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.

Primary HIV Infection

The earliest stage of HIV infection is called primary HIV infection, but it may also be called: acute HIV infection; HIV "seroconversion" illlness; acute retroviral illness; or just new HIV infection.  “Sero” means blood and “conversion” means changing as the blood changes over from HIV negative to HIV positive. HIV is a retrovirus--more about that later.

The person with primary HIV infection will usually feel sick 1-4 weeks after getting infected.  In most cases, the person may feel ill, but won't relate their feeling bad to their recent risky behavior.   

Primary HIV infection is the earliest stage of the infection, from the time the virus first enters the body to the time the body makes antibodies to fight against HIV.  

What are the symptoms of primary HIV infection?

During the time immediately after HIV-infected blood enters the body--either through the blood, the vagina, the rectum, or the mouth--until the body develops antibodies, the person may feel ill.  Somewhere around 50-90% of newly-infected people will experience a sudden illness.  At this time, high levels of virus (more than 100,000 copies or particles) are running rampant through the bloodstream, but the body has not yet had enough time to mount a defense against this new invader. 

Here are the symptoms of primary HIV infection:

Fever; red raised rash; fatigue (tiredness); sore throat; swollen glands; itching; painful muscles or joints; sores in the mouth; headache; pain behind the eyes; meningitis (inflammation of the covering of the brain); myelitis (inflammation of nerves); loss of appetite

These symptoms may be so slight as to almost go unnoticed or may make the person feel quite ill.  Unfortunately, if the person does go to a medical provider, they will probably be misdiagnosed--perhaps told they have the flu, or mononucleosis, or some other viral infection.  That’s because primary HIV infection symptoms are the same as these other common illnesses.

In some cases, the medical provider will suspect primary HIV infection.  One important thing to remember is that the HIV ELISA antibody test will be negative until an average of around 25 days after getting infected.  So even if a HIV ELISA test is done, it may come back as negative.  Sometimes the HIV ELISA test results will be "indeterminate".  This just means not negative and not positive.  The HIV test will need to be repeated in a few weeks.  

The test to find out if someone has primary HIV infection is the HIV viral load test (or HIV-1  RNA).  This test measures the actual amount of HIV virus in your blood.  Unlike the ELISA HIV antibody test, which measures HIV antibodies in the blood, this test is measuring the actual virus particles in the blood. 

If someone has just gotten infected with HIV, the HIV viral load will be very high, or more than 100,000 particles (copies) in 1/5 teaspoon of blood.   During primary HIV infection, if the HIV viral load is less than 100,000, that person is not considered to be HIV positive. 

Consider the following example:

Bob goes to an urgent care center with around 2 days of a sore throat,  fever, and muscle aches.  Marie,  the physician assistant on duty, thinks Bob has the flu, which is going around right now.  She asks Bob about any recent unprotected sex with a new partner.  At first, Bob is annoyed by what he thinks is a stupid question, but then Marie tells Bob why she wants to know the answer.  Bob calms down and says that about two weeks ago, he went to a bar and went home with another man.  They had sex just that one time and the man refused to wear a condom.  Marie is worried that Bob may have a new HIV infection and asks Bob for permission to run an HIV test.  Bob’s HIV ELISA test is negative. Marie is really worried about Bob, so she sends his blood for an HIV viral load test.  The next day, Bob’s HIV viral load results show 250,000 particles (copies) of HIV.  Marie calls Bob and asks him to come to the clinic because she must talk to him in person.  What’s the bad news?  Bob has primary HIV infection.  Is there any good news here?  Yes, actually there is.  Catching HIV in the earliest stages is much better than going for years not knowing you have the infection.  Early diagnosis means that Bob will have a chance to treat his HIV before he gets sick.
 

Since most people don't know when they have primary HIV infection, these people find out they have HIV quite accidently, perhaps 10 to 20 years after infection, when they develop an illness that points to the diagnosis.  This illness is called an opportunistic infection, abbreviated OI.  That's why all sexually active people (or those who inject street drugs) should get an HIV test once a year. 

