The Virus

This morning, I was listening to National Public Radio.  The radio host was interviewing an artist who was famous for designing sculptures.  What was so interesting about this artist is that his sculptures were so tiny that they could not be viewed with the naked eye.  To see the sculptures, one had to look through a microscope.  Amazingly, this artist had designed a sculpture of the President Obama’s family and the entire family could fit in the eye of a needle!  This report fit in perfectly with the subject matter that I was trying to understand.  Just how big are viruses and how is something as tiny as Human Immunodeficiency Virus (HIV) capable of causing so much destruction?

Artist Willard Wigan creates micro-sculptures that fit in the eye of a needle

Think of a head of a straight pin.  Now think of a virus particle.  One million virus particles can fit on the head of a pin.  Viruses are also much smaller than bacteria.

All cells in nature are capable of being infected by viruses.  All viruses have several things in common.  First, they are incapable of multiplying on their own.  To make new virus particles, they must take over a cell--either a plant cell, animal cell, or a human cell.  Once inside that cell, the virus is capable of taking over the entire cell and directs the cell to perform activities that result in the making of new virus particles.  That is the only thing the virus is concerned with--the making of new virus particles.  Once the virus is done using the cell to make “copies” of new virus, the new viruses leave the cell and the original cell dies.  That’s a virus.  Of course, it’s more complicated than that.  Read on.

The current scientific beliefs about what happens when HIV enters the human body are as follows.  When a person has oral, anal, or vaginal sex, body fluids containing HIV meet the mucosa (linings) of the mouth, anus, or vagina.  In the area of this mucosa is a type of body cell called a dendritic cell.  This dendritic cell looks like a cross between a fried egg and an octopus.  The dendritic cell’s nucleus is in the center (the egg yolk) and the rest of the cell is spread out like an egg white with many fingers or spikes.

Dendritic cell. From Wikipedia, the free encyclopedia

en.wikipedia.org

This dendritic cell’s main duty is to hang around body “entrances” and look for foreign material like viruses, parasites, and bacteria.  Once these dendritic cells find a virus, parasite, or bacteria, it is their duty to pick up this foreign material (called an antigen) and bring it to the attention of the cells of the body’s immune system.  These dendritic cells can be found mainly in body tissues that are in contact with the outside world--the skin, and the inner linings of the nose, mouth, lungs, vagina and rectum.  

The dendritic cell is just hanging out in one of these areas when, all of a sudden, it comes across a particle of HIV.  This wakes up the dendritic cell (it becomes activated).  The dendritic cell attaches one of it’s spiky fingers to the virus and drags it along to the body’s lymphoid organs and tissues.  Scientists are not sure whether the dendritic cell is actually infected or if the dendritic cell is merely dragging the virus along so that it can “show” the virus to the body’s defense system--the immune system.  The dendritic cell uses either the blood stream or “lymphatic vessels” to travel, with it’s captured virus, to the lymphoid organs and tissues.  

The lymphoid organs and tissues is where the body’s defense system, or the immune system, lives. The main organs of the immune system are: the lymph nodes; the tonsils and adenoids in the throat; the thymus, located behind the breastbone; and the spleen.  The bone marrow is also part of the immune system and is the source of all blood cells--red cells to carry oxygen, white cells to fight infection, and platelets to help blood clot.  It is the white cells--also called lymphocytes or leukocytes--that fight HIV and all types of infection, and which are the main concern of this chapter on the HIV virus.  

Nearly everyone knows about lymph nodes.  When these swell or become tender, the person will say, “I have swollen glands”.   There are 100 or so of these lymph nodes in the human body and they are placed along the lymphatic vessels. Many lymph nodes are in clusters in the neck, armpit, and groin.  One blood vessel and one lymphatic vessel leads to each lymph node; however, the only way out of a lymph node is through a lymphatic vessel as there is no blood vessel leading out of the lymph node.  

Back to the HIV particle.  In the lymph node, the dendritic cell presents it’s finding (the evil virus particle) to the two types of white cells, or lymphocytes: T lymphocytes (T cells) and B lymphocytes (B cells).  It’s like the dendritic cell is saying, “Hey, wake up!  Look what I found!  Don’t you think you need to kill this thing?” 

