Retroviruses and anti-retroviral drugs

The human immunodeficiency virus (HIV) is an enveloped retrovirus which targets macrophages, T helper cells and dendritic cells of the human immune system. A retrovirus contains a single-strand of RNA as its genome, and replicates by transcribing a complementary DNA copy from its RNA genome (reverse transcription) and then uses the DNA strand to make more RNA, as a template for more copies of the viral genome or as messenger RNA to make viral proteins.

The reproductive cycle of HIV:

1. The virus attaches to the cell membrane (at CD4); upon binding the membranes of the host and the virus fuse, the viral capsid breaks down and the viral genome is able to enter the cell
2. In cell cytoplasm, the viral genome is replicated to form complementary DNA (cDNA) which is then integrated into the host’s genome – called a DNA provirus
3. When the provirus is activated, messenger RNA is produced and the host’s machinery is used to create viral proteins
4. Viral glycoproteins are inserted into the host’s plasma membrane, which, when the virus buds off, will become the viral envelope.
5. The new virus assembles itself in the cytoplasm and is released from the host via exocytosis.

Several proteins are especially vital for HIV infection and replication:

• Membrane proteins gp120 and gp41 to attach to human cells (gp = glycoprotein).
• Reverse transcriptase – catalyses the transcription of cDNA from RNA
• Integrase – catalyses the insertion of cDNA into the genome of the host
• Protease – is responsible for post-translational processing and is necessary to cleave larger initial products of translation to form individual viral proteins

Understandably, these essential proteins would be targeted by anti-retroviral drugs to inhibit infection and replication of HIV. However, scientists must take care to block only steps that are unique to the virus so that drug medications do not harm the patient. 3 general types of anti-retroviral drugs exist:

Reverse transcriptase inhibitors

If the cDNA cannot be formed, the virus’s RNA genome will be vulnerable to destruction by the host’s cellular enzymes. There are 2 types of reverse transcriptase inhibitors:

Nucleoside reverse transcriptase inhibitors – contains altered forms of deoxynucleosides, substrates in transcription and the formation of complementary DNA. These dideoxynucleoside forms have the hydroxyl group at the 3’ position replaced by an azido, hydrogen, or another group. Thus, when the HIV reverse transcriptase adds the altered substrate to the growing viral DNA chain (competitive inhibition), transcription will be inhibited as the normal 5’ to 3’ links will no longer to able to form i.e. the DNA strand will be truncated.

Non-nucleoside reverse transcriptase inhibitors – these bind to a site other than the active site of reverse transcriptase (non-competitive inhibition), causing a conformational change in the structure of the reverse transcriptase enzyme (at the active site) and therefore rendering the enzyme useless.

Protease inhibitors

These inhibitors were introduced in 1996 and work by binding competitively to the active site of the HIV protease.

HAART (Highly active anti-retroviral therapy) was developed in the late 1990s. It is similar to cancer treatment, and involves a combination of drugs that attack different parts of the life cycle of HIV. The therapy generally uses a protease inhibitor and two reverse transcriptase inhibitors (usually in the form of a pill). However, due to the lack of proofreading in HIV’s reverse transcriptase, there is a high HIV mutation rate, and unfortunately many patients who take HAART develop mutant strains that are resistant to the drug therapy. Similarly, specific genetic mutations in the protease gene may result in resistance towards to protease inhibitors. The toxic side effects of anti-retroviral drugs can be very severe e.g. diabetes, hepatitis, hypersensitivity. Scientists are continually striving to come up with new and better treatments to fight HIV.

Maria Nguyen

Sources:

Sadava et. al., Life, The Science of Biology. 8^th ed.

http://www.bmj.com/cgi/content/full/322/7299/1410