 

Resistance and Resistance Tests

Resistance is a very important term for you to understand, because it will come up again and again when you discuss your HIV medicines with your health care team.  Resistance means that your particular virus will not respond to certain HIV medicines, called antiviral drugs.  Think anti (means against) and viral--put together, means against the virus.  Health care providers will abbreviate this term to ARV (anti-retro-viral) drugs.  An older term you may still hear, is HAART, or highly active anti-retroviral therapy, but this term has led to confusion in those who thought the word meant “heart”.  So, if you have resistance, your virus may not respond to some HIV medications.

If you remember from an earlier chapter when I talked about viral load, HIV medicines (ARV medicines) are supposed to suppress the virus to undetectable levels (less than 48 or 50).  If the medicines are unable to do this, and the virus is able to make more virus copies of itself, despite the medicine, you may have resistance. 

Resistance is all about the HIV drugs.  Before the HIV drugs came upon the scene, there was no resistance.  

Resistance is dependent on the level of drug in your body, which exerts pressure on the virus, and “host factors”...  Also, those with lower CD4 counts and higher viral loads, before starting the HIV medicine, are more likely to get resistance.

The reason you have resistance is because your particular virus has changed (or morphed, or mutated, whatever you want to call it) into a virus that is able to “get around” the medicines you are giving it. You can take these medicines until the cows come home, and they will never work.   Here’s the kicker, however.  You may even have resistance before you ever even start the HIV medicines.

How is this possible to get resistance if I’ve never even been on HIV medicine? you ask.  Because, it depends on the particular virus that was given to you by the person who gave you your HIV infection.  If the person who infected you with HIV had resistant HIV, you may have it, too.  It’s very unfair, but true.   Nowadays, HIV care providers are seeing more and more resistance in patients who have never before taken HIV medicines.  Today, in the United States, nearly one out of four newly diagnosed HIV positive people will have drug resistance.  This rate is increasing every year.

How do we know you have resistance?  Before your first visit to the HIV clinic, your medical provider will test your particular virus for resistance.   The resistance test that is done on newly diagnosed HIV positive patients is called a genotype test.  There are two other types of tests, a phenotype test, which is used for those who have been on lots of different HIV drug regimens and/or have lots of genotype HIV mutations; and a Virco-type test.  These last two tests are not used as much as the genotype test, so we will spend more time talking about the genotype test.

Genotype Test

All newly diagnosed HIV positive patients, including pregnant women, should have a genotype test done, immediately upon HIV diagnosis.  If a long period then goes by without taking HIV medicines, like a year or so, another genotype should be done before you start the HIV medicine.  Another test is needed just in case, during the year you did not take HIV medicine, you obtained another strain of HIV from another sex  or needle-sharing partner (hopefully not, but this does happen, so please use condoms and don’t share drug needles).  

The genotype test actually looks at the genetic make-up of your virus.  If the virus is mutating, or changing, these changes can be detected.  However, there must be enough mutated virus to measure.  If the mutated virus makes up less than 20% of your total virus, it can’t be measured.  Here is an example of a genotype test.

HIV-1 genotypic mutations detected and corresponding level of resistance.medscape.org 

A genotype mutation is reported as a letter, and a number, and another letter.  For instance, a very common genotype mutation is the Epivir/Emtriva mutation, M184V.  The M184 refers to the position of the amino acid and the V means that there is a mutation at that position.  

The choice of medicine you start will be based on the results of this genotype test and your HIV medicine history.  Some patients have heard of the very popular HIV drug called Atripla, a 3-drugs-in-one combination that is taken just one pill at night before going to bed. 

Everyone loves this idea of just one pill to fight the virus.  However, based on your genotype results, you may not be able to take this combination pill if you already have resistance to one or more of the drugs in the pill.  The genotype test results are needed before you know if that particular pill can be used on your particular virus.  Otherwise, you may waste a few months taking the Atripla, just to find out that this medicine is not working, and may never work.  Also, consider the money cost of taking a drug that is not working.  It’s like throwing good money away for no benefit. 

