Evolution Exam 1: Chapter 1

The evolution of X4 virions is an example of:

"Short-sighted" evolution that hastens the death of all the HIV virions in the host.

Not all viruses are dangerous. HIV, however, is nearly 100% lethal. Describe three major hypotheses for why HIV is so highly lethal.

(1) Short-sighted evolution: Within each patient, competition between HIV virions results in evolution of HIV strains that are more aggressive, replicate more rapidly, and can evade attack by that host's T cells. This evolution is not to the virus' long-term benefit, however, because it ultimately kills the host-and kills all virions within that host. (2) Evolution for transmission to new hosts: Traits such as high viral load that can cause high virulence may also allow HIV to spread to new hosts. (3) Host has not had time to "counter-evolve:" HIV is a new disease for humans, and our species has not yet had time to evolve defenses. We are still within the first generation of humans to be exposed to HIV. In addition, the frequency of the CCR5 delta-32 (resistant) alleles is very low in the parts of the World where HIV infection rate is the highest.

Rank these world regions in order of the number of people infected with HIV from greatest to least.

1. Sub-Saharan Africa 2. India and Southeast Asia 3. North America 4. China 5. Europe

Epitope

A short piece of viral protein displayed on the virus's surface, and which immune system cells use to recognize the virus

Reverse Transcriptase

A viral enzyme that can synthesize DNA from an RNA template

Which of the following does not describe HIV-1?

A virus that is primarily transmitted by casual contact.

Retrovirus

Any RNA virus that can synthesize DNA from its own RNA

Evidence that transmission of HIV from an SIV relative in chimpanzees to humans has taken place multiple times includes the finding that ______________.

Each of three human HIV subgroups is most closely related to a different chimp SIV strain.

In what sense is evolution of AZT resistance "automatic" rather than directed or planned? Is it accurate to think of HIV as "trying" to evolve?

Evolution is "automatic" because it is simply an inevitable consequence of the mathematics of mutation, differential survival, and reproduction in large populations. In the case of HIV resistance, whenever AZT is applied to a large, dividing population of HIV, sooner or later AZT resistance will inevitably evolve. This process occurs simply due to mathematics, without any guidance, planning, or "desire" on the part of the HIV virions, so it is not correct to think of HIV, or of any evolving population, as "trying to evolve."

True or false. Because of the difference in transmission to new hosts, HIV-2 is more common worldwide.

False

True or false. HIV-2 is another form of HIV that is derived the same primate species as HIV-1.

False

Some physicians have advocated "drug holidays" as a way of helping HIV patients cope with the side effects of multidrug therapy. Under this plan, every so often the patient would stop taking drugs for a while. From an evolutionary perspective, does this seem like a good idea or a bad idea? Justify your answer.

From an evolutionary perspective, this is a risky idea. Recall HIV's high mutation rate and large population size. A break in multiple drug therapy allows the surviving HIV virions—most of which will be those with partial resistance to one or two of the drugs—to multiply and generate billions of offspring with new mutations, some of which will confer mutations to additional drugs. However, a break in the therapy might promote an increase in the frequency of "wild type" or non-resistant virions too, which could lead to a more effective treatment

Researchers are pessimistic about the prospects of developing an effective AIDS vaccine because ______ and ______.

HIV evolves extremely rapidly; transmission of SIVs to humans is likely to happen again in the future.

What traits of HIV contribute to its rapid evolution?

HIV has a very high mutation rate, a rapid reproductive rate, and an enormous population size

When did HIV enter the human population, and from what source? How do we know?

HIV is a new disease for humans, and it probably came to the human population from a simian host (an SIV strain). The genetic sequence data indicates that the last common ancestor of the M HIV-1 viruses lived in the 1930's or earlier. This strain is primarily responsible for the AIDS epidemic. The key to HIV's rapid evolution is a very high mutation rate, an extremely fast reproductive rate, and a very large population size within one host. This makes it virtually inevitable that at least one HIV virion within one patient will, by chance, acquire a key mutation that will cause increased replication or resistance.

