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This issue’s Backgrounder shows how different drug classesA group of anti-HIV drugs with the same target of action. Anti-HIV drug classes include nucleoside analogue reverse transcriptase inhibitors, protease inhibitors and non-nucleoside analogue reverse transcriptase inhibitors, as well as several others. Combining drugs from three or more classes is the basis of Highly Active Antiretroviral Therapy (HAART). target different stages in the HIV life cycle.

The number and variety of anti-HIV treatments expands almost every year. There are now 19 different HIV medications available on the Pharmaceutical Benefits Scheme[Pharmaceutical Benefits Scheme] The federal government program which subsidises medication costs in Australia. Anti-HIV drugs are part of a special part of the PBS called Section 100 (S100) which is used for expensive, highly specialised drugs., and more are in various stages of development.

Most readers will be aware that, to be effective, antiretroviralA medication or other substance which is active against retroviruses such as HIV. combinations typically include at least three different drugs from at least two different drug classes. The drugs we have available now are classified into four classes, but new drugs are being developed which will expand the number of drug classes and promise to radically improve the effectiveness(Of a drug or treatment). The maximum ability of a drug or treatment to produce a result regardless of dosage. A drug passes efficacy trials if it is effective at the dose tested and against the illness for which it is prescribed. In the standard procedure, Phase II clinical trials gauge efficacy, and Phase III trials confirm it. of anti-HIV therapy.

In this Backgrounder we take a look at what drug classes are, and how they target HIV at specific points in its life cycle.

The circle of HIV

Once HIV has entered the human body, it follows a very specific routine: infecting cells, making new copies of itself, which then seek out new cells to infect. Like all virusesA small infective organism which is incapable of reproducing outside a host cell., HIV cannot replicate by itself — it needs a host cell to reproduce.

The reason for this is that viruses are incredibly simple organisms. In fact, HIV has just nine genesThe most basic unit of genetic information. which carry all the genetic information which enables HIV to go about its dastardly work. By comparison, human DNA contains somewhere between 20,000 and 35,000 genes.

With so few genes, the HIV genome simply doesn’t have enough storage room to carry the instructions it would need to reproduce like other organisms — just as you can’t run a word-processing computer program on a pocket calculator.

Because of their simplicity, and their inability to reproduce without outside help, there’s an ongoing scientific debate about whether or not viruses are truly ‘alive’. But alive or not, HIV is plainly capable of reproducing, spreading from person to person and wreaking terrible damage along the way.

The key to this is the sophisticated and carefully choreographed ballet which the virus performs, once it gets into the human bloodstream, to infect cells, take over the cell’s internal processes, and turn them to its own purpose.

The process can be divided into five discrete stages; HIV drugs work by interrupting the virus’s work at any one of these. The particular stage at which the drug works defines which class that particular treatment falls into.

Let’s look at each of these stages — and the drug classes that target them — in turn.

Entry

Once it has found its way into the human body, the virus needs to locate and enter a cell before it can reproduce. HIV targets a specific type of cell, called a CD4 cell, which is part of the immune system.

Gaining entry to a human cell from the bloodstream probably doesn’t sound too hard — after all it’s just a tiny speck of protein, water and DNA. But in the microscopic world in which HIV operates, it’s actually no picnic. Human cells may be very tiny, but they have evolved with a tough outer coat which is designed specifically to keep intruders like HIV out.

So HIV can’t just knock on the door and waltz inside, it has to pick the lock.

To do this, a chemical on the virus’s surface called gp120 first binds (attaches to) not just one, but two chemicals on the surface of the cell. The first is CD4 (after which the cell is named); the second can be either of two different chemical markers called CCR5 and CXCR4 (‘R5’ and ‘X4’ for short). HIV then uses another protein called gp41 to penetrate the cell membrane and get to work.

