Human immunodeficiency virus (HIV) - life cycle, pathophysiology, investigations, diagnosis and AIDS

Armando Hasudungan
Gives instructions to
  The medical students in his
  video Lecture
 
https://youtu.be/KvvECcXnDks

The human immunodeficiency virus or hiv
is a retrovirus that infects cd4-t
lymphocytes among many other cells
leading to the destruction of these cd4
t cells and thereby impairing
cell-mediated immunity and increases the
risk of cancer and opportunistic
infections
hiv-1 is the most common species
worldwide hiv-2 is restricted almost
completely to west africa
the structure of the virus is that it's
icosahedral meaning a polyhedron with 20
faces
with a conical capsid a protein shell of
a virus
the capsid contains two strands of rna
the capsid also contains two enzymes
essential for hiv replication
the integrase
and the reverse transcriptase
the capsid also contains two strands of
rna
which holds the hiv's genetic material
hiv's rna is made up of nine genes
which contain all the instructions to
make new viruses
three of these genes gag pole and env
provide this instructions to make
proteins that will form the new virus
particles consisting of the core
proteins the enzymes and the envelope
glycoprotein
the outer shell of the virus is called
the envelope and is made up of lipid
layers which are covered in spikes of
the glycoproteins i mentioned
here you can see glycoproteins gp41 and
gp120
these glycoproteins allow the hiv to
lock
onto the cd4 receptors
on the cd4 t cells
and enter the cell
so let's take a look at how the virus
does this
and also learn about the life cycle of
the hiv
virus by looking at some key steps
the hiv virus gains entry into the cell
you know following sexual intercourse
which is a major cause
once the virus is within the body they
will infect immune cells which have cd4
receptors on the surface
the main cells here that contain the cd4
receptors are the cd4-t lymphocytes
when hiv makes contact with a cd4 cell
the gp120 spike on the surface of the
hiv
lock onto the cd4 receptor
and another co-receptor
ccr 5 or cxc
this first step is called attachment and
this step essentially will result in the
fusion of the viral membrane with the
cell membrane
the second step
of the life cycle is fusion
the process of fusion allows the hiv
capsid to enter the cd4 cell
the gp41 protein is used to fuse the hiv
envelope with the cell wall
the capsid releases the viral rna
the reverse transcriptase and the
integrase as well
the third step is reverse transcription
here the hiv uses its reverse
transcriptase enzyme to convert the rna
it contains into a pro viral dna inside
the cell
so now you have the double stranded blue
dna which is the viral dna
once this is done the next step is
integration
the hiv's integrase enzyme attaches
itself to the end of the proviral dna
strands
and carries the viral dna into the cell
nucleus
once the pro-viral dna enters the cell
nucleus it binds to the host dna
and then the hiv dna strand is inserted
into the host cell dna
after the pro viral dna is integrated
into the dna of the host hiv either
continues to use the body's own cell
machinery to replicate
or
it will remain dormant within the
cellular dna
this stage is called latency and the
cell is described as latently infected
next step is transcription
when the cell becomes active the hiv
uses the host enzyme rna polymerase to
read the hiv gene to make messenger rna
and genomic viral rna
this is called transcription
focusing on the mrna
the next step is translation
the messenger rna provides the
instructions for making new viral
proteins including structural proteins
and the viral enzymes
the viral genomic rna
and these viral proteins will prepare to
be assembled
in assembly and release what happens is
the enzymes and the hiv rna will begin
to assemble into the new
viruses at the cell wall
after the new virus is assembled it must
leave the cell by pushing through the
cell wall
the virus must take lipids the fat from
the cell wall to make the surface
glycoproteins including the gp120 and
the gp41
shortly after the virus is released from
the cell
the viral protease actually cleaves some
of the precursor proteins which will
help form the mature capsid as we know
it
this makes the virus mature and
infectious
the cycle can continue
this hiv virus can then
infect other people or infect other
cells
the root of transmission of the hiv
virus is via sexual intercourse majority
of cases
it can also be transmitted parentally
so through the blood or vertical
transmission from mother to baby
so we looked at the life cycle of hiv
and how it infects a cd4 t cell
and how it also replicates within these
cells
but what does the body actually do when
hiv infects the cd4 t cell
how does the body's immune system you
know respond to the hiv infection
next we will focus on the
pathophysiology and the natural history
and progression of hiv
so what happens is you have these
dendritic cells which are the first to
recognize a hiv virus
and present them to the immune system to
mount an immune response
what they do is that they engulf the
virus process them and then present them
on their cell surface via mhc class ii
they then travel to the lymph nodes and
what's called the galt
gastric associated lymphoid tissue
carrying this viral particle where they
activate or stimulate cd4 t lymphocytes
the cd4 t cell will then activate b
cells and plasma cells to produce
antibodies against hiv
cd4 t cells will also activate cd8 t
cells also known as the cytotoxic t
cells
during this time the hiv continues to
infect cells
the only cells that can be infected by
the hiv virus are those that have the
cd4 receptor
these cells as mentioned are the
monocytes macrophages dendritic cells
microglial cells
but more specifically the
t lymphocytes
the greatest concentration of these
cells is in the gut associated lymphoid
tissue and lymph nodes
as the virus replicates within the cd40
lymphocytes it kills the cells and
spreads again
about three to four weeks after the
initial infection the hiv viral load
increases
and is detected
the hiv p24 antigen is also detectable
the hiv antibody is detectable in weeks
two to four roughly
and once this occurs this is called
seroconversion
when you get serial conversion where you
get presence of the antibodies as well
as you get this increase in the viral
load this causes what's called
seroconversion sickness or