Recall that we discussed two different types of selection in this chapter: selection of different virus strains within one host and selection of those virus strains that are able to transmit themselves from host to host. Now consider the hypothesis, traditionally championed by biomedical researchers, that disease-causing agents naturally evolve into more benign forms as the immune systems of their hosts evolve more efficient responses to them. Is the evidence we have reviewed on the evolution of HIV within and among hosts consistent with this hypothesis? Why or why not?

HIV is a relatively new virus, so the human immune system has not had much time to respond to it yet. So far, HIV has shown no tendency to evolve into a more benign form. Within one host, HIV almost always evolves to become more virulent, as demonstrated by the multiple studies reviewed in this chapter on AZT resistance, epitope evolution, replicative speed, etc. Across hosts, the form of HIV that has spread most widely is the more virulent one, HIV-1. It appears that the same traits that cause increased virulence might also cause increased transmission to new hosts. A virus must only keep its host alive long enough to spread to a new host; once it spreads, it doesn't matter (for the virus's continued survival) if the first host dies.

Would evolution of AZT resistance still occur automatically if any of the following were true: HIV's reverse transcriptase never made mistakes; there were only a tiny handful of HIV virions (say, ten) per human patient, instead of millions; or if each HIV virion could only produce one daughter virion, instead of hundreds?

If any of these three conditions were true, evolution would not occur. It is essential that many mutations (mistakes) happen, and that they are happening in a large population - this is what makes it virtually inevitable that the "right" mutation will occur eventually. Finally, for the survivors to "take over" the population and for the mutation to spread, it is essential that any surviving HIV virion makes many daughter virions, and can repopulate the entire population. These themes are generally true for evolution in all species.

Suppose that HIV were the ancestor of the SIVs, instead of the other way around. If immunodeficiency viruses were originally transmitted from humans to monkeys and chimpanzees, make a sketch of what Figure 1.25a would look like.

In Figure 1.25a, all the SIV strains from monkeys and chimpanzees would cluster together, branching off from the one HIV strain that jumped from humans to other primates. Other HIV strains will be more distant branches on the tree (branching off closer to the base of the tree).

What is the result when helper T cells fall below about 200 cells per cubic milliliter of blood?

Inability to defend the body against opportunistic infections as well as the onset of AIDS.

Why has HIV been difficult to develop treatments for?

Its high mutation rate leads it to evolve resistance rapidly and because it is a virus, any drugs that disrupt viral replication may harm the host too.

The idea behind multidrug therapy for HIV is to increase the number of mutations required for resistance and thus reduce genetic variation in the viral population for survival in the presence of drugs. Could we achieve the same effect by using antiretroviral drugs in sequence instead of simultaneously? Why or why not?

No, we could not achieve the same result if we administer the drugs in a sequence. The unfortunate result would likely be development of resistance to all the drugs. This is because the HIV population would only have to develop resistance for one drug at a time, which is quite easy for it to do. The key to multiple drug therapy is that the drugs are given simultaneously, so that HIV virions must have four or five simultaneous mutations (one for each drug) to survive. Even with HIV's high mutation rate and large population size, the simultaneous occurrence of multiple resistance mutations in one virion is unlikely.

Homosexual sex is the major mode of transmission of HIV in how many of these regions of the world: China, Europe, North America, India and Southeast Asia, and Sub-Saharan Africa

Only in North America and Europe

What is the evidence that the evolution of our ancestors to resist infection with an extinct retrovirus necessarily left us vulnerable to HIV-1? Can you think of a genetic change that ight simultaneously protect and individual against both HIV-1 and PtER V1?

