To understand how HIV breaks down your immune system, you first need to know how the immune system works. Your immune system protects you from harmful pathogens, such as bacteria, viruses, fungi, parasites and malignant cells (cancer cells). In the first instance, your skin and mucous membranes protect you against these external invaders by preventing pathogens or harmful substances from getting through. But if your skin is damaged and viruses, bacteria or fungi do enter your body, your immune system springs into action to render the invaders harmless. The white blood cells or leukocytes play an important role in this immune response. These immune cells protect you against external invaders and can detect and recognize these foreign substances anywhere in your body – in circulating blood, but also in your skin or your intestines.

There are different types of immune cells and each cell has its own task: detecting, surrounding, consuming and killing pathogens. Once the immune cells have taken action, they also clear everything up. Immune cells are also referred to as protective soldiers, because they protect the body against foreign invaders. When your immune cells are working well, you have good resistance and you do not get sick, despite coming into contact with pathogens every day.

One of the immune cells that is affected by an HIV infection is the T cell. T cells are made in the bone marrow and grow further in the thymus (T). In the thymus, they learn the difference between the body's own substances and foreign substances. Then they leave the thymus and enter the bloodstream, spleen and lymph nodes.

What does HIV do to your body if you don't take any medication?

If you have an HIV infection, special immune cells break down. This is because the HIV particles use these immune cells to replicate themselves. An HIV particle cannot do this by itself. In your blood, they go looking for immune cells that have a CD4 receptor on their outside, the CD4 cells. These are usually T cells, but also macrophages (which eat pathogens) and dendritic cells (which detect pathogens). A receptor is a sort of antenna to which another particle can bind. The HIV virus has an envelope protein on the outside, which fits exactly onto the CD4 receptor and with which the virus particle binds to the cell and works its way inside. To enter the cell, the HIV particle also uses an auxiliary receptor, which is on the outside of the CD4 cell along with the CD4 receptor. The HIV virus therefore uses the CD4 cell as a sort of copying machine to replicate itself and forces the healthy CD4 cell to make new virus particles. In this way, an HIV particle can make a large number of copies of itself.

In order to make these copies, however, the genetic material (RNA) of HIV must first be integrated into the hereditary material (DNA) of the CD4 cell, which is located in the nucleus of the cell. Viral proteins (enzymes) are indispensable for the copying process. Examples of these enzymes include reverse transcriptase, integrase and protease.

Reverse transcriptase is required to make a DNA copy (cDNA) of viral RNA.
Reverse transcriptase then ensures that the viral RNA is broken down and the viral DNA is replicated, creating two strands of viral DNA (viral double-stranded DNA).

Integrase ensures that the viral DNA then enters the cell nucleus and is integrated into the DNA of the CD4 cell. Integrase cuts the viral DNA and the DNA of the CD4 cell in certain places and then sticks them together. The hereditary material of the host cell, the host genome, then contains viral DNA. We call this proviral DNA.

In order to make new strands of viral RNA, the proviral DNA must be read (this is called transcription). Some of the viral RNA becomes messenger RNA (mRNA), which is important for the production of viral proteins. These proteins are the building blocks for the new virus particle. The other viral RNA strands do not change and instead combine with the newly formed viral proteins to form new virus particles.

Protease
The new virus particle is eventually produced by 'budding'. In this process, under the influence of viral proteins and viral RNA, a small bulge is formed on the surface (cell membrane) of the CD4 cell. Protease then makes sure that viral amino acid chains are cut into smaller pieces. This produces a number of proteins, allowing the virus particle to develop into a working and infectious virus that can infect the new CD4 cells. The viral RNA is integrated in a protein coat (capsid) that is in the middle of the new virus particle. Eventually the bulge forms a virus particle with viral proteins and the viral RNA inside and the envelope proteins on the outside.

