Question 1: State
each of Darwin’s four postulates. Fully explain how each of the three themes in
this article (antiretroviral therapy, different anatomical compartments, and
neutralizing antibody) meets each of the four postulates for evolution of HIV
by natural selection.
Darwin’s four postulates:
A. Antiretroviral
Therapy:
1.
Individuals within species
vary:
a. HIV
is a single standard RNA retrovirus. HIVs ability to reverse transcribe its own
genetic material to DNA through the enzyme called reverse transcriptase allows
for mutations to occur at a rapid rate. Reverse transcriptase does not have
proof-reading characteristics like the enzyme DNA Polymerase III present in
eukaryotes. The result is at least one nucleotide mutation for every HIV
genetic material assembled. When a drug is designed to treat HIV, like AZT, it
has the ability to eliminate most of the viruses. However, due to the high
mutation rate, there will always be a few numbers of viruses that will be
resistant to AZT. Therefore, individual variation in HIV viruses helps the
virus build up resistance to the treatment.
2.
Some of these variations are
passed on to offspring:
a. When the AZT or any other therapy eliminates most of the
retrovirus, the number of viruses that are resistant to the drug pass on that
characteristic to their offspring.
3.
Individuals vary in their
ability to survive and reproduce, and:
a. The ability of being resistant to the drug allows the offspring to
survive and reproduce in the presence of the drug, returning the HIV virus
population to the normal numbers.
4.
Individuals with the most
favorable adaptations are more likely to survive and reproduce:
a. High mutation rates allow HIV to not just develop resistance to
one drug, but to multiple drugs. These individuals become predominant in their
population and are able to successfully reproduce. Therefore, multiple drugs
are needed, cocktails, to suppress the virus. In the contemporary world, three or
more antiretroviral drugs are needed to successfully decrease the virus in the patient.
B. Different
anatomical compartments
1.
Individuals within species
vary:
a. Variation in HIV viruses also results from cellular composition,
drug disposition, and distribution of cellular and humoral responses according
to Douglas D. Richman in the research paper “HIV Evolution and Escape.”
Different anatomical compartments like the CNS, and the genital tract offer
cellular variety, meaning different types of receptors, which through random
mutations can select for tissue specific HIV variants. Thus, a human can be
infected with one HIV variant, but as the infection spreads, through random
mutation, and environmental selection, specific HIV variants will become more
predominant in different parts of the hosts body. The CNS will have a different
array of HIV variants than the genital tract.
2.
Some of these variations are
passed on to offspring:
a. Developing these variants increases the fitness level of the HIV
virus. For example, one drug cannot effectively reduce the virus number in the
host body because the drug will not be able to treat variants that are found in
the CNS. The viruses with advantageous variation have high survival rates and
can reproduce to pass those on to the offspring further increasing the
variation of the gene pool that already exists. This rapid mutation and increase
in the variation of gene pool due to the creation of tissue specific variants
gives HIV viruses the ability to pass those advantageous traits on to their
offspring.
3.
Individuals vary in their
ability to survive and reproduce, and:
a. Antiretroviral drugs that cannot cross the blood-brain barrier
allows for the evolution of the virus. While the antiretroviral drug can fight
the infection in the host’s circulation system, the variants in the CNS do not
develop resistance because they are never exposed to the drug. Therefore,
resistance only develops in the circulatory system and other parts of the host
body. The same can happen in other anatomical structures as in lymph nodes and
spleen. Introducing and then withdrawing an antiretroviral drug has the potential
to create major variation and increase the survivability of the HIV virus.
4.
Individuals with the most
favorable adaptations are more likely to survive and reproduce:
a. Those variants that are tissue specific are not affected by the antiretroviral
therapies and have a higher fitness level than the HIV variants that are in the
blood plasma. Furthermore, resistant variants have the ability to infect new
tissues which the drugs cannot penetrate, creating a “super” HIV virus that is
resistant and tissue specific.
C. Neutralizing
antibody
1.
Individuals within species
vary:
a. The human immune system fights HIV through the production of
neutralizing antibodies. These antibodies are not the same as binding
antibodies produced by B lymphocytes. Binding antibodies will tag the antigen
while neutralizing antibodies will bind to either the host cell surface
receptor or the HIV envelope surface protein to block the virus’s ability to
enter the host cell. Due to high mutation rates and recombination, the primary
immune response allows for the major HIV variant to be stopped in its tracks.
However, some isolated variants, which have been changed due to antigenic
shifts, are not affected by the neutralizing antibodies. These variants have
small differences in their epitopes that render the neutralizing antibodies
useless. Therefore, the host’s immune system allows variability in the surface
proteins of HIV viruses, further hindering human abilities to make effective
vaccines.
2.