All cells in nature are capable of being infected by viruses.  A virus particle is made up of an outer shell called an envelope, and a core.  The outer shell is made up of protein.  To make it easier to understand, we can compare the virus particle to an apple.  The peel of the apple is the envelope.  Inside the virus particle, surrounding the central core--where all the important stuff is--is the capsid. The capsid’s main function is to protect the inner content of the core.

chm.bris.ac.uk

The viral envelope surface is capable of attaching to only certain types of cells.  It is because of the envelope, that the virus is able to attach to a cell and infect it.  Now think of an apple with 1000 tiny straight pins, with round heads, stuck into the apple, covering the entire surface of the peel. (Yes, it’s a pretty big apple so use your imagination.)  That’s what the virus particle looks like.  The round heads of the straight pins are the attachment area where the virus hooks up to infect certain types of immune system cells--CD4 positive T-lymphocytes (CD4 cells, or T-cells) and CD4 positive macrophages, in the case of HIV.  More about this later.

Beneath the virus envelope/apple peel is the virus core or apple core.  The core contains either RNA or DNA or apple seeds.  In the case of HIV, it’s RNA or ribonucleic acid.  The core of the virus also houses enzymes which are special proteins that will be needed to make successful copies of itself once it takes over a cell. 

From now on, we will concern ourselves only with HIV.  Human immunodeficiency virus outer envelope/apple peel is made up of protein, fat, and sugar.  The envelope is protecting the core which contains RNA, or ribonucleic acid, which  is the genetic information of the cell, as well as special enzymes, or proteins.  

Tiny spikes (remember the straight pins?) stick out of the virus envelope.  These spikes are called glycoproteins--sugar proteins, in other words.  These spikes look like a stem with three bulbs on the top.  The stem is called glycoprotein 41 (GP 41) and the bulbs on the top are called glycoprotein 120 (GP 120).  These sugar protein spikes form a substance that is capable of attaching to only certain types of human cells.  They can only attach to human cells with CD4 “receptors” on them.

Drawing of cell with major parts labeled  sahsrojas.pbworks.com

So, after hitchhiking a ride on the dendritic cell’s spikes, HIV shows up in the lymph node where the T-lymphocytes (T-cells) and B-lymphocytes (B-cells) are lounging.  The lymphocytes “see” the virus and become activated, or wake up.

Now, the dendritic cell is supposed to be doing the body a favor--after all, it’s presenting the invader HIV to the lymphocytes that are supposed to get rid of the invader.    But, as you will soon see, things do not go well for the human body after it meets this strong virus.   

The virus is soon surrounded by the body’s immune system defense team--T-cells, B-cells, and macrophages.  These cells swarm around the invading HIV and get a good look at this new enemy.  

Because of the receptors on the virus envelope (apple peel with straight pins sticking out), HIV is capable of attaching itself to CD4 positive T-lymphocytes.  From now on, we will refer to these as CD4 T-cells.  HIV is also capable of infecting other types of cells--dendritic cells and macrophages also have the same type of CD4 positive receptors on them.  However, it is the CD4 T-cell that is the immune system defender that is destroyed in the fight between the body’s immune system and HIV.  HIV nearly always wins the fight.  Here are the steps of HIV infection of the CD4 T-cell.

Step 1: Binding and Fusion

The sugar protein, named glycoprotein or gp 120, rounded bulb on the stem of the end of the sugar protein spike--gp 41--fits perfectly into the CD4 positive T-lymphocyte receptor.  It’s just like a key fitting into a lock.   The CD4 T-cells also have tiny spikes sticking out of their outer shells.  These spikes are called CD4 receptors and the tips of the spikes fit perfectly with the rounded bulbs of the virus.  These CD4 receptors are made of protein.  

Once the HIV sugar protein bulb attaches to the CD4 T-cell receptor, it must also reach and attach to two other types of receptors--these other types of receptors are called CCR5 and CXCR4.  These receptors are shaped differently than the CD4 receptors on the the outside of the CD4 T-Cell. These receptors look a bit like miniature football goal posts.  

Once HIV binds to the CD4 T-cell receptor, changes occur in the sugar protein bulb (gp 120) that leads to the viruses ability to make contact and bind to the co-receptors CCR5 and CXCR4.   In other words, the gp 120 sugar melts into the CD4 receptor and then the melting sugar protein gp 120 can then melt into either the CCR5 or CXCR4 co-receptor.  

Remember, the sugar protein bulb, gp 120, is attached to a stem, made up of sugar protein molecules called glycoprotein, or gp, 41.  Once the bulb attaches to the CD4 receptor, the sugar protein gp 41 becomes exposed and it, in turn, melts into the CD4 T-cell outer shell.  Now we have both the HIV and the CD4 T-cell fused together.  Binding and fusion are complete.

