The Viral Life Cycle

Like all viruses, HIV cannot multiply by itself. It must get inside a cell in order to make copies of itself. When HIV infects a cell, it takes over the cell's control centre. From there, the virus starts to make new copies of itself (it reproduces or replicates). These newly minted viruses then go on to infect other cells. Without treatment, experts estimate that up to 10 billion copies of HIV may be made every day. Understanding how HIV replicates can help you understand how antiretroviral drugs work. All of these drugs interfere with key stages of viral replication.

NOTE: See "Appendix A, Antiretroviral Drugs," for a listing of all the drugs now approved in Canada, as well as those currently being studied. This listing includes the names of all the drugs and their manufacturers.

The HIV Virus

Human immunodeficiency virus (HIV) is made up of two strands of genetic material called RNA. Along with the RNA, HIV contains three key enzymes:

• reverse transcriptase

• integrase

• protease

These enzymes are chemicals that help the virus make copies of itself. The outer surface of the virus is covered with proteins called gp120 and gp41.

HIV Enters a Cell

HIV uses the proteins on its surface to lock on to the parts of the cell called the CD4 receptor and the co-receptors, such as CCR5 and CXCR4. Once HIV is attached to the receptors, the virus can fuse with the cell. Then the contents of the virus are inserted into the cell. Not all of the cells in your body have CD4 receptors; the most important cells that do are called CD4+ T cells or T4 cells.

Drugs known as entry inhibitors are being developed to prevent HIV from getting inside cells. Some of these drugs are designed to block the co-receptors while others prevent the virus from fusing with the cell. The first entry inhibitor approved in Canada was T-20 (enfuvirtide, Fuzeon)

HIV Takes Control of the Cell

Inside the cell, the reverse transcriptase (RT) enzyme converts the viral RNA into DNA. Now the genetic material of the virus matches the genetic material of the cell. Drugs called reverse transcriptase inhibitors slow down or stop the action of the RT enzyme. The three types of these drugs are:

• nucleoside analogue reverse transcriptase inhibitors (NRTIs)

• non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs)

• nucleotide analogue reverse transcriptase inhibitors (nucleotide RTIs)

The NRTIs, commonly referred to as nukes, were the first drugs approved for the treatment of HIV and continue to be a major part of many PHAs' drug regimens. Currently approved nukes are (in alphabetical order):

• 3TC (Epivir, lamuvidine)

• abacavir (Ziagen)

• AZT (Retrovir)

• d4T (Zerit)

• ddI (Videx)

• FTC (Emtriva)

There are also combinations of nukes, taken as one pill:

• AZT/3TC (Combivir)

• AZT/3TC/abacavir (Trizivir)

• 3TC/abacavir (Kivexa)

• FTC/tenofovir (Truvada)

Many other nukes are being studied.

The NNRTIs, or non-nukes, were developed later than the nukes, but due to their powerful ability to suppress HIV they have also become an important component of many PHAs' approaches. Currently approved non-nukes are:

• delavirdine (Rescriptor)

• efavirenz (Sustiva)

• nevirapine (Viramune)

The nucleotide RTIs are very similar to the nukes but require one less processing step to work in the body. The one nucleotide RTI available in Canada is:

• tenofovir (Viread)

There are several other nucleotide RTIs being studied.

HIV Becomes Part of the Infected Cell

The second viral enzyme, called integrase, inserts the newly converted viral DNA into the cell's own DNA. With the viral DNA integrated into the DNA of the cell, the virus has become part of the cell. This process has sometimes been compared to putting a "bug" in a computer software program. Researchers are working to develop drugs that will interfere with the action of integrase. Right now, there are no approved integrase inhibitors.

HIV Tricks the Infected Cell Into Making Copies of Itself

At this point, if the infected CD4+ cell is activated -- which happens any time the immune system is called upon to respond to an infection or allergen or cancerous cell -- instead of performing its proper functions, it will start making and releasing new virus. The first step is to make long chains of viral protein. The protease enzyme works like scissors to cut these protein chains into the smaller pieces that make up HIV. The newly cut pieces are assembled into new virus particles, which then "bud" out from the host cell and can go on to infect other cells.

Protease inhibitors (PIs) are drugs that interfere with the action of protease. They prevent the protease enzyme from cutting the long chains of new viral protein. Although new virus can be formed, it is defective and cannot infect new cells. Protease inhibitors have a very powerful ability to suppress the virus and are an important part of many drug combinations.

Currently approved protease inhibitors are:

• amprenavir (Agenerase)

• indinavir (Crixivan)

• lopinavir and ritonavir (Kaletra)

• nelfinavir (Viracept)

• ritonavir (Norvir)

• saquinavir (Invirase)

• tipranavir (Aptivus)

• fosamprenavir (Telzir)

• atazanavir (Reyataz)

Sometimes your doctor may prescribe two PIs together. This is because one PI, usually ritonavir, can "boost" the level of the other PI. Examples of dual-PI or PI-boosted regimens include the following:

• ritonavir/amprenavir

• ritonavir/indinavir

• ritonavir/saquinavir

• ritonavir/atazanavir

• ritonavir/tipranavir

Many other PIs are being studied.

Another group of drugs that is being studied is called immune boosters. These can help raise the level of CD4+ and other cells. An example of an immune booster is IL-2 (interleukin-2). You may also hear about "therapeutic vaccines." These are meant to be used in HIV positive people to help improve their immune system's ability to fight HIV. Many of these products are being tested in clinical trials.