Running Head: AN UNDERSTANDING OF HIV- 1, SYMPTOMS, AND TREATMENTS An Understanding of HIV- 1, Symptoms, and Treatments Benjamin Mills
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Running
Head:
AN
UNDERSTANDING
OF
HIV-‐1,
SYMPTOMS,
AND
TREATMENTS
An
Understanding
of
HIV-‐1,
Symptoms,
and
Treatments
Benjamin
Mills
AN UNDERSTANDING OF HIV-‐1, SYMPTOMS, AND TREATMENTS Abstract HIV-‐1 is a virus that has had major impacts worldwide. Numerous people have died due to infection caused by HIV. Around the world, HIV is contracted in areas that are full of infection and disease. Without a cure, it is impossible to get rid of HIV once a person has been infected. Many treatments exist to counteract symptoms of HIV, but a cure has yet to be found. One reason that scientists have not discovered a cure yet is that we do not entirely understand how HIV works. In order to effectively create a vaccine, it is crucial that we understand how the virus works. This paper creates a very simply, light-‐hearted approach into the molecular biology of HIV.
AN UNDERSTANDING OF HIV-‐1, SYMPTOMS, AND TREATMENTS Introduction By 2008, twenty-‐five million people had died of a similar, unnatural cause: the human immunodeficiency virus type-‐1. At that point, forty million people were living under the effects of HIV-‐1. With no easy, quick treatment in the near future, the prospects were drab. However, scientists were quickly discovering the method with which HIV attacked one’s immune system. This report gives a basic understanding of what HIV RNA codes for, how it attacks the body, and some treatments. Cell Entry HIV-‐1 is a virus. It is shaped like a mushroom, complete with a capsid and an envelope glycoprotein. The capsid contains the viral RNA. The envelope glycoprotein recognizes a surface glycoprotein. These surface glycoproteins can be found in abundance in the phospholipid bilayer of T-‐lymphocytes and lymphocytes of helper-‐T cells (Haseltine). In this way, developing cells of the immune system are targeted. Because these cells traverse all the pathways of the body, HIV-‐1 is carried throughout the entire body. The two glycoproteins fuse together. Once the glycoproteins fuse, the viral RNA is inserted past the phospholipid bilayer and into the cell. Once in the cytosol, the viral RNA is transported to the nucleus. Genetic Code HIV-‐1 is a retrovirus. A retrovirus is a virus that contains RNA rather than viral DNA. This viral RNA is “reverse-‐transcribed” into the DNA in the infected cell.
AN
UNDERSTANDING
OF
HIV-‐1,
SYMPTOMS,
AND
TREATMENTS
This
process
is
carried
out
using
the
reverse
transcriptase
enzyme
carried
in
the
capsid.
The
reverse
transcriptase
will
use
the
viral
RNA
as
a
template,
and
synthesize
an
entirely
new
DNA
strand.
Once
the
new
viral
DNA
has
successfully
been
synthesized,
it
is
integrated
into
a
host
chromosome
using
the
integrase
enzyme.
The
viral
DNA
in
the
chromosomes
is
now
known
as
“pro-‐viral
DNA”
or
a
provirus
(Ward).
At
this
point,
the
viral
DNA
goes
through
normal
cell
processes
in
order
to
create
proteins.
The
proteins
created
by
the
viral
DNA
go
on
to
perform
specific
functions.
Proteins
made
by
the
viral
DNA
are
used
to
make
the
budding
viruses.
In
order
to
understand
the
way
that
a
virus
infects
a
cell,
one
must
understand
the
genes
in
a
virus
and
for
what
they
code.
HIV-‐1
has
9
genes
in
all.
However,
it
codes
for
17
proteins.
This
is
possible
through
a
unique
process
in
which
the
viral
mRNA
codes
for
several
proteins
that
are
bonded
together
to
form
a
polyprotein.
Three
of
HIV’s
genes
code
for
polyproteins:
Gag,
Pol,
and
Env(Ward).
The
Gag
gene
codes
for
four
different
proteins.