Some of these variations are
passed on to offspring:
a. After
the primary immune response, the immune system produces memory B cells that
will be activated when the same type of antigen infects the host again. This
secondary immune response helps the host fight the antigen swiftly. In the case
of HIV, a phenomenon known as the Original Antigenic Sin occurs: The memory B
cells produce neutralizing antibodies in the second infection that are exactly
identical to the first infection. However, due to antigenic drift, the HIV
virus has small variations in its epitopes allowing for selection for these new
variants and the ability to pass on the variation to the next generation of HIV
viruses.
3.
Individuals vary in their
ability to survive and reproduce; and:
Furthermore, the
neutralizing antibodies produced by the memory B cells in the secondary immune
response inhibit naïve B cells. The naïve B cells have never been introduced to
an antigen, so they have the ability to fight new infections. In the secondary
immune response, the inhibition of naïve B cells, hinders the host’s ability to
produce antibodies that can actually fight of the new variants. Those variants
then are able to survive and reproduce to keep the HIV viruses population at
large numbers.
4.
Individuals with the most
favorable adaptations are more likely to survive and reproduce.
a. It
is difficult to create a vaccine against the HIV virus. Numerous environmental
factors allow HIV to produce variant offspring. Even the host immune system,
which is designed to protect the host, further progresses the disease but
increases the variability of HIV surface proteins. HIVs rapid mutation rate
helps the virus survive and proliferate at an alarming rate in our world today.
Question 2: What happens to HIV populations in the absence of pharmaceutical (environmental) pressure? Why?
HIV has a mutation rate of about one nucleotide change per genome, per replication cycle; a relatively high rate that is characteristic of all microbes with single stranded RNA. This is because single stranded RNA contains a reverse transcriptase enzyme that does not have the ability to proof-read genetic material like eukaryotic DNA is able to. When HIV enters the body and there are no pharmaceutical pressures working against it, the rate of evolution is magnificently accelerated and every possible kind of mutation is produced, combined with other mutations, and reproduced throughout the body at an incredible speed.
Question 3:
Examine Figure 5. What does it tell us about the strains in the spleen (lymph)
compared to those in the central nervous system (brain and CSF)? Why use a
phylogenetic tree to give us information about anatomic compartmentalization of
HIV populations?
A researcher, JK Wong, and his team took brain tissue from four cadavers,
all of whom had been pateints on a failed antiretroviral therapy before their
deaths. In each brain tissue sample, Wong discovered differences in patterns of
genetic resistance between the human brain and in the lymph nodes/spleen. There
were populations of the virus in the brain; however, they were not the same
populations as found in the lymph nodes/spleen. The two populations didn’t
differ by just a couple mutations, but rather were entirely different viruses
with different genomes. The one found in the lymph nodes/spleen is probably
mainly different in the respect that it cannot cross the blood-brain barrier.
Also, if only one medication was used to treat the viruses, even if it was
effective on the virus in the lymph nodes/spleen, it would probably not be able
to cross the blood brain barrier to treat that virus. A phylogenetic tree was
used in this paper to actually be able to show the reader about the
compartmentalization. One virus is shown as circles, while squares depict the
other virus. It clearly shows that the two viruses form two separate clades.
This suggests that the virus in the brain and CSF is different from the virus
in the lymph nodes and spleen.
Question 4: Why would HIV populations in distinct anatomical areas evolve differently?
Cell compositions, distributions and drug dispositions differ between circulatory and anatomical parts and each anatomical area may have distinctive environments with different host cell tropisms or differential immune selection. The genital tract is the primary source of transmission of HIV and the central nervous system (CNS) is a target for both HIV pathology and drug treatment. Researchers identified that HIV exhibits a trade-off between developing resistance to antibody neutralization or infecting cells with a low density of viral receptors. Cells in the CNS show both low receptor expression and a distinct amount of effective neutralizing antibody concentrations, making the CNS an optimal environment for HIV reproduction and a target area for drug treatment. The male genital tract has a unique environment that allows for the development and maturation of sperm. It is possible that HIV strains have a similar sequence as semen and are prolific in the same environments, thereby making the genital tract an ideal location for HIV. Additionally, antimicrobial medications including HIV antiretroviral medications do not penetrate all of the subcompartments within the genital tract so these areas provide safe havens for HIV against antiretroviral treatment.
Bonus question:
The meaning of perspicacious is one who has a keen mental perception and understanding of a given subject. In the article, Darwin is described as having a perspicacious insight about the theory of evolution by means of natural selection. This is an accurate description of Mr. Darwin because he was the first person to gather and analyze empirical data to develop the theory of evolution. Charles Darwin did not intend to study or design a theory to explain how organisms have changed over time. Plus, he did not know that all the data he had collected on the trip to the Galapagos would allow him to hypothesis the theory of evolution. After returning from the trip and discerning his research, Darwin established the theory of evolution which has been a pivotal aspect in today's scientific research.