The new virus particles then leave the CD4 cell (primarily T cells). The CD4 cell is usually so abused and damaged in the process that it dies. The new virus particles eventually get into the lymphatic system, mucous membrane and blood. There they attach themselves to new CD4 cells and the whole process starts all over again. More and more CD4 cells become infected with HIV in this way.

Billions of new virus particles are produced every day and billions of T cells and other CD4 cells die. The T cells have a very important role within the immune system. They control everything and manage all the other immune cells so that each cell knows exactly what it has to do. If a large number of T cells die, your immune system is no longer well managed and is unable to defend you against pathogens. You then become much more susceptible to normal, common viruses, bacteria and fungi. Eventually you can even get infections from viruses, bacteria or fungi that would not normally make you sick. We call these 'opportunistic infections'.

Your body tries to do something about the HIV infection, as it is aware that foreign invaders are active. Your immune system actually has exploratory cells that continuously scan your body. CD4 cells that are infected with HIV are recognized in this way and your immune cells will attack and destroy them as well as possible. However, because the virus replicates itself as fast as possible, mistakes are made and such a copy will look slightly different. That is called mutation (alteration in genetic material). Your immune system therefore does not recognize all virus particles right away and some are not immediately eliminated. The mutated virus particle has some time and continues to replicate itself at a rapid pace, causing more cells to become infected. If you do not take your medication regularly or according to the schedule, you will give the virus this opportunity.

If the virus changes, some medications become less effective or even stop working altogether. This means resistance has occurred. A different combination of drugs is then required. You can only switch to a different combination a small number of times. Therapy compliance is therefore very important!

What happens if you do not treat HIV?

If you do not take any medication, your immune system will be seriously damaged. This is mainly due to the destruction of the HIV-infected CD4 cells. You become susceptible to serious infections that are difficult to treat and you can develop rare forms of cancer.

If you have fewer CD4 cells, your body can no longer defend itself and you can get sick more quickly and more frequently from normal, common viruses, bacteria and fungi. Everyone can get infections from these, but with a well-functioning immune system it happens less frequently and the infections are less serious.
If the number of CD4 cells continues to decrease, you can get infections that other people would not get. Infections from viruses, bacteria or fungi that normally would not make you sick. We call these opportunistic infections.

It is not only HIV that leads to an increased risk of opportunistic infections; the use of strong immunosuppressive drugs or leukemia can also lead to this.

What is AIDS?

You have AIDS if, due to the HIV infection, the number of CD4 cells is so low that you get opportunistic infections. If the number of CD4 cells is below 200/mm3, you have a chance of this.
Examples of opportunistic infections are:

• A severe lung infection (pneumonia) caused by the bacterium Pneumocystis jiroveci (PJP, Pneumocystis jiroveci pneumonia). The bacterium used to be called Pneumocystis carinii (PCP).
• A severe infection with Candida albicans. This is a yeast-like fungus that can cause infections in the esophagus, brain, blood and various other places.

If you have AIDS, the immune system is also unable to keep your own cells properly under control. When you are healthy, cells that change into cancer cells are detected and eliminated. But if the immune system can no longer do its job, special and rare forms of cancer have a chance to develop. Forms of cancer that often occur with AIDS are Kaposi's sarcoma, non-Hodgkin lymphoma and cervical cancer.

What types of HIV are known?

There are two types: HIV-1 and HIV-2. HIV-1 is most common in the Netherlands and the rest of Europe. HIV-2 occurs mainly in western Africa. The virus behaves in the same way with both types, but HIV-2 is less easily transmitted than HIV-1, and does not make you sick as quickly.

HIV-1 can be divided into four subtypes, M, O, P and N.

• M (main) is the most common, especially in pandemic areas. Within this subtype, ten clades (groups) can be distinguished: clade A to J. HIV clade B is most common in Europe and the U.S.
• O (outlier) only occurs in Cameroon, Gabon and Equatorial Guinea.
• P (pending) is very rare; there are a small number of patients in Cameroon.
• N (non-M/non-O) is very rare; there are a small number of patients in Cameroon.