One set of HIV genes is known as the structural genes: gag, pol, and env. These genes govern the structure of the virus, including its envelope and its internal structures. gag and pol also give rise to three enzymes which are essential for HIV replication inside cells: reverse transcriptase, protease and integrase.

The use of reverse transcriptase is a unique characteristic of retroviruses such as HIV. After HIV has attached itself to a human cell and released its genetic material in the form of RNA into the cell, reverse transcriptase converts the viral RNA into a piece of DNA using the 'nucleotide' building blocks in the cell. This process is known as reverse transcription.

Reverse transcriptase works by looking in turn at each of the nucleoside blocks that make up the viral RNA and then using it as a blueprint to assemble a matching DNA chain of nucleotides from the supply in the cell. This chain is held together by chemical bonds between the individual component nucleotides.

The piece of viral DNA is called the provirus. Another HIV enzyme called integrase then inserts this piece of viral DNA into the human DNA of the cell.

Nucleoside reverse transcriptase inhibitors

The main class of reverse transcriptase inhibitors is the nucleoside reverse transcriptase inhibitor (NRTI) drugs. They include 3TC (lamivudine, Epivir), abacavir (Ziagen), AZT (zidovudine, Retrovir), d4T (stavudine, Zerit), ddC (zalcitabine, Hivid), ddI (didanosine, Videx / VidexEC) and FTC (emtricitabine, Emtriva). NRTIs must be converted into their active 'triphosphate' forms within cells by a process known as phosphorylation. These NRTI triphosphates resemble the nucleotides found in the human cell.

To compare all antiretroviral drugs licensed in the European Union, see NAM's drug chart. The chart contains illustrations of the drugs, as well as information on drug doses, formulations, pill burdens, main side-effects and food restrictions.

When reverse transcription occurs in the presence of one or more of these drugs, they disrupt the construction of the piece of proviral DNA. Instead of taking up a nucleotide from the supply in the cell, reverse transcriptase may use the NRTI triphosphate instead. Because the form of these drugs is slightly different from that of natural nucleotides, they cannot form the necessary chemical bonds with natural nucleotides that allow the DNA chain to continue to grow. Consequently the DNA chain is left incomplete. As HIV has no mechanism for correcting such 'mistakes', the presence of NRTI triphopshates in the cell interrupts the process of reverse transcription.

While this process can stop reverse transcription, this mechanism of action also accounts for the main drawback of this family of drugs. Because they resemble the building blocks of DNA, there is also a risk that they will be taken up when healthy human cells reproduce and will prevent the production of new cells. However, researchers are confident that while reverse transcriptase has a relatively high affinity for the NRTI triphopshates, the equivalent human enzyme, called DNA polymerase, has a low affinity for the drugs. This means that reverse transcriptase is more likely to use the drugs than the human enzyme and that, while reverse transcription is disrupted, normal cellular processes like cell division are unaffected by the drugs' presence. Moreover, unlike HIV, human cells have 'repair' enzymes which are designed to correct mistakes in DNA production during the normal reproduction of human cells. These enzymes can remove any NRTI triphosphates that are mistakenly incorporated into the human DNA, replacing them with natural nucleotide building blocks.

Nevertheless, drugs such as AZT do have side-effects which have been attributed to damage to a specific type of DNA found within cells. This DNA is found in the 'mitochondria', tiny components of human cells that are responsible for the release of energy from fuels such as glucose. The DNA in mitochondria also must be copied when the cell divides, and this process is co-ordinated by an enzyme called polymerase gamma. This enzyme has a relatively high affinity for NRTI triphosphates, so mitochondrial DNA is more vulnerable to damage from NRTIs.

When mitochondrial DNA is damaged by NRTIs, the cell may die because it cannot produce enough energy from fuels. Fast-replicating cells such as those in the bone marrow may also be inhibited by AZT, resulting in blood side-effects such as anaemia and neutropenia. Peripheral neuropathy and pancreatitis are also signs of mitochondrial toxicity. Different NRTIs affect the mitochondria of different types of cell, which is why the side effect profiles of the nucleoside analogues are distinct from one another.

NRTIs in development include racivir, elvucitabine, stampidine, AVX754 and alovudine.

Nucleotide reverse transcriptase inhibitors

A similar group of drugs is called nucleotide reverse transcriptase inhibitors (NtRTIs). These drugs differ from the NRTIs in that they require only one phosphorylation step within the cell to become the active form. In contrast, the NRTIs require three phosphorylation steps to become active.

Unlike all the NRTIs apart from ddI, NtRTIs are active against HIV in resting lymphocytes which are not currently producing infectious virus, as well as activated ones. These drugs can also persist in the cell for much longer, and only require once daily dosing. Tenofovir (Viread) is the only NtRTI to be licensed for HIV treatment, and no others are currently under investigation.

To compare all antiretroviral drugs licensed in the European Union, see NAM's drug chart. The chart contains illustrations of the drugs, as well as information on drug doses, formulations, pill burdens, main side-effects and food restrictions.

As NRTIs and NtRTIs are extremely similar in their mode of action, they are usually regarded as being the same class of drug.

Non-nucleoside reverse transcriptase inhibitors

Researchers have also developed a number of non-nucleoside reverse transcriptase inhibitors (NNRTIs). This class of drugs includes efavirenz (Sustiva) and nevirapine (Viramune). The NNRTIs also inhibit the activity of reverse transcriptase, but not by acting as dummy building blocks as the NRTIs and NtRTIs do. In many cases the precise way by which they inhibit reverse transcriptase remains unknown.

To compare all antiretroviral drugs licensed in the European Union, see NAM's drug chart. The chart contains illustrations of the drugs, as well as information on drug doses, formulations, pill burdens, main side-effects and food restrictions.

NNRTIs in development include etravirine and calanolide A. Boehringer Ingelheim, the manufacturers of nevirapine, are developing advanced derivatives of the drug which may be active against NNRTI-resistant strains of HIV.

Several drug companies are working on new categories of NNRTIs, such as benzophenones, diarylpyrimidines (DAPYs), diaryltriazines and tricyclic NNRTIs. There is considerable excitement about the development of DAPYs, such as etravirine. These compounds have been designed to be flexible, so that they fit into pockets in the reverse transcriptase enzyme that are of varying shapes. It is thought that this may enable the drugs to overcome changes in enzyme shape that occur after resistance mutations have developed. Another similar drug in development is rilpivirine.