A timeline

HIV is a relatively new human disease. The U.S. Centers for Disease Control and Prevention (CDC) first reported on what we know now was the beginning of the AIDS epidemic in 1981. It wasn't until 1983 that the virus causing the disease, HIV, was identified.

Yet even though the disease was first recognized in 1981, it obviously was present before that time. Virologists decided to review old medical records and tissue samples to see whether anybody had suffered from the condition in the past.

People in the medical field often keep tissue samples in cases in which diagnosis proved to be difficult and an unknown disease seemed to be the culprit. Using modern molecular techniques in a process that can be thought of as a hunt for viral fossils, researchers were able to examine these historical samples for the presence of the human immunodeficiency virus.

You may be surprised to know just how early AIDS reared its head:

1 The earliest known case of AIDS dates from a British sailor who developed AIDS-like symptoms in the late 1950s.

1 The earliest known case of acquired immune deficiency in the United States (that is, the earliest date for which molecular evidence exists) occurred in 1968, involving a teenage male who reported that he'd been symptomatic for at least two years. Because he had never traveled outside the country, he must have caught the virus in the United States sometime before then.

1 A survey of preserved blood samples has revealed antibodies to HIV dating back to the late 1950s.

1 The degree of divergence between HIV and the suggested SIV source suggests that HIV mutated from SIV between 50 and 100 years ago.

So HIV was around possibly up to a century ago. A little more than 50 years ago, it presented itself in isolated cases. In the early 1980s, many people began to fall ill. What scientists don't know is whether the virus persisted at low levels until the later outbreak was noticed or whether it had gone extinct in the United States and then was reintroduced. What they do know is that by the end of the 1980s, AIDS was terrorizing the world.

The Path and Evolution of HIV in the Patient

Every person infected with HIV has his or her own story, and the disease takes a dramatically different course in different people. Yet when you take all the sufferers in total, you get a picture — albeit a general one — of what HIV does when it enters the body.

Basically, right after infection, the levels of HIV in the blood increase rapidly, but then the body's immune system kicks in and is successful in reducing the amount of HIV virus present. Yet over time, the amount of HIV in the blood increases as the number of T cells decrease. Eventually, HIV destroys the immune system, eliminating T cells until almost none are left. At this point, the patient succumbs to infections that the immune system is no longer able to battle.

A key component of understanding the progression of HIV infection is understanding how the viral population evolves in the patient. The following sections explain these different evolutionary stages of HIV in the human body.

¿jjjABEft During the course of HIV infection the viral population evolves, first in response to the host immune system, then in the absence of immune response. Viral types unlike those in the initial infection arise during the course of the infection and are associated with later stages of disease progression.

Increasing and growing more divergent

Right after infection, the levels of HIV in the blood increase very rapidly, yet the immune system is strong enough to fight back. As it suppresses the initial outbreak, the infected person's immune system also exerts a powerful selective force on the HIV virus.

The infected person's immune system recognizes HIV as a foreign invader and attacks it. But HIV has a high mutation rate, and not all of the individual viruses produced in the infection are exactly same, so some are able to avoid being targeted. So now the immune system has to go after these slightly different viruses and, in doing so, selects for viruses that are even more different. This cycle—in which the attacks launched by the immune system attacks select for slightly different viruses—goes on, back and forth for quite some time. The immune system puts up a valiant fight, often for years. During this period the HIV population evolves in two ways.

The viral population becomes progressively different from the original strain

The viral population evolves to be progressively more different from the original infecting strain. Initially, the person's immune system is pretty good at battling the virus. So although HIV increases immediately after infection, it drops back down when the immune system fights back.

But as the disease progresses, the HIV population in the person evolves. Mutant virus progeny that are less susceptible to the immune system increase in frequency. Over time, the virus population becomes more and more different from the original infecting particles. The viral population is evolving in response to the immune system — the immune system is fighting hard and only new viral mutants can avoid it.

The virus population grows increasingly diverse

The virus population as a whole becomes increasingly diverse — that is, there are progressively more different HIV types within the patient as the disease advances. The most fit HIV viruses will be the ones that are different from those that the immune system has responded to, but there are many ways to be different so viral diversity goes up.

Reaching a plateau

HIV destroys one of the key components of the immune system, a type of T cell. When enough of these cells have been destroyed, the immune system can no longer contain the virus, and the HIV population starts to evolve in a new way.

As T cells are destroyed, the crippled immune system no longer acts as an agent of selection on the HIV viruses. At this point, selection no longer favors viruses simply because they are different — they don't have to escape the immune system, which is worn out and can fight no more. The difference from the original strain reaches a plateau. Mutations still occur during HIV replication, but now if a particular strain is especially good at growing in the host, there's no immune system to knock it back down.