In rare cases, you may know the HIV medication history of the patient that gave you HIV.  This information can be also be used, along with your genotype results, to figure out which HIV medicines you should take.  

Resistance is something that lasts for years, and no one knows if eventually it goes away.  Also, sometimes you can have resistance but the genotype test won’t find the resistance.  That’s why your provider must use the genotype results plus your past HIV medicine history to figure out what to start you on now.  Here are two examples of how the genotype is used to figure out what HIV medicines you should take.  

Example 1Vivian once took an HIV drug called Viracept.  She took this drug on and off, for years, as part of a 3-drug “cocktail” to treat her HIV.  Every month, she ran out of her medicines and half the time, she forgot to take her evening doses of medicines.  She has now been off her cocktail for a year now, and comes into the clinic today wishing to “turn over a new leaf and take my medicine right.”  Her CD4 count is 10 and her viral load is more than 2,000,0000.   Her current genotype results show no resistance.  She liked her old regimen and wants to restart the same drugs she took in the past.   Do you think that Vivian can restart the Viracept and the other two HIV drugs she used to take?  The medicines should work, since Vivian’s genotype doesn’t show resistance to any HIV medicine.  Right?  Wrong.  Vivian’s medical provider may assume, based on Vivian’s history, that she does have resistance to the Viracept, even though the genotype doesn’t show the resistance.  That’s because the virus mutations may only show up when Vivian is actually taking the drugs. Because Vivian only has a CD4 of 10, she doesn’t have time to play around waiting to see if the drugs she’s taking will work.  So, her health care provider will most likely avoid two or even three of the past drugs Vivian use to take. 

Example 2Lee once took the drug Viracept as part of a 3-drug cocktail, from 2001 to 2007.  He was then thrown in jail for 9 months, “through no fault of my own,” he tells his doctor upon meeting him in the clinic the first time.  Lee took his HIV medicine religiously, and never ran out of the medicines, even though he didn’t like having to take the medicine twice a day.  Lee’s CD4 is 300 and his viral load is 80,000.  He prefers to start a new HIV regimen that is taken just once a day.  Lee’s current genotype shows that he has no resistance to any HIV drug.  What should Lee’s medical provider do?  Start Lee on new medicine or put Lee back on his old medicine?  Does it matter?  Yes, it does matter. What Lee’s doctor will probably do is restart the old HIV medicines Lee took in the past, see if Lee’s viral load becomes undetectable on the medicine (less than 48 or 50), and then change Lee to a once-a-day regimen.  This is so his doctor can figure out if Lee really does not have resistance.  This is nice to know in case his doctor wants to use the drug Viracept in the future.  It’s good to have lots of options when it comes to HIV medicine.So, you can see from the above two examples, how important the genotype resistance test is.  

Here is another instance when a genotype will be needed.  Supposing you are already taking HIV medicines, and your CD4 has risen slightly, but you are unable to achieve an undetectable viral load.  You have been on your 3-drug cocktail for 6 months now.   If your HIV viral load is approximately 1000, your health care provider may order a genotype to figure out if you have resistance to the drugs you are taking.  If your viral load is less than around 1000, a genotype will not be able to be done and you will just have to wait until either you become undetectable or your viral load goes up. 

Please be honest with your medical provider--if you are not taking the medicines right, that’s the reason that the medicines aren’t working, not resistance.   

The genotype test gives the best results when a person is actually taking the medicines.  However, you can still get accurate genotype test results within 4 weeks of stopping your particular HIV medicines.  If more than 4 weeks go by, your HIV virus may  go back to what is called “wild-type” virus, the type of virus it once was before changing in response to low levels of medicine.  

Notice I said low levels of medicine.  That’s because high levels of medicine in your body are what is needed to keep the virus from mutating or changing.  High levels of medication actually keep the virus suppressed so much that the virus can’t make more copies of itself.  That’s what you want.  Total suppression.  And the only way to get this is by taking the medicine faithfully, every day--twice a day, if necessary--without missing doses.  