Step 2: Reverse Transcription

Remember when I told you that the core of the virus contained enzymes, or proteins--the “apple seeds”?  These enzymes/seeds are brought into the infected CD4 T-cell when the entire contents of the virus is emptied inside the T-cell.  One of these enzymes is called reverse transcriptase.  

Reverse transcriptase is capable of reading the blueprint of how to copy the virus and then transcribing the HIV one-stranded ribonuceic acid (RNA) into the two-stranded deoxyribonucleic acid (DNA).  If the virus did not carry this enzyme into the infected cell, it would not be able to make copies of itself.  

The interesting thing is that the enzyme reverse transcriptase sometimes has trouble reading the steps necessary to make new DNA and it makes mistakes.  So while many of the new virus particles being made look exactly alike, others have some slight defects, or variations in either their outer shell or their enzymes.  Over time, the new virus particles outer shells are constantly changing.  

Step 3: Integration

The third step is integration.  Now that reverse transcriptase has changed single-stranded RNA into double-stranded DNA--remember the double helix “twisted ladder”  we learned about in high school--this DNA strand must be inserted, or “integrated” into the DNA of the CD4 T-cell.  The HIV DNA strand enters the T-cell’s nucleus (“brain” of T-cell) and out pops another HIV enzyme called integrase.  Integrase was brought into the CD4 T-cell along with the enzyme we learned about earlier--reverse transcriptase.

Integrase is able to insert the new virus DNA right into the normal DNA present in the nucleus of the CD4 T-cell.  To picture this step in your mind, think of the twisted DNA ladder cut into 3 sections--the bottom of the ladder, the middle of the ladder, and the top of the ladder.  The virus DNA is now inserted into the broken out sections of the ladder and becomes one with the ladder.  This new section of the DNA ladder is called a provirus.  

Now that the provirus is there in the nucleus of the CD4 T-cell, it may remain in an inactive or sleeping state for years.  If it remains in this inactive state, either very few or no virus will be made from this particular CD4 T-cell.  

Step 4: Transcription

If the CD4 T-cell receives a signal to become active, or wake up, the phase of transcription begins.  Transcription means to copy, or duplicate, or reproduce.  Another enzyme, called RNA polymerase (that’s three enzymes so far counting reverse transcriptase and integrase) makes copies of the HIV DNA.  This RNA polymerase also makes short strands of “messenger” RNA.  Messenger RNA is then used as a pattern to make long strands of virus proteins.  These long strands are made up of reverse transcriptase, protease, and integrase.  

Step 5: Assembly

These long strands of virus proteins are unable to be packaged into a new virus until the strands are cut.  Think of a hot dog factory.  Long strands of hot dogs several feet long must be cut in a way so that 10 hot dogs will fit in a package.  You sure don’t want to bring home a big package of uncut hot dogs.  It would be like trying to fit a garden hose into your grocery bag.  

In this step, another enzyme, protease, (that’s four enzymes now--remember reverse transcriptase, integrase, and RNA polymerase that was brought into the cell with the other enzymes?) goes to work.  Protease works like a scissors to cut the long strands of virus protein (or chicken, pork, beef or turkey) into smaller single proteins (or hot dogs). 

These separated proteins along with the viral RNA are now packaged or bundled together in a new virus package and ready to be released from the CD4 T-cell.  The new virus package moves toward the outer shell of the CD4 T-cell and pushes through the T-cell membrane (remember the apple peel).  When the virus breaks through the T-cell wall/apple peel, it brings along a little bit of the T-cell’s protein outer shell/apple peel with it--the virus particle then uses this protein piece to enter another CD4 T-cell.  

microvirology.blogspot.com

The new free virus particles are often exactly like the original virus; however, remember that mistakes were made in the reading of the directions or “blueprint” to make new virus.  These mistakes cause some viral particles to be different from other particles that were made in the same T-cell.  

Step 6: Budding

In this last step, the new virus pushes itself out of the host cell--in other words, the virus "buds" out of the cell.  As the virus pushes itself out of the host cell, it takes a bit of the host cell's covering (remember the capsid or envelope) out with it.  If you recall, the envelope acts as a cover and contains protein and sugar (glycoprotein).  The virus will use these glycoproteins to bind to other CD4 cells.  The new virus goes looking for a new CD4 cell and the process begins again.

A new HIV virus pushes out, or "buds" from the host cell.