HIV is a retrovirus which destroys the host’s immune system by attacking T4 helper cells. In the absence of a fully functioning immune system, hosts are far more susceptible to opportunistic infections such as TB and pneumonia, which are responsible for the death of HIV and AIDS patients, as opposed to the actual HIV virus itself.
As HIV is a retrovirus, it contains no DNA, only RNA, and as such contains the enzyme reverse transcriptase, which enables DNA to be replicated from the viruses RNA and inserted into the host’s genome. Once within the host’s genome the viral DNA may become active and code for new viral components, allowing the virus to replicate and go on to infect other healthy host cells, or remain latent for a number of years.
Image interpreted from Encarta.msn.com and howstuffworks.com (01/11/2010)
gp41 Envelope Protein
gp120 Envelope Protein
Retroviruses such as HIV are treated using antiretroviral therapy. There are several different classes of antiretroviral drugs, each class dealing with a different stage in the HIV life cycle.
The HIV life cycle begins when it is introduced into the hosts’ blood stream via a fomite such as an infected needle. The virus then attaches to the host cell via CD4 receptors and CCR5, CXCR4 co receptors. Once attached, the HIV virus then fuses with the host cell membrane, this is initiated by the gp41 protein, which is changed in shape when the gp120 envelope protein interacts with CD4 during attachment of the HIV virus (www.mcld.co.uk 01/11/2010). The virus’ capsid then breaks down, releasing the viral RNA from which viral DNA is replicated. The viral DNA is then integrated into the hosts DNA and new viral proteins are coded for. The newly synthesised viral proteins migrate to the cell surface where they are assembled and the newly formed virus is then released from the host cell via lysis or budding, where it is then able to go on to infect other healthy host cells.
HAART (Highly Active Anti-retroviral therapy) combines several classes of antiretroviral drugs.
At present there are 3 licensed classes of antiretroviral drugs, with a further two currently in research. The first of the licensed drugs are RTI’s (Reverse transcriptase inhibitors). These inhibit the construction of viral DNA by interfering with the reverse transcriptase enzyme involved in replicating viral DNA from RNA. Within RTI’s there are two different types which use different mechanisms to interfere with the reverse transcriptase enzyme. The first of which is a nucleoside-analogue RTI- these are incorporated into the viral DNA and lead to chain termination. Non-nucleoside analogue RTI’s use a different mechanism by which they inhibit the ability of the reverse transcriptase to bind effectively (www.medic8.com 01/11/2010).
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PI’s (protease inhibitors) are the second class of licensed antiretroviral drugs used in the treatment of HIV. PI’s interfere with the ability of proteases in the assembly of new virons, thus meaning that viral particles are unable to mature. This essentially means that HIV continues to make copies of itself, but these copies are unable to infect new cells (ww2.aegis.org 01/11/2010).
The final licensed class of antiretroviral drugs is fusion inhibitors. As its name suggests, they prevent the HIV virus from fusing with host cell membranes, which it must do in order to infect cells. When HIV binds to the CD4+ receptor, the GP120 protein deforms and allows embedding of the viral protein GP41 into the host cells membrane. Fusion inhibitors bind to the viral protein GP41 which prevents the creation of a pore through which infection occurs (pharmamotion.com.ar 01/11/2010).
The two currently unlicensed classes of antiretroviral drugs are integrase inhibitors and entry inhibitors. These antiretroviral drugs could offer those who have developed resistance to other classes of antiretroviral drugs, such as the drugs that target reverse transcriptase and protease enzymes, an effective method of treatment (www.aidsmeds.com 01/11/2010)
Antiretroviral drugs are most commonly used in combination when treating HIV. This is due to the life cycle of HIV being relatively short (sometimes as short as 1.5 days) and the absence of ‘proof reading enzymes’ which correct transcription errors between the RNA and DNA via reverse transcriptase. These properties also enable the virus to mutate very rapidly and although most of these mutations are either less or no more beneficial than the parent virus, some of them are superior and can go undetected by the immune system and therefore are not targeted by the antiretroviral drugs. Combination therapy helps to reduce the risk of HIV mutations leading to antiretroviral resistance by inhibiting several stages of the HIV life cycle and presenting multiple barriers against HIV replication. (www.medic8.com 01/11/2010)
Should the two currently unlicensed classes of drugs become licensed there is the possibility that a combination of all 5 classes of antiretroviral drugs could reduce the mortality rate of HIV sufferers by a significant amount. A further two available classes of drugs would also help a large number of individuals who have already developed resistance to the three currently licensed classes of antiretroviral drugs.
The HIV virus isn’t intelligent and so does not know which mutations will result in drug resistance, thus HIV mutations are random. HIV can become resistant to some drugs, non-nucleoside reverse transcriptase inhibitors for example, with just a single mutation. For HIV to become resistant to other antiretroviral drugs such as protease inhibitors, a series of mutations must occur. (www.aids.org 01/11/2010) This would suggest that antiretroviral drugs such as PI’s would be effective for longer than NNRTI’s and other drugs to which HIV can develop resistance to with a single mutation.
Developing resistance to one drug can also cause resistance to other antiretroviral drugs, especially those within the same class. This is known as cross resistance. With the prevalence of drug resistant HIV ever increasing, the strains of HIV that are being passed on and newly infecting people are becoming less susceptible to antiretroviral drugs, as they have already become drug resistant. This could potentially shorten the life span of those who are infected with the resistant strains compared to those who are infected with the non resistant strains of the HIV virus.
In short, the level at which HIV can be managed by antiretroviral drugs could become substantially reduced as a result of widespread antiretroviral drug use and the development of drug resistance HIV strains. This would have a severely detrimental effect on the life span and quality of life of HIV sufferers. This is why combination therapy is so vital, as when taken consistently by the sufferer, it reduces the possibility of mutations of the HIV virus that could potentially result in the HIV virus becoming resistant to one or more antiretroviral drugs.
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