typically involve a combination of an inhibitor of the enzyme that converts RNA into DNA, a “protease inhibitor” that blunts the molecular scissors that HIV uses to assemble its gp120 envelope protein, and unconventional nucleotides that substitute into the viral genome as it replicates. For example, AZT, also known as Zidovudine or Retrovir, was the first antiviral approved by the Food and Drug Administration for the treatment of AIDS. It looks a lot like thymidine (the T in the genetic code) but does not work like it. Similarly, Abacavir, ABC, or Ziagen, is an analog of guanine (the G in the code) that makes for a dyslexic virus.
Taken regularly and according to prescription, which is easier said than done, these combination therapies ought to extend the life expectancy of an HIV-infected adult from less than ten years to more than 30. Failure is often attributable to lapses in treatment due to lack of access to finances, clinics, or social support, but also reflects genetic variation for drug responses. Thus, a considerable proportion of patients are hypersensitive to Abacavir due to the specific variation in their MHC complex (the same genes that are so important in type 1 diabetes, lupus, multiple sclerosis, and other autoimmune diseases). We seem likely to be headed toward an era of personalized medicine in the treatment of AIDS, as for many genetic diseases.
How to Resist a Virus with Your Genes
You might think that since it is an infectious disease, genetics would not play much of a role in susceptibility to AIDS. This intuition turns out to be wrong, as in fact a person’s genome can affect the course of disease in many ways. These include establishing complete resistance to the virus, setting the amount of virus in the blood in the years following infection, and influencing the impact of HIV on the rate of decline of the T-cell population. Certainly too there is a lot of variation for how resistant a patient is to all the pathogens that actually cause tuberculosis, pneumonia, or cancer.
A great example of this is the Δ32 mutation of the CCR5 gene. Several years after AIDS was first recognized, it became apparent that a small number of Caucasian men were apparently immune to the disease. They engaged in high-risk lifestyles and were unquestionably exposed on multiple occasions to the virus, but never seroconverted to HIV-positive status. Some molecular sleuthing soon revealed that the reason for this is that they are missing a sizeable chunk of the back door that HIV uses to get into T-cells, the CCR5 coreceptor. The frequency of this mutation is up to twenty percent in northern Europeans, though it is essentially absent from Africans.
Something called the molecular clock allows us to infer that this mutation is probably new in the human genome. Population geneticists have sophisticated mathematical tools that they can use to date the time of origin of mutations by counting up how many differences in the DNA of the mutated gene make it different from “normal” copies of the gene.
It is a little like guesstimating how long a boy has had a broken leg by counting up how many scribbles are on his cast. A day after the plaster has set, he might have a couple of Jenny-was-here type scrawls from his sister, but weeks later the thing will be covered with limericks and all sorts of symbols and messages. So too with genetic mutations. A few generations after one appears, the chromosome is essentially identical to the original one, but hundreds of generations later it will have picked up more mutations. There is a lot of randomness to this molecular clock of accumulating differences, so the best we can do is infer an interval of time in which an event happened.
In the case of the CCR5 Δ32 mutation, we’re reasonably confident that it was somewhere between 300 and 1,800 years ago, most likely some time in the Middle Ages. An origin 600 or so years ago is pretty intriguing given that this is when the Black Death decimated Europe. Several authors have, in fact, argued that the mutation offered protection against bubonic plague, and this is why it is highly prevalent north of the Alps. This would be a great example of how our recent history of disease may have shaped resistance to a new pathogen, preventing us from getting sick.
It is a nice idea, but the details are almost certainly wrong. To see why, imagine a medieval village of 10,000 people in which, for one reason or another, the CCR5 Δ32 has already attained a frequency of one percent even before the plague arrives at the town gates. Even at this frequency, there would likely only be one person in the town with two copies of the mutation. If HIV resistance is anything to go by, then only this individual would be completely resistant to the plague, but, for the sake of argument, suppose that even those carriers with a single copy are afforded complete protection. Suppose further that it is a really catastrophic plague and that one quarter of the townspeople die the horrible death. Then among the 7,500 survivors would be every one of the 200 or so carriers, and the frequency of CCR5 Δ32 would have risen to 200 in 15,000, or just one and a third percent. It would take dozens of such calamities for natural selection on this scale to get the allele anywhere near ten percent. Bad as it was, nothing like that scale of devastation occurred: Only two extreme plague outbreaks centered three centuries apart in 1350 and 1665 are documented.
A more likely culprit is smallpox, or some other hemorrhagic fever virus, that may have claimed the lives of a few percent of the population a year for 700 or more years. Others have played with the models and come up with plausible scenarios. If transmission is more likely within families than among the general populace, because of shared exposure and care giving, then any protected individuals also protect their relatives to some extent. This notion of inclusive fitness allows for a wide range of conclusions depending on the assumptions that are made, so it is difficult to be sure. In any case, it does seem likely that some modern Whites are at reduced risk of succumbing to AIDS thanks to the unconscious sacrifice made by millions o
f people hundreds of years ago in the face of the new urban plagues and fevers of the time.
For the vast majority of patients who do not have the mutant receptor, there is some hope that drugs might be used to throw a blanket over CCR5 instead. Pfizer is currently carrying out advanced clinical trials for its compound, Maraviroc, which it is hoped will prevent the spread of the virus. Unless of course HIV uses its shape-shifting capacity to evolve to enter through the CXR4 back door instead.
What about those people who do become infected? Is there anything about their genetic constitution that might make them more or less susceptible to AIDS progression? Evidence is accumulating that there is, some of it coming from another one of the whole genome association studies that we met in the previous few chapters. It seems that in this case the geneticists need not have cast their net so wide, because our old friend the MHC is cropping up yet again—but in novel and unexpected ways.
During the quiet phase after a person converts to being HIV positive but before she starts showing the symptoms of AIDS, the virus is detected at a level in the blood that is characteristic of the patient. This level, called the viral set point, ranges over five orders of magnitude, meaning that some patients have 10,000 times more circulating HIV than others do. It stays that way for several years. Oddly, the amount of virus does not necessarily determine how quickly the disease will progress. It may, however, impact the likelihood that a person will transmit the virus to others.