Phenotype Testing

If you have lots of genotype mutations and have been on lots of HIV medicine in the past, your medical provider will probably want a phenotype test in addition to the genotype test.  The phenotype test may be ordered along with the genotype, or a PhenoSense test, a combined genotype and phenotype, may be ordered.

While the genotype looks at genetic mutations, the phenotype test looks at the amount and type of HIV drug that is needed in order to stop the virus from multiplying.  In other words, the test can measure the virus’s ability to multiply when exposed to different types and different levels of drug.  Can your virus still multiply when exposed to more and more of a particular drug?  Which drug will work better?

This test is similar to the “culture and sensitivity” test that your medical provider will order if you have a urinary tract infection.  First, the lab person finds out which bacteria is causing your urinary infection, then he/she puts the bacteria in a culture dish, then puts different medicines and different concentrations of those medicines on top of the bacteria.  Then, the lab person looks to see which medicine worked in eliminating the bacteria.  Some drugs may not get rid of the bacteria at all (the bacteria is resistant), other drugs will work a little bit (intermediate resistance), and some drugs will be very likely to kill the particular bacteria the patient has in their urine (the bacteria is susceptible).  The medical provider will give the patient the best drug for that particular infection.

The good thing about the phenotype test is that it can tell you if a drug will be partially effective against your virus.  This is important, especially if you have taken lots of drugs in the past and have lots of resistance and limited options.  You may want to take the drug that works a little bit, rather than not have that option on the table at all.  On the other hand, the phenotype test will tell you if a particular drug will not work at all.  

Another advantage of the phenotype is that it is useful for the new HIV drugs and for persons infected with rare types of HIV. (The genotype tells you what “type” of HIV you have).  Like the genotype test, the test should be done while you are taking HIV medicines or within 4 weeks of stopping your medicine.  

One interesting thing about the phenotype test is that your particular virus will be compared to the virus of other HIV positive people who have “wild-type” virus, or virus that has never been exposed to HIV medicine. This wild-type virus is susceptible to all the medications--there is no resistance. 

Like the genotype, the phenotype can’t tell you very much if your resistant virus is less than 10 to 20% of your total virus, or if you have been off medications for more than one month or so.  The phenotype is also more expensive than the genotype. 

Virco-type Test

This is an interesting type of resistance testing that predicts your phenotype by first analyzing your virus’s genetic mutations (your genotype) and comparing those results to data they have gleaned from other HIV positive people in their genotype-phenotype data base.  

What is Cross-Resistance?

Your medical provider may tell you that you have cross-resistance.  Cross resistance means that not only do you have resistance to one drug in a class of drugs, but, because of that type of resistance, you will not be susceptible to other drugs in the same class.  For instance, Viramune (nevirapine) and Sustiva (Efavirenz) are in the same class of drugs, called NNRTIs, or non-nucleoside reverse transcriptase inhibitors.  (Whew, what a mouthful.  It’s not important to remember the names of the different classes, but only to know that there are different classes of medicines and sometimes, if you are resistant to one drug in a certain class, you might be resistant to all the drugs in the class).  If you have resistance to Nevirapine, you will probably have resistance to Sustiva and that takes this drug off the table in terms of medicines that you will be able to take to treat your virus.  Not only that, there is another medicine in this class called Rescriptor, or Delavardine.  No one uses this medicine much anymore, but if you have cross-resistance to one medicine in the class, you won’t be able to use this medicine either.  You can see how this can be serious stuff, because you now have an entire class of medicines, that won’t work for you. 

Your medical provider will know which drugs make it more likely that you will get cross-resistance.  At any rate, the way to prevent cross-resistance, is to take your medicine without missing doses.  

Figuring out which drug you should take is not easy.  This decision should be made by you and your medical provider and this medical provider should, in nearly all cases, be an HIV specialist.  In addition, some cases are so complex, that the skills of a clinical pharmacology HIV expert is needed. 