After
reverse-‐transcription,
transcription,
and
translation,
a
polyprotein
is
produced.
The
polyprotein
is
then
cleaved
by
HIV’s
protease
enzyme.
The
resultant
proteins
are
a
matrix
protein,
a
major
capsid
protein,
a
nucleic
acid-‐binding
protein,
and
a
small
proline-‐rich
protein
that
helps
with
virion
assembly.
The
next
gene
is
called
the
“Pol”
gene.
It
is
reverse
transcribed
into
a
cell’s
DNA
and
then
transcribed
into
viral
mRNA.
The
mRNA
exits
the
nucleus
without
any
post-‐transcriptional
modifications.
When
being
translated
in
a
ribosome,
the
AN UNDERSTANDING OF HIV-‐1, SYMPTOMS, AND TREATMENTS viral mRNA experiences a process called “frame shifting”. While the enzyme is reading the viral mRNA,it will stop at a certain base and jump back one base. Then the enzyme will continue reading the viral RNA from that point on. “Frame shifting” creates a whole new sequence of proteins for which the viral mRNA codes. Not only does frame shifting create a whole new sequence of proteins, but it also creates a point at which the Gag polyprotein can fuse to the Pol polyprotein(Ward). Pol codes for 3 major enzymes. The three enzymes it codes for are a viral protease, reverse transcriptase, and integrase. These enzymes are then released into the cytoplasm for virion assembly. When the budding virus, or the second generation, infects a different cell, protease, reverse transcriptase, and integrase will be used to create the third generation of HIV viruses. However, when these enzymes are made, they are bound together to form a polyprotein. The Pol polyprotein is fused to the Gag polyprotein, and will remained fused until it is cleaved by an enzyme(Ward). The last gene that codes for a polyprotein is called Env. Env is responsible for two major proteins. Like all the other genes in the HIV genome, Env goes through reverse-‐transcription, transcription, and translation without any post-‐ transcriptional modifications. When translation is finished, the final product is a polyprotein called gp160. gp160 is cleaved by a natural protease enzyme created by the cell. gp160 then becomes two glycoproteins, gp120 and gp41(Ward). The gp120 glycoprotein becomes the viral envelope of the budding HIV virus. This envelope is what fuses to the CD4 receptor in the first stage of infection. The gp41 glycoprotein is stem-‐shaped. It joins with gp120 to form the
AN
UNDERSTANDING
OF
HIV-‐1,
SYMPTOMS,
AND
TREATMENTS
mushroom
shape
of
the
HIV
virion.
These
two
structures
are
what
make
up
the
exterior
of
the
HIV
virion.
The
term
virion
refers
to
the
completed,
mature
virus
as
it
is
outside
of
the
host
cell
(Ward).
The
HIV
genome
also
contains
a
section
called
Tat.
This
gene
codes
for
the
Tat
protein,
the
ref
protein,
and
the
nef
protein.
The
Tat
protein
is
also
known
as
the
transactivator,
and
is
used
for
increasing
the
rate
of
viral
RNA
translation.
Tat
does
this
by
moving
to
the
nucleus
and
nucleolus
of
the
cell.
It
then
binds
to
the
new
viral
RNA
being
formed.
The
transactivator
allows
an
entire
sequence
of
RNA
to
be
translated
at
once.
This
is
how
polyproteins
are
made.
The
transactivator
also
increases
the
frequency
of
RNA
initiation.
The
other
two
proteins
created
by
Tat,
ref
and
nef,
are
both
regulatory
and
regulate
infection
of
a
cell(Haseltine).
Also
important
to
the
replication
process,
the
Rev
gene
codes
for
one
Rev
protein.
The
Rev
protein
can
be
found
primarily
in
the
cytosol.
In
the
cytosol,
Rev
gathers
spliced
transcripts
and
moves
them
to
ribosomes,
where
the
transcripts
can
be
translated
into
capsid
and
envelope
glycoproteins.
Without
the
RNA
transcripts
being
gathered
together
by
the
Rev
protein,
only
regulatory
proteins
could
be
made
through
translation
(Kula).
