Aids Disease In Humans And Hiv Management Biology Essay

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Acquired Immunodeficiency Syndrome (AIDS) is a disease firstly appears in the 1980s and now it is one of the major causes of death of the human population in the globe. AIDS is caused by HIV-1 and HIV-2. The discovery and isolation of the virus which causes AIDS happened by the use of tissue from patients with AIDS. The clinical investigations showed that the HIV virus disable and kills the CD4+ T lymphocytes cells which are playing a main role in the immune responses of the human organism. The killing of these cells do not allow the organism to detect and response to any other infectious organisms making the organism vulnerable.(Brigid M. K. 2008)

HIV virus in order to gain access to the interior of the cell binds to the CD4 receptors which are found on the surface of the T-cells. HIV binds to the CD4 receptors by the help of the gp120, at the same time HIV must bind to a co-receptor in order to gain entry to the CD4+ T cell. There are two receptors (CCR5 and CXCR4) which are important for the entry of the HIV into the cell.

At first, HIV was unmanageable but nowadays the uses of drugs help to manage the virus but not curing it. Firstly antimicrobial drugs where used in order to treat other infections which were able to infect the human organism because of its low immune response. These drugs help a lot because they were able to allow the organism to be free of infection by microbes and other infectious organisms, therefore increasing the lifetime of the AIDS-patients. Later on, in the late 90s and the beginning of the 21st century after clinical trials and more research in the subject of HIV scientists realise that the use of a combination of three drugs had amazing results against AIDS compare to the use of one drug only.

HIV is a retrovirus , it has ribonucleic acid as a genetic material. RNA of the virus undergoes a pathway in order to convert RNA into DNA. On the other hand organisms like mammals and plants have their DNA converted into RNA. Therefore this process which happen in HIV is a reverse pathway ( RNA into DNA).

Moreover the drugs used against retroviruses are called antiretroviral. These drugs can act in different parts of the life cycle of HIV, but until now there is no cure for the HIV/AIDS.

During the HIV life cycle some proteins are require for the replication of the virus. These proteins are: reverse transcriptase, integrase and protease. They are very important for the replication of the virus and continued infection of the cells. Therefore the drugs against HIV are design to inhibit (knock out) these enzymes in order to make HIV less aggressive. Anti-HIV drugs were design to inhibit the parts of the life cycle of HIV. These parts are: reverse transcriptase (RNA is converted into DNA), integration (helps viral DNA to be inserted into the DNA of the cell). And also to the polyprotein processing (protease is taking the large proteins of the virus and make them smaller).

Therefore the inhibition of the above enzymes will disturb the HIV replication and infection of cells and improve the immune system of the host. However the improvement in the immune system will not improve anymore and will start to fall. This is because the HIV is developing resistance to the drugs which are used. Probably HIV will develop resistance to the drugs which are going to be discovered in the future. Moreover the antiretroviral therapy must be followed for a lifetime. If the treatment is stopped by the patient, HIV will come back; activated and the CD4+ T-cells will drop rapidly to dangerous levels which will put the life of the patient in danger. Therefore the selection of drugs must be the best suited one to the patient, with less adverse effects (toxicity - leading to death because of drugs).Thus design of anti-HIV drugs need a lot of study and trials in order to get drugs with less adverse effects.

Nowadays there are four classes of anti-HIV drugs in use:

Reverse transcriptase inhibitors

-- Nucleotide reverse transcriptase inhibitors

-- Non-Nucleoside reverse transcriptase inhibitors

Protease Inhibitors

Integrase inhibitors

Entry Inhibitors

The reverse transcriptase inhibitors are divided into two subgroups. The nucleotide reverse transcriptase inhibitors and non-nucleoside inhibitors. The reverse transcriptase inhibitors were the first drugs introduced for the treatment of HIV as they target the reverse transcriptase enzyme of which is vital for the virus existence. The inhibitors are affecting the reverse transcriptase of the virus but they do not do a lot of damage if they are used in doses safe for humans. Therefore the RT inhibitors were not doing the work which the scientists were expecting to do. (disable the RT totally). In higher doses probably they will work but they will cause death to the host because of their high toxicity. The reverse transcription in HIV life cycle could be terminated but toxicity of the drugs used will kill the HIV-free host cells which are following their cell division as well. Moreover the reverse transcriptase enzyme it does not copy always the RNA sequence into DNA exactly as it should, therefore HIV has a high mutation rate and a high diversity around the world.

The first and major drugs used against HIV are reverse transcriptase inhibitors. There are nineteen drugs which are approved for the treatment of HIV. Eleven of them inhibit the reverse transcriptase. Seven out of eleven are nucleoside reverse transcriptase inhibitors (NRTIs). Some NRTIs are Zidovudine (AZT, ZDV), Didanosine (ddI), Zalcitabine (ddC), Stavudine (d4T).