 

Your medical provider may also use the internet resources of the Stanford HIV Drug Resistance Database and the Los Alamos National Laboratory HIV Drug Resistance Database to help choose the particular drug regimen which will be effective against your particular virus.  These resources are constantly being evaluated and updated by HIV experts.  

History of the HIV Epidemic

In this section, I will address the question, “What came first: the chicken or the egg?  If HIV is the chicken, and AIDS is the egg, the egg came before the chicken.  Yes, AIDS was identified several years before it was known that HIV was the cause of AIDS.  

In late 1980 and 1981, medical experts in three United States cities--Los Angeles, San Francisco, and New York City described a rare crop of pneumonia cases in previously healthy young homosexual men in the three cities.  A rare cancer, called Kaposi’s Sarcoma, was also noticed at the same time in the same group of men.  The medical experts noticed that the men all had one important thing in common; they had low levels of a type of white blood cell called CD4 positive T-lymphocytes (also called CD4 cells or T-cells).  

HIV officially became known to medical experts and the public on June 5, 1981.  On that date, the United States Centers for Disease Control and Prevention (CDC) published a warning about this unusual type of pneumonia affecting young gay males in Los Angeles, California.  The pneumonia was pneumocystis carinii (jirovecii) pneumonia (PCP) and was extremely rare in young healthy males.  The cases of PCP along with the low CD4 counts in these previously healthy men gave experts the information that the men had an acquired immune system problem, rather than an immune system problem they were born with.   The Associated Press and the LA Times reported this news on the same day.  One month later, on July 4, 1981, the CDC reported on the unusual type of cancer hitting the young gay males.   

By 1982, the CDC pulled enough information together from the cluster of cases to develop a definition of the new disease and put forth the words: Acquired Immune Deficiency Syndrome (AIDS).  They looked at the population of people who were getting the disease, the signs and symptoms of the new disease, and the similarities in those people’s immune system.  By this time, they knew that AIDS was being spread sexually and through contaminated blood.  They identified four groups of people who were getting AIDS: gay men, heterosexual intravenous drug users, immigrants from Haiti, and those with the blood problem, hemophilia (hemophiliacs require blood transfusions).  

Medical experts began to look hard at these four groups of people and noted these signs and symptoms were occurring: swollen lymph nodes on various parts of the body, thrush (white patches in the mouth), herpes zoster (shingles), low platelets (used for blood clotting), and weight loss. These people were noted to have low CD4 cells.   Scientists later gave these signs and symptoms a name: AIDS-Related Complex, or ARC.  Scientists believed that there some healthy people could “carry” whatever was causing AIDS, and have no symptoms at all.  

On October 18, 1982, ABC World News Tonight reported that AIDS was spreading to many US states and that the cause of AIDS was unknown.  Media and some scientists began to use the term “GRID” or “gay-related immune deficiency,” believing that this disease affected only gay males.  In San Francisco and New York City, groups began to form to address the AIDS crisis.  Congress held hearings to find out more about this strange new epidemic.  

In 1983, AIDS was deemed a reportable disease in the US and the US Public Health Service presented recommendations of how to avoid spreading the disease.  The CDC tried to squash public fear that AIDS could be spread by “casual contact” like hugging, kissing, and sharing eating utensils and urged people not to discriminate against those who had AIDS.  The CDC now recognized a new group that was getting AIDS--female sex partners of males who had AIDS.  National organizations began to form to address the AIDS crisis.  The Orphan Drug Act, was passed, giving extra money to drug companies to quickly develop new drugs for rare diseases.  A doctor in France, Luc Monagnier, discovered the virus that caused AIDS--he named it lymphadenopathy-associated virus (LAV). The name was later changed to human immunodeficiency virus (HIV).  The first AIDS candlelight memorial was held.  

