BIOL-1005 Lecture Notes - Sub-Saharan Africa, Integrase, Body Fluid

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Published on 25 Nov 2012
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Chapter 1- Understanding HIV
Why study evolution?
oThe tools and techniques of evolutionary biology offer crucial insights into matters of life and death
Human Immunodeficiency Virus (HIV) causes Acquired Immune Deficiency Syndrome (AIDS)
oHIV is an emerging virus, it rapidly evolves drug resistance and it is deadly
Evolutionary biology is the science devoted to understanding two things:
oHow populations change through time following modifications in their environment
oHow new species come into being
1.1- The Natural History of the HIV/AIDS Epidemic
List of worst epidemic in human history according to the number of deaths:
oInfluenza-50 to 100 million deaths-across the globe
oBlack Death (1347-1352)-took 30%-50% of the European population-about25 million lives
oNew World small pox-released in 1520 by European conquistadores-decimated Native American
populations across two continents
AIDS is among the worst epidemics in human history
oWas first recognized in 1981
oSo far infected more than 65 million people
o25 million have already died
oBy year 2020, a total of 90 million lives would have been claimed by AIDS
oAccording to World Health Organization, AIDS is responsible for about 4.9% of all deaths worldwide
oSub-Saharan Africa is mostly affected by this epidemic
HIV establishes a new infection when a bodily fluid holding the virus, usually a blood or semen, carries it
from an infected person directly onto a mucous membrane or into the bloodstream of an uninfected person
oCan be passed during heterosexual sex, homosexual sex, oral sex, needle sharing, transfusion with
contaminated blood products, childbirth, and breastfeeding
An HIV infection can be acquired only from someone else who already has it!
What is HIV?
Like all viruses, HIV is an intracellular parasite that cannot reproduce on its own
oIt invades specific types of cells in the human immune system
oIt uses enzymatic machinery and energy of these cells to make copies of itself, killing the host cells
in the process
Figure 1.5 (Pg. 7) contains the life cycle of HIV in detail.
oThe life cycle includes an extracellular phase and an intracellular phase
oDuring the extracellular phase, the virus moves from one host cell to another, and can be
transmitted from host to host
oExtracellular form of a virus is called a virion, or virus particle
oDuring intracellular or parasitic phase, the virus replicates
HIV initiates its replication phase by latching onto two proteins on the surface of a host cell
HIV binds to two surface proteins on the target cell called CD4 and coreceptor
This binding fuses the virion’s envelope with the host’s cell membrane and spills the contents
of the virion into the cell
These contents include the virus’s diploid genome (two copies of a single-stranded
RNA molecule) and 3 proteins:
oReverse transcriptase- transcribes the virus’s RNA genome into DNA
oIntegrase- splices the DNA genome into the host cell’s genome
oProtease- which plays a role in the preparation of new viral proteins
In HIV and other retroviruses, flow of genetic information is different than in cells and
in viruses with DNA genomes
In retroviruses, genetic information does not follow the familiar route from DNA to
mRNA to proteins
oInstead it flows from RNA to DNA, then to mRNA to proteins
Once HIV’s genome is inserted into the host cell’s chromosomes, the host cell’s RNA
polymerase transcribes the viral genome into mRNA, and the host cell’s ribosomes synthesize
viral proteins
New virions assemble in the host cell cytoplasm, then bud off the cell membrane and
enter the bloodstream
There, the new virions may find another cell to infect in the same host, or be
transported to a new host
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oSignificant feature of HIV’s life cycle is that the virus uses the host cell’s own enzymatic machinery,
its polymerases, ribosomes, and tRNAs – in almost every step
How Does HIV Cause AIDS?
HIV parasitizes immune system cells, particularly helper T cells. After a long battle against the virus, the
immune system’s supply of helper T cells is badly depleted. Because helper T cells play a crucial role in the
response to invading pathogens, this leaves the host vulnerable to a variety of secondary infections.
Through research on how SIVsm (simian immunodeficiency virus) in monkeys, it was concluded that the
host’s own immune response contributes to the development of immunodeficiency
oHuman HIV patients treated with antiretroviral drugs plus the immunosuppressant cyclosporine
maintained higher helper T cell counts than control patients treated with antiretrovirals alone
T cells derive from stem cells in the bone marrow
These stem cells generate precursors that mature into naive T cells in the thymus
Naive T cells are activated in lymph nodes
An activated T cell undergoes a burst of proliferation, yielding effector and memory cells
oThese circulate in the blood and move through tissues
A large fraction of the body’s memory cells reside in lymphoid tissue associated with mucus membranes
lining the nose, mouth, lungs, and especially the gut
Naive T cells and memory T cells are long lived
oBut effector cells, which actively engage in the fight against invaders, are short lived
Any given T cell lineage has a finite capacity for replication-a capacity that is reduced with each cell division
oSo with each burst of replication within a T cell lineage brings that lineage closer to exhaustion
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
oThese 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
oAt the same time, the concentrations of CD4 T cells plummet, largely because HIV kills them while
replicating
oHardest hit are the memory helper T cells in the lymphoid tissues of the gut
oSince 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
oThis 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
oThe 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 from its initial losses while continuing
to fight the virus
oThroughout 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
oAnd 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
oReplacement of lost helper T cells ultimately depends on the production of new naive T cells by the
thymus
oThymic output declines with age, however and is also impaired by HIV infection
oHIV 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
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