The
Rev
protein
is
able
to
transport
spliced
transcripts
by
interacting
with
an
export
receptor
called
Crm-‐1.
The
Rev
protein
and
spliced
viral
mRNA
transcripts
will
bind
together
via
the
Crm-‐1.
This
occurs
in
the
nucleus.
Once
the
binding
occurs,
Crm-‐1
can
interact
with
the
nuclear
pores
in
the
nuclear
membrane,
allowing
the
Crm-‐1,
Rev
protein,
and
mRNA
transcripts
to
enter
the
cytosol.
Once
in
AN UNDERSTANDING OF HIV-‐1, SYMPTOMS, AND TREATMENTS the cytosol, the Rev proteins drop the transcripts to be translated and then return to the nucleus (Kula). Effects of HIV on the Body and the Cell HIV-‐1 does not directly kill a cell. It has adverse effects on the cell, which may lead to cell death, but the actual virus does not attack a cell with malicious intentions. Instead, the intention of a virus is to replicate itself. All of the coding genetic material is meant to create proteins that are used for creating new viruses. However, there are still ways in which viruses can cause cell death. When HIV-‐1 virion enters the body, it seeks a certain type of cell that has the cell membrane protein receptor CD4. These CD4 receptors can be found in abundance in the phospholipid bilayers of T lymphocytes and lymphocytes of helper T cells. In this way, the immune system of an HIV-‐positive person is targeted upon infection. Because T-‐lymphocytes are responsible for triggering the production of antibodies, disabling these cells effectively halts the body’s attempt to fight the virus. Without antibodies to recognize the envelope glycoprotein responsible for cell fusion on an HIV virion, macrophages will not destroy infected cells and HIV can continue replication in the body undisturbed (Haseltine). HIV-‐1 virions fuse with the CD4 receptors in order to inject the genetic material into a cell. After the cell has created budding viruses inside itself, the new viruses can leave the cell. However, the first generation of budding viruses will often fuse directly with the cell that it just left. The fusion between HIV virions and a
AN
UNDERSTANDING
OF
HIV-‐1,
SYMPTOMS,
AND
TREATMENTS
cell
will
quickly
deteriorate
a
cell
membrane,
resulting
in
death
of
the
cell.
In
this
way
the
first
generation
of
budding
HIV
viruses
can
kill
a
cell
(Haseltine).
A
second
way
that
HIV-‐1
virions
can
kill
a
cell
is
very
dramatic
and
rapid.
When
a
virus
fuses
with
the
CD4
receptor
on
a
cell
membrane,
this
can
trigger
other
CD4
receptors
along
the
cell
membrane
to
fuse
with
other
cells
that
have
the
CD4
receptor
along
their
cell
membrane.
One
HIV-‐infected
cell
can
fuse
with
up
to
500
uninfected
T-‐cells.
The
result
of
this
reaction
is
one
giant
multinucleated
cell.
The
half-‐life
of
this
multinucleated
cell
is
very
short.
This
means
that
individual
cells
inside
the
multinucleated
cell
can
die
very
quickly
because
of
cell
membrane
deterioration
(Haseltine).
Many
diseases
are
associated
with
HIV-‐1.
When
HIV-‐infected
cells
get
into
the
bloodstream,
they
can
travel
around
the
entire
body.
HIV-‐infected
cells
can
have
the
most
damage
on
the
brain.
HIV-‐infected
cells
will
travel
via
the
bloodstream,
where
they
can
be
dropped
off
into
vascular
tissue.
Once
in
these
capillaries,
these
cells
diffuse
across
the
selectively
permeable
blood-‐brain
barrier
(BBB).
Scientists
are
unclear
of
how
the
HIV
virus
crosses
the
BBB,
but
several
theories
exist.
One
such
theory
is
the
“Trojan
Horse”
theory-‐
that
HIV
can
“hide”
its
receptors
in
order
to
be
disguised
as
something
else
and
cross
the
BBB
(Ghafouri).
Once
the
virus
is
inside
the
brain,
the
infected
human
can
acquire
many
diseases.