In 1984, an American physician researcher, Dr. Robert Gallo, and his colleagues identified a virus called HTLV-III--later known as HIV-1--as causing AIDS.  This virus was the same virus as the lymphadenopathy-associated virus discovered by Dr. Luc Monagnier the previous year.    Frantic over the spread of this new disease, San Francisco officials ordered bathhouses to be closed, a move that angered many citizens.  Several AIDS service organizations formed a new group called the AIDS Action Council.  The CDC advised the public to stay away from intravenous street drugs and not to share street drug needles.  

The World Health Organization (WHO) and the US Department of Health and Human Services (DHHS) hosted the First International AIDS Conference in 1985.  At the conference, every region of the world, including China, reported at least one case of HIV/AIDS.  In 1985, the US Public Health Service put forth recommendations to prevent a mother from giving HIV to her newborn child.  The U.S Food and Drug Administration licensed the first HIV test.  In the meantime, U. S. blood banks began to check the blood supply for the virus and military recruits were tested for the virus before they were allowed to join the armed services.  Ryan White, a teenager with AIDS living in Indiana, was told to stay away from school.  He would go on to become the face of HIV/AIDS and pave the way to ending some of the ignorance and discrimination against those with the virus. The actor, Rock Hudson, well-loved by many in the US and around the world, told the world he had AIDS and died several months later.  This year was the beginning of the American Foundation for AIDS Research (amfAR) and Project Inform--an organization aimed at getting quicker approval for HIV drugs. 

Ryan White at school

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In 1985, the Center for Disease Control and the World Health Organization met in Bangui, the capital of the Central African Republic.  They talked about the problem of some countries not having HIV antibody tests.  They developed a new definition of AIDS that was not based on lab results but on symptoms.  For example, the symptom of continuous fevers would be given a score of “3.”   If the symptom scores added up to “12,” the person was considered to have AIDS.  This new way of defining who had AIDS received much criticism; however, the new definition did prove to be useful. 

The biggest news of 1986 was a new drug to treat AIDS: AZT (Zidovudine or Retrovir) was found to be effective against AIDS and would be tested in humans. Some US cities began to give out clean syringes to drug addicts.  Someone handy with a sewing needle put together the first block of the AIDS memorial quilt, representing someone who had died of AIDS. (The project would take off like wildfire and later be composed of 46,000 individual blocks, honoring 91,000 dead. The quilt now stays in a warehouse in Atlanta, Georgia, weighs approximately 108,000 pounds, and covers 1,293,300 square feet.  It would take someone more than 33 days to view the entire quilt, spending one minute on each individual square.)

This same year, 1986, nine year-old Ricky Ray, the oldest of three brothers all with hemophilia and HIV, was not allowed to attend his Florida school.  The next year, arsonists set fire to his family home.  The Robert Wood Johnson Foundation founded the AIDS Health Services Program which provided money to cities which were hit hard by the AIDS epidemic.  The program was the forerunner to the Ryan White Care Act.  The US Surgeon General, C. Everett Koop, called form more education about HIV/AIDS and more condom use. 

The next year, 1987, marked big news.  The first HIV drug, AZT (zidovudine or Retrovir) was approved for use.  The approval for this drug was the fastest in US history.   The US Congress provided $30 million in emergency funds directly to states so that they could buy the drug.  Again, the US Center for Disease Control expanded the list of criteria that identified AIDS to include those with an AIDS-disease, even without lab results.  International groups began to form to address the AIDS crisis. The first human tests of an HIV vaccine began.  A history of the early years of the HIV/AIDS epidemic was published by Randy Shilts.  The book was called “And the Band Played On; Politics, People, and the AIDS Epidemic.”  (Randy Shilts would later die of AIDS himself in 1994, at the young age of 42.)  The great pianist, Liberace, died of AIDS in 1987.  The U. S. began testing all immigrants who wished to come to the U. S.; those with HIV were forbidden entry.  The AIDS memorial quilt, now made up of 1,920 blocks and larger than a football field, was displayed in Washington, D. C.  National groups were formed to address the impact of HIV/AIDS on U. S. minorities.