Recent molecular studies point out an unusual property of HIV, leading to the progression and deadly outcome of the disease, rather than being a benign chronic infection seen in cases of primate SIV. This property might be a mutation in the Vpu gene and its product. Vpu protein interferes with tetherin, another viral protein that keep maturing virions in the host cell and prevents their release. A mutant Vpu gene was picked up from chimp SIV when two different strains of SIV infected the same animal. In humans ("patient zero") tetherin does not keep maturing virions in the host cell and prevents their release. In fact the Vpu gene in the HIV-1 (group M) blocks the action of tetherin, which in turn allows greater production of virions and faster progress of infection in human patients. Another protein, TRIM5a found in human cells, blocks retroviral transcription, but it cannot affect HIV transcription as well. In the evolutionary history of primates, TRIM5a protein is much diversified and confirms the hypothesis of the long running arms race between retroviruses and their mammalian hosts. Human TRIM5a gene might, in the future, contribute to the evolution of resistance to HIV in humans. However, TRIM5a probably evolved in a fight with an extinct retrovirus

In the early 1990s, researchers began to find AZT-resistant strains of HIV-1 in recently infected patients who had never received AZT. How can this be?

Since an HIV population already has heritable variation for resistance to AZT before exposure to AZT, some patients would quickly develop resistant HIV strains as soon as they began taking AZT. Although early application of AZT in the 1990's showed some success in preventing or slowing replication of most HIV virions, the resistant virions with the right mutation would survive and replicate. In more general terms, there is differential reproductive success among the virions that is linked with a heritable trait, such as AZT resistance.

Reverse transcriptase inhibitors

Some, like AZT, inhibit reverse transcriptase by mimicking the normal building blocks of DNA. Others inhibit by interfering with the enzyme's active site.

The problem, the Pope said, "cannot be overcome by the distribution of condoms. On the contrary, they increase it." Consider the relevant scientific evidence. Is the Pope's first statement correct? How about his second statement? How do we know?

The Pope's first statement is that Africa's problem with HIV/AIDS "cannot be overcome by the distribution of condoms." The statement is true in that no single strategy will prevent the transmittal of HIV/AIDS. For instance, condoms provide some protection from sexually transmission of HIV/AIDS, but they would not prevent an infected mother from passing the virus to her babies via breast milk. The Pope's second statement is that the distribution of condoms actually increases the problem of HIV/AIDS transmission. We know this second statement could be argued against from numerous data collected in South Africa and elsewhere showing that consistent use of condoms reduces HIV infection significantly. There is no data to suggest the use of condoms increases the problem of HIV/AIDS transmission.

Virion or virus particle

The extracellular form of a virus

CD4

The first protein that HIV binds to on human T cells

Given the risk of evolution of resistance, why do you think the two patients shown in FIgure 1.11 were not given high doses of AZT immediately, rather than starting them with low doses?

The patients were probably not given higher doses because of the serious side effects of antiviral drugs. Since viruses use their host cell's molecular machinery, any drug that can stop viral replication usually interferes with normal healthy cells as well. AZT can disrupt cell division because it interferes with DNA transcription in healthy cells, not just in HIV-infected cells.

Coreceptor

The second protein that HIV binds to on human T cells

Fusion Inhibitors

These bar HIV from entering host cells by interfering with HIV's gp120 or gp41 proteins

Coreceptor Inhibitors

These bar HIV from entering host cells in the first place by preventing them from latching onto the host cell's CCR5 molecules

Integrase inhibitors.

These block HIV's integrase from inserting HIV's DNA into the host genome, preventing the transcription of new viral RNA's

Protease inhibitors

These prevent HIV's protease enzyme from cleaving viral precursor proteins to produce mature components for new virions

In a monograph published in 1883, Alexander Graham Bell wrote that "natural selection no longer influences mankind to any great extent." Do you agree? What is your evidence?

This statement of A. G. Bell seems very inappropriate in the light of many challenges humanity faces today, including the evolution of resistance (from the antimicrobial drug resistance to the resistance to pesticides). Think about other examples where the human future depends on the outcomes of natural selection.

True or false. Compared to HIV-1, HIV-2 produces a lower viral load in patient blood samples, and is consequently less damaging to its host and less able to move to new hosts.

True

What best describes the evolutionary rationale behind Highly Active Anti-Retroviral Therapy (HAART)?

With multiple drugs, more mutations must be present in a virion's genome for that virion to be resistant. The more mutations that must be present, the less likely they are to occur together in the proper combination.

Is evolution an irreversible process?

Yes