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Lecture

BMEN 515 Lecture Notes - Cytotoxic T Cell, Memory T Cell, Epitope


Department
Biomedical Engineering
Course Code
BMEN 515
Professor
William Huddleston

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Why is HIV Fatal?
The idea that evolution by natural selection, is an automatic process that simply happens whenever a population shows the necessary
heritable variation in survival and reproductive success
o Traits conducive to surviving and reproducing spread throughout the population; traits conducive to dying without issue
disappear
Short-Sighted Evolution
If there is a resistant to HIV and Aids, then we can expect that resistance will spread throughout the human population as generations
pass
Antibodies and killer T cells recognize HIV and HIV-infected cells by binding to epitopes- short pieces of viral protein displayed on the
surface of the virion or the infected cell
o These epitopes are encoded in HIV’s genes
Mutations in the genes can change the epitopes and may enable the mutant virion to evade detection by the host’s current arsenal of
antibodies and killer T cells
As the infection progresses from the acute phase to the chronic phase, the HIV population has already evolved
Variants easily recognized by the first wave of the immune attack have disappeared; variants less easily recognized persist
Because the immune system never completely curtails HIV’s replication, the HIV population inside a host evolves throughout the
chronic phase of infection
The evolution of the HIV population appears to contribute to the collapse of the immune system in at least three ways
o First- it is the continuous evolution toward novel epitopes that enables the viral population to stay far enough ahead of the
immune response to keep replicating in high numbers---these novel epitopes will enable the viral population to be
undetected by the immune cells of the host’s body
Eventually, the continuously replicating viral population burns through the host’s supply of naive and memory T cells
and destroys the body’s ability to replace them
o Second- the viral population within most hosts evolves toward ever more aggressive replication
The longer a patient harbours an HIV population, the more damaging the virions in the population become
o Third- in at least half of all hosts- and possibly many more- strains of HIV evolve that can infect naive T cells
An HIV virion’s ability to infect a given cell type is determined by the coreceptor the virion uses
The coreceptor is the second of two proteins the HIV latches onto to infiltrate a host cell
Early in most HIV infections, most virions in the HIV population use as their coreceptor a protein called CCR5
o CCR5 is found on dendritic cells, macrophages, and regulatory, resting, and effector T cells
As the infection progresses and the HIV populations evolves, virions often emerge that exploit a different
coreceptor, a protein called CXCR4
CXCR4 is found on naive T cells
Because naive T cells are the progenitors of memory and effector T cells, the emergence of virions that can infect and kill naive T cells
is typically bad news for the host
The rapid evolution of the HIV population inside a host hastens the collapse of the host’s immune system. This evolution is short-
sighted because it also hastens the extinction of the HIV population.
The evolution of the HIV population within a host is short-sighted
The virions do not look to the future and anticipate that as their population evolves it will ultimately kill its host and thereby cause its
own extinction
The virions cant look to the future, they are just tiny, thoughtless molecular machines
Evolution by natural selection does not look to the future either
o It can’t; it is just a mathematical process that happens automatically
Therefore, the HIV population in any particular host ultimately evolves itself right out of existence
HIV infection is fatal, because of the short-sighted evolution of the HIV population inside the host
o Lethal strains of HIV become predominant in the host because they enjoy a short-term advantage in survival and reproduction
A Correlation between Lethality and Transmission?
Short-sighted evolution is not the only reason HIV infection is fatal
o There is evidence that there are rare strains of HIV exist that kill their hosts more slowly than common strains
Important point is that, alterations to HIV’s genome can render the virus less damaging to the host, but still able to survive in the
host’s body
If the host lives longer, then the HIV population persists longer too
To persist beyond the lifespan of the host, a viral population must at some point colonize new hosts
o This means that there is a second level of natural selection acting on HIV
o First level of selection is the one we have already explored:
There are differences among virions in their ability to survive and reproduce within a given host
o Second level of selection occurs when there are differences among viral strains in their ability to move from one host to
another
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