December 1, 1988, was named the first World AIDS Day by the World Health Organization.  For the first time, the number of women in the African region south of the Sahara Desert with HIV/AIDS was more than the number of men with the disease. The International AIDS Society (IAS) was formed.   The number of AIDS cases, according to the World Health Organization, jumped 56%.  Major research groups were formed.  A U. S. schoolgirl with AIDS was told she could only attend classes if she was enclosed behind a glass window.  Ironically, the same year, the U. S. Department of Justice changed their policy and said that those with HIV/AIDS could not be discriminated against. 

In 1989, the U. S. Center for Disease Control put forth new guidelines for preventing pneumocystis carinii pneumonia (PCP), a common serious disease in those with AIDS.  If you recall, PCP was the disease that was first noticed in June 1981 and marked the beginning of the AIDS epidemic.  New policy allowed those with AIDS who were not eligible for clinical trials access to new experimental treatments.

Ryan White, the boy who was prohibited from attending school, died on April 8, 1990.  He was just 18 years old.  The next day, the U. S. Congress enacted the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act of 1990.  This act gave federal dollars to U. S. communities for the care and treatment of those with HIV or AIDS.  The first year, more than $220 million dollars was given out.  The drug AZT was now approved for use in children.  This year marked the American Disabilities Act--HIV or AIDS was now considered a disability and those with HIV or AIDS could no be discriminated against.  A woman in Florida believed she got HIV from her dentist, who may have used contaminated dental tools. 

In 1991, the famous basketball player, Magic Johnson, announced that he had HIV.  The U. S. Congress enacted the Housing Opportunities for People with AIDS (HOPWA) Act.  This act provide federal money to cities and states to assist those with HIV/AIDS to have adequate housing.  The U. S. Center for Disease Control recommended that HIV positive health care workers stay away from certain types of health care procedures that could expose patients to the health care worker’s infected blood.  The red ribbon was introduced at the annual Tony Awards and quickly became the international symbol of AIDS awareness.    

Ricky Ray, the child who was barred from school and home was burned by arsonists, died in 1992.  He was just 15 years old.  (His HIV positive brother, Robert, would die 8 years later, at age 22; the third HIV positive brother, Randy, remains alive and is taking HIV medicines.)  The International AIDS Conference, now in it’s eighth year, was moved from Boston to Amsterdam due to strong feelings against the U. S. banning HIV positive immigrants.  

The next year, 1993, marked “the year of the HIV positive woman.”  A new female condom hit the U. S. marketplace in 1993.  Researchers received federal money to study women with HIV/AIDS.  Women and minorities were now to be included in all HIV/AIDS research.  The CDC came up with a new broader definition of AIDS--adding invasive cervical cancer, pulmonary tuberculosis, recurrent pneumonia, and a CD4 count less than 200 (or CD4 percentage less than 14) as new criteria to define AIDS.  Federal money would now be aimed at preventing HIV.  Immigrants with HIV were now officially forbidden entrance into the US.

In 1994, the U.S. Public Health Service recommended that all pregnant women receive the drug AZT, as the drug had been shown to drastically decrease a mother’s chances of giving HIV to her newborn baby.  There was now an HIV test that could use saliva instead of blood.  AIDS was now the leading cause of death of all young Americans, age 25 to 44.

AIDS continued to be the leading cause of death in young U. S. adults in 1995.  Fortunately, a new class of drugs, called protease inhibitors, was available and would breathe new life into AIDS sufferers. The first protease inhibitor, Saquinavir, was rushed through the drug approval process--the drug would not be used alone, but with other HIV medicines. This marked the beginning of the use of 3-drug HIV regimens--also called “HIV cocktails.”  The proper term is highly active antiretroviral therapy, or HAART.  The U. S. Center for Disease Control issued guidelines to prevent certain types of infections (called opportunistic infections or OIs) in those with AIDS.  

The next year, 1996, heralded the arrival of another new class of drugs, called non-nucleoside reverse transcriptase inhibitors (NNRTIs).  Nevirapine (Viramune) was the first NNRTI to be approved.  The “viral load” test, a test which measures the amount of HIV in the blood, became available.  HIV could now be detect in urine so one could test for HIV in the comfort of one’s own home.  For the first time since 1981, new AIDS cases began to decrease.  AIDS was no longer the leading cause of death in all young adult Americans but was still the leading cause of death in young adult African Americans. 