One
of
the
most
general
and
prominent
diseases
is
HIV-‐associated
dementia.
Dementia
is
described
as
damages
and
disorders
to
the
brain
and
has
a
wide
variety
of
symptoms.
Dementia
can
be
expressed
in
many
different
ways,
including
cognition,
behavior,
affection,
motor
skills,
and
psychiatric
disorders.
In
AN
UNDERSTANDING
OF
HIV-‐1,
SYMPTOMS,
AND
TREATMENTS
humans
under
60
years,
HIV
is
the
most
common
cause
of
dementia
worldwide
(Ghafouri).
Many
STD’s
can
result
from
HIV
infection
as
well.
Herpes
is
a
virus
that
can
be
very
easily
acquired
once
HIV
has
infected
a
person.
HIVE
stands
for
HIV-‐related
Encephalitis,
and
is
a
common
disease
in
HIV-‐positive
patients.
Encephalitis
is
described
as
an
inflammation
of
the
brain,
and
has
many
serious
symptoms.
HIVE
occurs
when
the
aforementioned
large,
multinucleated
cells
enter
the
brain.
These
giant
structures
act,
virtually,
as
tumors
in
the
brain.
This
is
how
the
swelling
results
(Ghafouri).
Treatment
Unfortunately,
HIV
has
no
direct
cure.
Because
HIV
targets
T-‐cells
and
prevents
the
production
of
antibodies,
the
body
has
no
way
to
stimulate
the
production
of
antibodies.
The
job
of
antibodies
is
to
find
and
recognize
a
virus.
Once
it
has
found
and
recognized
a
virus,
it
can
kill
it
and
recognize
it
in
the
future.
However,
because
HIV
stops
the
production
of
these
antibodies,
the
body
cannot
recognize
HIV
upon
entry
of
the
body.
This
is
why
there
is
no
vaccination
to
encourage
immunity
to
HIV
in
the
body.
One
way
to
treat
HIV
symptoms
is
through
inhibitors.
Inhibitors
are
drugs
that
inhibit
the
reacting
of
certain
processes.
For
example,
the
most
common
inhibitors
are
protease
inhibitors.
Each
HIV
virion
has
a
protease
enzyme.
This
enzyme
is
coded
for
in
the
Gag
polyprotein
and
is
necessary
for
the
virion
to
become
mature
and
have
the
ability
to
harm
cells.
A
protease
inhibitor
will
prevent
protease
AN
UNDERSTANDING
OF
HIV-‐1,
SYMPTOMS,
AND
TREATMENTS
enzymes
from
being
active.
This
treatment
can
help
slow
down
or
stop
HIV,
but
it
cannot
cure
a
person
of
the
virus
(Ghafouri,
Jr.,
J.E.).
Other
such
inhibitors
work
as
well.
There
are
5
FDA-‐approved
inhibitors
on
the
market
today.
All
of
these
can
help,
but
none
can
cure
a
person
of
HIV.
There
are
also
drugs
to
help
treat
the
symptoms
of
HIV.
These
drugs
may
relieve
HIVE
symptoms,
or
help
boost
the
immune
system.
However,
none
of
these
deal
directly
with
the
HIV
virus
(Jr,
J.E.).
Conclusion
Although
there
is
no
immediate
cure
for
HIV,
scientists
are
researching
and
growing
closer
to
a
cure.
Some
scientists
believe
that
a
cure
will
be
found
within
the
decade,
while
others
believe
that
it
may
be
farther
away.
What
we
do
know
is
that
the
more
research
that
is
conducted,
the
closer
we
are
to
finding
a
cure.
And
as
2.6
million
people
are
being
diagnosed
as
“HIV-‐positive”
each
year,
the
need
to
find
a
cure
is
very
real.
Understanding
HIV
is
a
great
way
to
begin
people
along
the
path
of
contributing
to
finding
a
cure
for
the
human
immunodeficiency
virus-‐type
1.
AN
UNDERSTANDING
OF
HIV-‐1,
SYMPTOMS,
AND
TREATMENTS
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