Transcript HIV and immunity

The branch that breaks
Is called rotten, but
Wasn’t there snow on it?
Bartolt Brecht
Haiti after a hurricane
Your body has evolved complex
mechanisms of recognizing “non-self”
and fighting against it
The Immune System is the Third
Line of Defense Against Infection
Antibodies are
Produced by
B Lymphocytes
(B cells to
their friends)
T Lymphocytes
(T cells)
provide
“cell based”
immunity
Cytotoxic (Killer) T Cells
Recognize, Attack and Kill
Virus-Infected Cells
CELLS alive!
The immune system is complex and
we are going to stick to the basics!
i.e. don’t worry about this slide
Let’s start with the role of B cells and
antibodies in the immune response
Some definitions are in order
Antigen
A substance produced by a pathogen
(e.g., protein, complex sugar)
capable of producing an immune response
Some definitions are in order
Antibodies
Protein molecules (immunoglobulins)
produced by B cells
to help eliminate an antigen
and the pathogen that made it
B cells
Make
Antibodies
In response to
antigens
Molecular Biology of the Cell Alberts et al
These
antibodies
can bind to
and “neutralize”
Viruses
or can direct
immune attack
of virus-infected
cells
Molecular Biology of the Cell Alberts et al
Antibodies can also direct
phagocytosis of pathogens
Molecular Biology of the Cell Alberts et al
Let’s focus first on antibodies
Molecular Biology of the Cell Alberts et al
Antibodies are proteins that have evolved
to recognize molecules from pathogens
Molecular Biology of the Cell Alberts et al
These molecules from pathogens
are called Antigens
Let’s use as an example an antibody that recognizes
a protein on the surface of flu (influenza) virus
Antigen
Binding Region
Hypervariable
Region
Heavy
Chain
Light
Chain
Constant Region
courses.washington.edu/medch401/pdf_text/401_07_lect2.ppt
Here is the antibody
Bound to the “antigen” =
influenza hemagglutinin
Hemagglutinin
Human antibody
The antibody recognizes the antigen by a lock-and-key fit
Rotate ~90
Add all atoms
This interaction is VERY specific
Antigen residues
at the interface
= epitope
Epitopes are
typically ~5
Amino acids long
This interaction is VERY specific
hemagglutinin
antibody
Space-filling mode
You can generate antibodies against HIV
like you do against other viruses
Given thousands of pathogens
each of which is constantly evolving
how do we generate
antibodies against each?
Molecular Biology of the Cell Alberts et al
We cannot dedicate all 25,000
genes in the genome
just to make antibodies.
What’s the solution?
Molecular Biology of the Cell Alberts et al
We cannot dedicate all 25,000
genes in the genome
just to make antibodies.
What’s the solution?
Put antibodies together
by a mix-and match approach!
Molecular Biology of the Cell Alberts et al
requires rearranging the DNA
Molecular Biology of the Cell Alberts et al
requires rearranging the DNA
Molecular Biology of the Cell Alberts et al
The result:
an antibody
light chain
Molecular Biology of the Cell Alberts et al
Since there are multiple types of each
gene segment, there are thousands of
possible V-D-J combinations
Each B cell gets a unique combination
Since there are multiple types of each
gene segment, there are thousands of
possible V-D-J combinations
Each B cell gets a unique combination
When a pathogen enters the body
it stimulates proliferation of the
specific B Cells that recognize its Antigens
Once you are exposed to an antigen
your B cells “remember” this
OK, that explains
antibodies and B
cells
but what about us?
CELLS alive!
T cells carry antibody-related proteins
on their plasma membranes
called T cell receptors
Molecular Biology of the Cell Alberts et al
T cell receptors are also assembled
by gene rearrangement,
creating great diversity
Molecular Biology of the Cell Alberts et al
However, T cell receptors
(unlike antibodies) cannot
recognize
antigens from pathogens all by
themselves!!
T Cells Only Recognize Antigen when
it is presented by another cell
Antigen presentation is done by
another family of proteins called
MHC proteins
Viral or bacterial proteins are digested by
Cellular proteases inside the cell and
pieces of them bind the MHC proteins
Molecular Biology of the Cell Alberts et al
This allows T cells to recognize HIV infected cells,
for example, and even internal proteins
like reverse transcriptase can serve as antigens
Molecular Biology of the Cell Alberts et al
Here is where our
old friend CD4
comes into the picture
Molecular Biology of the Cell Alberts et al
Let’s come back to
the immune response
to HIV
People initially mount a strong
immune response
However, this response
ultimately fails for five reasons
However, this response
ultimately fails for five reasons
Integration and latency
Destruction of CD4+ T cells
Inaccessible epitopes
Antigenic escape
Downregulating MHC
We already discussed
two of these
Integration and latency
Destruction of CD4+ T cells
Inaccessible epitopes
Antigenic escape
Downregulating MHC
First, the ability to integrate into the
host genome allows HIV to lurk
undetected
Second, by killing CD4+ Helper T Cells
HIV ultimately disables both
antibody production and
Killer T cells
What about the other three means
HIV uses for immune evasion?
Integration and latency
Destruction of CD4+ T cells
Inaccessible epitopes
Antigenic escape
Downregulating MHC
One way HIV “hides” is by hiding
its most “antigenic” regions
Integration and latency
Destruction of CD4+ T cells
Inaccessible epitopes
Antigenic escape
Downregulating MHC
Most antibodies against the virus
do not block viral entry
Why not?
Regions of gp120 and gp41 key for viral entry
are hidden until after the shape change we
discussed
Natural selection also shapes
the sequence of viral proteins
Integration and latency
Destruction of CD4+ T cells
Inaccessible epitopes
Antigenic escape
Downregulating MHC
Remember that while reverse transcriptase is an amazing
Enzyme, there was something it lacks—which was….
Remember that while reverse transcriptase is an amazing
Enzyme, there was something it lacks—which was….
This has major consequences
RT makes 1 error /10,000 bp
=1 error per replicated genome
And since the viral generation time
Is 2.5 days and one infected cell produces
~1010–1012 new VIRIONS each day…..
Do the numbers!
Do the numbers!
Given that billions of cells are infected per day
There will be thousands of copies of
EVERY possible mutation
Present in the gene pool!!
Remember these sequence based “trees” we used
to study the evolution of different HIV and SIV strains?
We can use the same approach to study the evolution
of a single virus after it infects a single person
HIV rapidly evolves into different “strains”
after the initial infection
Viral diversity in 9 AIDS patients
How could
That happen?
Can you say
Natural selection?
We start with the tremendous amount
Of viral variation caused by RT errors
+
Now we add the selective pressure
Exerted by the immune response
In response to antibody selection
Viruses with mutations
in gp120 and gp41 accumulate
T cell selection selects for changes in
peptide “epitopes” so they no longer
bind to MHC proteins
The result: despite high levels
of anti-HIV antibodies
viral variants escape from the immune response
HIV also has another trick
Integration and latency
Destruction of CD4+ T cells
Inaccessible epitopes
Antigenic escape
Downregulating MHC
Remember our discussion of Long-term non-progressors:
Some are infected with a mutant HIV virus
lacking the accessory gene Nef
What does Nef do?
Nef prevents infected cells
from putting MHC proteins
on their cell surface!
Without MHC proteins
infected cells become
Invisible to T cells
This formidable array of defense mechanisms
Allows HIV to avoid being suppressed by our immune system
Integration and latency
Destruction of CD4+ T cells
Inaccessible epitopes
Antigenic escape
Downregulating MHC