In 1997, AIDS deaths markedly declined, due to the effects of the 3-drug HIV regimens (HAART).  By 1998, AIDS was hitting the U. S. black community hard and African American leaders declared this “a state of emergency.”  The Minority AIDS Initiative was created to address the prevention and treatment of HIV/AIDS in the nonwhite community.  The first national guideline on the use of HIV medications became available.  Large-scale human trials of an HIV vaccine were begun.  

The years 1999 to 2000 marked numerous national and international efforts aimed at providing HIV treatments, decreasing the cost of HIV medicines, and giving money and resources to those with the disease.  In 1999, the Center for Disease Control (CDC) Division of HIV/AIDS prevention gave money to five U. S. nonprofit groups known as the Community Capacity Building Coalition. In 2000, the Ryan White Care Act was reauthorized.  

On February 23, 2001, the first annual National Black HIV/AIDS Awareness Day was held in the US.  (The event was permanently switched to February 7 the next year.) United States drug companies agreed to allow generic drug manufacturers in developing countries to make and supply HIV drugs to their people. United States Secretary of State, Colin Powell, said that HIV was a threat to the national security. 

In 2002, HIV/AIDS killed more adults aged 15-59, around the world, than any other cause of death and women made up one half of the cases.  A new HIV test could detect HIV antibodies with just a jab of a needle to a finger. 

The first annual National Latino AIDS Awareness Day was held in the US on October 15, 2003.  A new HIV medication treatment program was begun in South Africa.  President Bush put forth a new plan: The President’s Emergency Plan for AIDS Relief (PEPFAR) would give $15 billion over 5 years to 15 countries suffering large amounts of HIV/AIDS, tuberculosis, and malaria.

The year 2004 marked the year that international policy-makers called for better efforts to find a vaccine for HIV and for more focus on HIV/AIDS in females.  As part of PEPFAR, the US Food and Drug Association put forth a new plan allowing drug companies outside the US to receive quick approval to produce HIV medicines.  The companies could submit an application to make single or combined HIV drug products that had already been approved by the FDA, even if other drug companies still held the patent or exclusive market protection. By the end of this year, over 700,000 HIV positive people in developing countries had received HIV medications.  

The first annual National Asian and Pacific Islander HIV/AIDS Awareness Day was celebrated on May 19, 2005.  An Indian drug company received US FDA approval to produce generic HIV medicines for the international organization, PEPFAR, in 2005.  

By 2006, the CDC recommended all adults age 13-64 visiting any type of health care clinics, for any cause, be tested at least once for HIV. They recommended that those in high-risk groups be tested yearly thereafter.  The first annual National Women and Girls HIV/AIDS Awareness Day was held in the US on March 10, 2006.  For the third time, the Ryan White Care Act was reauthorized.

In 2007, international HIV/AIDS organizations recommended males be circumcised as a way to control the spread of HIV.  The next year, 2008, PEPFAR was given $48 billion and given five more years to accomplish their goal of helping poor countries deal with HIV/AIDS, malaria, and tuberculosis.  This year, HIV positive immigrants would no longer be banned from entering the US.  The CDC’s new count of those in the US with HIV was worse than expected.  

On October 30, 2009 United States President Obama signed paperwork officially ending the 22-year-old HIV travel and immigration ban.  The International AIDS Conference, now in its eighteenth year, said that now that the travel ban was gone, the conference could now be held in the US. (The 2012 International AIDS Conference will be held in Washington, DC.)  Another change in policy allowed the US federal government to provide clean needles to drug addicts.  President Obama placed PEPFAR into his Global Health Initiative--$63 billion over 6 years was authorized to help poor countries deal with contagious diseases.  

The next year, 2010, US President Obama put forth the first National HIV/AIDS Strategy.  I'll add more history later.