All those numbers and letters may look like alphabet soup, but it’s helpful to understand them because they suggest different ways that entry and fusion inhibitors could work. To stop HIV at the entry stage, drugs could be developed to target HIV surface proteins (gp120 or gp41) or CD4 cell co-receptors (R5 or X4). By attaching to any of these points before HIV gets into the cell, they could interrupt the HIV cycle in the same ways that putting chewing gum into a lock interrupts someone trying to open a door.

We currently have one approved drug in this class — the fusion inhibitor T-20, which works by attaching itself to gp41. Drugs are currently in clinical trials to target the R5 co-receptor (called CCR5 inhibitors — see page 7 of this issue for more on these) and the gp120 protein has been the target of some (unsuccessful) vaccine research.

Reverse transcription

Once it gets into the cell, HIV has to insert its own genetic code into that of the host, reprogramming it from being an immune system cell to being an HIV factory. Before this can happen, HIV has to perform an extraordinary trick.

The human genetic code, found in the nucleus of every cell in your body, is recorded on two long chains of DNA. HIV’s genetic code is recorded in a single short strand of RNA, so HIV has to convert the RNA to DNA before it can hijack the cell. This process is called ‘reverse transcription’ and depends on an enzyme (a type of protein) called reverse transcriptase.

Drugs which interfere with the reverse transcriptase enzyme are called reverse transcriptase inhibitors and they come in three different flavours:

• nucleoside analogue reverse transcriptase inhibitors (NRTIs, or ‘nukes’) such as AZT, ddI, d4T, ddC, 3TC, abacavir and FTC.
• non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs, or ‘non-nukes’) such as efavirenz, nevirapine and delavirdine.
• nucleotide analogue reverse transcriptase inhibitors (NtRTIs) such as tenofovir.

Each type works in a slightly different way, but they all interfere with the reverse transcription process. Unable to convert its RNA into DNA, HIV cannot reprogram the cell to make more copies of itself.

The nucleoside and nucleotide drugs, while chemically different, are usually grouped together as one class for the purpose of making treatment decisions, while the non-nukes are in a class of their own.

Integration

After converting RNA to DNA (and then converting the resulting single strand of DNA to a double strand) the HIV DNA must be inserted into the human DNA. This process, called integration, is achieved with the help of another HIV enzyme, integrase.

There has been some research into drugs that would interfere with this stage of the HIV cycle — indeed, several years ago there was a great deal of hype about integrase inhibitors — but so far the results have mostly been disappointing. This drug class seems especially hampered by toxicity problems, but research is continuing.

Cleavage

Once the viral DNA has been inserted into the host cell’s nucleus, the cell starts producing copies of HIV. But, like Swedish furniture, some assembly is required.

The newly-repurposed CD4 cell produces long chains of proteins, which must be cut up and reassembled in the right order before they become new HIV viruses.

This process is called cleavage, and it depends on an enzyme called protease, which acts as a kind of molecular ‘scissor’ to chop up the long chains.

Drugs which interfere with this process are called protease inhibitors (PIs). There are seven PIs currently approved for use in Australia: saquinavir, indinavir, ritonavir, amprenavir, nelfinavir, lopinavir and atazanavir.

Assembly and budding

Finally, the new virus particle (virion) is assembled from the pieces prepared during the cleavage process. This stage is called assembly or maturation.

Drugs that target this stage of the HIV cycle are called maturation inhibitors. So far, only one drug in this class, called PA-457, has entered preliminary clinicalPertaining to or founded on observation and treatment of participants, as distinguished from theoretical or basic science. trials.

By this stage (if the process has not been halted by anti-HIV drugs at any of the earlier stages) the new HIV virion is ready to graduate to the big time, and start the process over again with a new CD4 cell. The virion moves to the surface of the cell and breaks through into the bloodstream. As it does so, it takes with it a small piece of the cell membrane. Over time, the cell membrane weakens and eventually the process destroys that CD4 cell.

As you can see, the large range of HIV drugs we have now are still only targeting a few of the possible points in the HIV cycle. Research is continuing on drugs that promise to improve options for HIV therapy by increasing the number of stages in the HIV cycle we can target.

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