seroconversion illness which manifests
as symptoms of acute hiv infection
interestingly these symptoms are very
non-specific and they include fevers
fatigue myalgia rash headache
pharyngitis and lymph lymphadenopathy
really symptoms of a standard viral
infection which vary and are
self-limiting and go away by up to two
weeks
so in summary the acute infection which
are in the first
weeks
causes an increase in viral load of the
hiv virus
you get the presence of hiv p24 antigen
you get presence of the antibodies
against hiv which actually begin to
appear between weeks 2 and 4
and you also get the cd
8 t cell being activated
in this period you also get
seroconversion illness which can be very
mild and even go unnoticed
only a small proportion of the infected
cd4 t lymphocytes allow the virus to
replicate
and you know get released again
these infected t lymphocytes usually
express mhc class 1 molecules
with the viral antigen which essentially
tags them so that they are recognized as
an infected cell
which allows the cytotoxic
cd8 t lymphocyte to destroy them
controlling the infection
unfortunately as the hiv infects more
and more cd4 t lymphocytes
they are able to form mutations in their
genetic material which allow them to
evade the immune system hide from the
immune system and they do this by down
regulating the mhc class one expression
essentially making it unrecognizable by
the immune system
hiv hides within cd4
cells where they remain dormant
hiv infection will not really cause
further illness
for
some years
and this period is known as the
asymptomatic phase which is roughly
about 10 years
hiv infected c4
remains dormant and slowly reduces the
cd4
t cell count
the viral load of the hiv remains steady
because the cd8 t cell the cytotoxic t
cell keeps their numbers in circulation
at bay
in the asymptomatic phase the viral load
and hiv antibodies are detectable
and remember the cd4 count will slowly
go down here
during the asymptomatic phase cd4 t cell
count and viral load tests can monitor
the progression of the hiv disease
looking at the two stages we have
learned so far using this graph with
time on the x-axis
we can see the viral load will increase
in the first few weeks during the acute
infection
but then drop and remain relatively
stable because the immune cells such as
the cd8 cytotoxic t cell
keeps it in check for around 10 years
this is the asymptomatic phase
until eventually after about 10 years if
left untreated the viral load will begin
to increase
looking at the cd4 cell count
from day one of infection the cd4 cell
count slowly dwindles
because as we have learned the hiv
infects cd4
cells such as the cd4 t cells and slowly
causes them to die during the
asymptomatic phase
here you have seroconversion illness
where the body begins producing
antibodies
the b cells plasma cells begin producing
antibodies by weeks 2 to 4 of the
initial infection
the cd8 t cells are created to destroy
the hiv infected cells
hiv levels begin to fall in the blood
because of this
and after a few weeks to months
the viral load and cd4 levels will
stabilize at a level known as the set
point
hiv gradually reduces the number of cd4
t cells in the body until the cd4 cell
count falls below 200 cells
per millimeters cubed
when the t cell count is this low they
are at risk of developing
aids also known as
acquired immunodeficiency syndrome
aids is defined by a cd4 cell count of
less than 200 cells per millimeters
cubed
or if they develop an aids related
illness
when someone has aids their risk of
infection increases
their risk of malignancy increases as
well as other comorbidities
aids defining infections are very
important
once the cd4 cell count drops below 200
you are likely to develop certain
infections
some infections develop at a much lower
c4 cell count
people with a cd4 cell count below 500
also develop aids
defining illnesses including carposi
sarcoma
invasive cervical cancer and
tuberculosis
i have a separate video that goes into a
lot of detail into the aids defining
illnesses please have a look
let's talk about screening and diagnosis
of hiv
so what you do is if you suspect someone
has hiv you can do what's called a
combination assay which is
basically looking at the hiv antibody as
well as the presence of the p24 antigen
if positive you can do what's called the
antibody differentiation essay which
essentially will tell you
which type of hiv
the person has either hiv 1 or hiv 2.
if the combination sa is negative
meaning there's no hiv antibodies
present you can
check the hiv viral load by looking at
the hiv rna nucleic acid amplification
test or naat
if the viral load is positive you can
also diagnose hiv because they have
viruses in the blood
if the viral load is negative then this
person does not have hiv at that
particular time
other investigations for hiv once
confirmed
firstly you know you always want to get
the viral load
by looking at the hiv rna
and this is to look at a baseline
also performing t cell subsets to
establish a cd4 cell count
you can also perform viral resistant
testing at baseline
for blood count
euc's lft glucose
fasting lipids
check for a latent tb performing a
tuberculin skin test and interferon
gamma release assay
hepatitis viral serology serology for
syphilis and other sexual transmitting
infections
serology for toxoplasmosis as well as
cervical pap smear
the management of hiv just briefly
education is very important
again
the infection is treatable and a person
can have a normal life
educate them on safe sex condoms
as well as educating them on the
complications of the disease and the
medications
treatment involves antiretroviral
therapy
and it's important to treat the person
right away and it is lifelong treatment
monitor for complications specifically
opportunistic infections that may arise
aids defining illnesses as well as
medication side effects
i will have a separate video that will
focus on the pharmacology of hiv and
i'll put the link at the end of the
video
so in summary hiv is a virus that
essentially infects cd4
cells such as your cd4 t cells
and what they do here is that they
replicate within the cells or they can
remain dormant
what they will do over time is that they
will deplete the cd4 count and when the
cd4 count is depleted it will increase
the risk of opportunistic infections
treating person with hiv early with
antiretroviral therapy is important
thank you for watching