BIOL 1004 Lecture Notes - Azide, Zidovudine, Mutation Rate

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30 Jan 2013
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Sustained immune activation during HIV infection can ultimately deplete the body’s supply of helper T cells and lead to
the collapse of the host’s defences
An untreated HIV infection exhibits distinct phases, in which the loss of helper T cells happens at different rates and
appears to be driven by different mechanisms
In the acute or initial, phase, HIV virions enter the host’s body and begin to replicate
HIV gains entry into a host cell by first latching onto the cell-surface protein CD4, then binding to a coreceptor
The coreceptor used by most of the HIV strains responsible for new infections is CCR5
o These viral strains can thus infect dendritic cells, macrophages, regulatory T cells, and especially memory and
effector helper T cells
HIV replicates explosively, and the concentration of virions in the blood climbs steeply
o At the same time, the concentrations of CD4 T cells plummet, largely because HIV kills them while replicating
o Hardest hit are the memory helper T cells in the lymphoid tissues of the gut
o Since the gut is both large and vulnerable to penetrations by pathogens, the loss of these T cells is a severe blow
to the body’s defenses
The acute phase ends when viral replication slows and the concentration of virions in the blood drops
o This slow down may be because that the virus simply runs short of host cells it can easily invade
In addition, the immune system mobilizes against the infection and killer T cells begin to target host cells infected with
HIV
o The host’s CD4 T cell counts recover somewhat
This slows HIV, but it has not been stopped
As the chronic phase begins, the immune system struggles to recover form its initial losses while continuing to fight the
virus
o Throughout the chronic phase, the immune system remains highly activated
Chronically activated state of the immune system may enhance some aspects of the host’s response to HIV
It also generates a steady supply of activated CD4 T cells in which HIV can replicate
o And it burns through the host’s supply of naive and memory helper T cells by stimulating them to divide and
differentiate into short-lived effector cells
o Replacement of lost helper T cells ultimately depends on the production of new naive T cells by the thymus
o Thymic output declines with age, however and is also impaired by HIV infection
o HIV infection also damages the bone marrow and lymph nodes
as the battle goes on, immune system’s capacity to regenerate steadily erodes
viral load climbs again and the CD4 T cell counts fall
Chronic phase ends when the concentration of helper T cells in the blood drops below about 200 cells per cubic
millimetre
With few helper T cells left, the immune system can no longer function
o The patient develops AIDS
o Syndrome is characterized by opportunistic infections with bacterial and fungal pathogens that rarely cause
problems for people with robust immune systems
An HIV-infected individual that does not have the effect of anti-HIV drug therapy, if the individual has begun showing
symptoms of AIDS, then the individual typically can expect to live two or three more years
AIDS begins when HIV infection has progressed to a point where the immune system does not function properly.
AZT, one of the first anti-AIDS drugs, turned out to be typical
1.1- Why does AZT Work in the Short Run, But Fail in the Long Run?
To combat viral infections, must look for drugs that are capable of inhibiting enzymes special to the virus
o a drug that blocks reverse transcription should kill retroviruses with minimal side effects
rationale behind azidothymidine (AZT)
HIV’s reverse transcriptase uses the viral RNA as a template to construct a complementary strand of DNA
o Reverse transcriptase makes the DNA using building blocks-nucleotides-stolen from the host cell
o AZT is similar in its chemical structure to the normal nucleotide thymidine-so similar that AZT fools reverse
transcriptase into picking it up and incorporating it into the growing DNA strand
There is a crucial difference between the normal thymidine and AZT
Thymidine has a hydroxyl group (-OH)
AZT has an azide group (-N3)
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