Destroying T-cells in a different Way

HIV disease progression can vary dramatically from patient to patient, and evolution does not occur along exactly the same trajectory in each case. But one major event which is observed repeatedly is the evolution of viruses later in infection that attack the immune system in a different way. These viral variants (called X4 variants) are able to attach to a different part of the surface of immune cells (a cellular feature called the CXCR4 receptor ) and destroy the T cells in a different way.

The X4 type begins to increase in frequency around the time that the overall genetic diversity of the viral population is decreasing, and the peak of the X4 virus type is associated with period proceeding transition to full blown AIDS symptoms.

Researchers don't completely understand how theses X4 viruses influence the disease or whether the X4 variants evolve in every patient. What they do know is that the X4 variants cause T cell death differently from the original variants.

Other Interesting Facts about HIV

HIV is as interesting as it is scary. Consider this to be the section of other cool things about the human immunodeficiency virus — if you can use the word cool when talking about a deadly pathogen. If you can't, consider this to be the section of noteworthy-but-not-vitally-important information for serious-minded readers.

Some people may be resistant

During the initial infection, the virus binds to a CCR5 co-receptor (refer to "Attacking T cells," earlier in this chapter). As it turns out, not everyone has that same molecule. Some people have a mutation that makes a slightly different CCR5 molecule. People who have one mutated copy of the CCR5 locus show delayed progression toward full-blown AIDS. And people who have two mutated copies appear to be resistant to HIV infection.

Interestingly, this mutation is found primarily in Europe, and its prevalence is correlated with the degree to which a particular location experienced plagues in the past. It's been hypothesized that this mutation may have made people more resistant to certain other disease organisms and that as a result the mutation increased in frequency in places that once experienced plague. Just by coincidence, the same mutation confers resistance to HIV infection.

Scientists aren't sure that the bubonic plague was caused by black-plague bacteria. Instead, it may have been caused by a viral hemorrhagic fever.

HlV evolves in a new host

Evolution within the patient selects for a more divergent virus, and that viral diversity increases through time in the individual (refer to the earlier section "HIV Evolution within the Patient"). When you compare the virus present during the initial period of infection across different people, however, you find less divergence among people than you see over time within one person.

Think about this for a minute: If the virus is diverging in one person, and that person infects a second person, you'd expect that the second person would start out with a more divergent population of the initially infecting virus. But that's not the case.

Here's why: After infection, strong selection for the ancestral viral type occurs, so the virus evolves back toward this condition. This selection may happen for at least a couple of reasons:

i The viral forms present in a person late in the infection may not be well suited to living in the environment present in a newly infected person. Hence, selection favors going back to an initial viral form.

i Although the diverse viral population may be perfectly capable of surviving in a newly infected host, this population may be outcompeted by viral variants that have mutations resurrecting the ancestral type.

HIV has a high recombination rate

One way that the HIV population generates all that diversity is via a huge amount of recombination among viruses. In recombination, a DNA or RNA sequence (whichever the critter uses for genomic information) is produced that's a combination of two original sequences. For most organisms, recombination is generally believed to happen far less frequently than mutation. But in HIV, the recombination rate may approach the rate of mutation.

Scientists know about the recombination rate by making and analyzing phylo-genetic trees for a group of viruses with different genes. For organisms with low rates of recombination, phylogenies constructed from different genes should have trees that match. The extent to which they don't match allows scientists to determine the frequency of recombination.

When you take a bunch of HIV viruses, determine the sequence of several genes, and then make phylogenetic trees from these different genes, the resulting trees don't always match. This shows that, rather than being a rare event, recombination is a major source of the diversity in the HIV population within a patient.

Using Evolution to Fight HIV

The major problem we face in coming up with a vaccine for HIV is that the virus mutates so rapidly that it ends up being different enough from the strain used to make the vaccine that the vaccine doesn't confer immunity. Scientists can use the techniques of phylogenetic analysis to study the evolution of HIV and identity which parts of the HIV virus are more or less likely to change, and it might, and I stress might, be possible to use this information in our hunt for an effective vaccine.

Morgane Rolland, David Nickle, and James Mullins at the University of Washington have been working on just this problem: how to design a vaccine that essentially sneaks up on the virus when it's not looking. They hypothesize that the trick might be to eliminate all the info from the parts of the HIV

genome that are mutating most rapidly and focus on the parts that aren't. The key is to figure out what parts of the HIV virus have been outwitting the immune system and then design a vaccine that targets parts of the virus that can't evolve.

By understanding how the virus evolves, we may be able to get a few steps ahead of it and make a vaccine that's harder for the virus to evade. This would be a remarkably cool application of evolutionary biology to a real-world problem.

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