Moreover the non-nucleoside reverse transcriptase inhibitors (NNRTIs) are nevirapine, efavirenz and delavirdine. There is also another one drug which is called PMPA-tenofovir. Some of the above drugs can be combined together for better results. In addition more reverse transcriptase are under trials and design. Some of them are the etravine (TMC125) and rilpirine (R278474) which show a high success against the HIV in clinical trials. NRTIs are very important because they miss a hydroxyl group at the 3’ end of the ribose ring. This help the drug to fit to the DNA of the virus and act as a terminator. Therefore while RT starts the reverse transcription of the RNA into DNA, it takes nucleosides but when it takes nucleosides from the drug instead of the ones from the host cell reverse transcription stops. During this process the drug is phosphorylated and it triphosphate form it is used by the RT enzyme of HIV. Moreover the NRTIs are similar to the nucleosides found in every cell, therefore they can bind to the DNA of the cell and probably cause death because of they are toxic. On the other hand drugs from the NNRTIs subgroup bind to the Reverse transcriptase enzyme active site. They are not toxic for the host cells because they only bind the RT enzyme of HIV. Another one characteristic of NNRTIs is the non competitive inhibition compare to the NRTIs.

Furthermore the uses of two to three drugs from different classes together have a major role against the increase of drug resistance of HIV.

The entire block HIV will decrease any chance of drug resistance. However the development of drug resistance derive from the variation and diversion of the HIV. Therefore there are cases where the drugs do not have any benefit because that specific type of HIV is resistant. This high variation of HIV is caused by the high replication rate and by the errors made by the RT of HIV and the polymerase of the host.

One of the fisrt drugs found was the AZT (azidothymidine), aldo called zidovudine (ZDV). It was used firstly in the late 80s and it was permitted to be used because it was found to decrease the number of deaths from AIDS. It was taken twice a day. For a couple of years it was the only drug used against HIV until the design of new RT inhibitors and then it was used in a combination with other anti-HIV drugs. It acts on the RT enzyme and it takes part during the reverse transcription and acts as a terminator.

All the NRTIs undergo phosphorylation and then they act as terminators.

A different category of anti-HIV drugs are the inhibitors of HIV protease enzyme. Protease inhibitors are acting on the HIV protease enzyme. They bind to the active site of the Protease enzyme and they disable it, causing the process of polyprotein processing to stop. HIV protease is found in every HIV particle and it is responsible for the creation of small protein by the breakdown of large non active proteins. This process is very vital for the HIV life cycle. When the process ends and smaller proteins are created, the viral particles can get out of the cell and infect the nearby cells. If the virus do not have the small proteins the virus is in an immature condition therefore it is not possible to get out of the cell and infect the other HIV-free host cells. The creation of this type of drugs put the standards in a higher level. They help a lot in the treatment against HIV and this can be seen by a lot of studies showing that the use of HIV protease inhibitors decrease the number of people dying from AIDS and also increase the life span of AIDS patients. Moreover a way to improve the PR inhibitors is the use of a second PR inhibitor. The second PR is used in a lower dosage. Normally the second inhibitor used is ritonavir. The role of ritonavir is to inhabit the cytochrome P450 enzymes. Which are found in every human cell and mainly in the liver and intestines. Their function is to breakdown drugs. The inhibition of CYP3A4 enzyme (mainly) by ritonavir causes the main PR inhibitor to remain for more time in the organism without breaking down. Therefore the main PR stay longer in the host and inhibit HIV.

Until now ten protease inhibitors are approved by FDA for the treatment of HIV. Some of them can be used in a combination with the ritonavir drug. The first protease inhibitor was saquinavir. It was approved in 1995. The design of protease inhibitors was very important because the drugs were remaining in the body for longer time and it was slowing donw the replication rate of HIV. However some side effects can be observed. Diarrhoea and headache can be occurring.

Another class of anti-HIV drugs were design. These drugs will act on the integrase enzyme of HIV. The function of this enzyme is to integrate the viral DNA into the DNA of the host cell. This function is very essential for the HIV life cycle. Integrase is an enzyme which appears only in the virus and it does not exist in the host cells, so the inhibition of this enzyme will occur only in the HIV. Integrase has a central core which is the place where the active site is situated. The integrase inhibitors bind to the active site and do not allow then enzyme to integrate the viral DNA and the DNA of the host. This fuction is very important for the existence of HIV and if it was going to be stopped then the drugs will do a lot of damage to the HIV life cycle. However integrase inhibitors are still in clinical trial stage. None was approved until now. There are three drugs waiting for approval from the FDA . These drugs are raltergravir, eltagravir and 364735. The approval of these drugs will be a great forward step in the treatment of HIV. (Lin S. S., Xu F., Liao P.-H., Yang C.-C. 2008)

Another class of drugs is the viral entry inhibitors. These drugs are divided into two subgroups. The attachment inhibitors and the fusion inhibitors. Attachment inhibitors are binding to the CD4 receptor or the other two co-receptors CCR5 and CXCR4 and they result in the inhibition of attachment.

The drugs approved until now are two: maraviroc and endfuvirtide. Maraviroc is an attachment inhibitor. It inhibits the binding of HIV to CCR5 receptors. The drug is mainly used by people which their HIV is binding to the CCR5 receptors. This drugs cannot be used by people which their HIV is binding to CD4 receptor or to both CCR5 and CXR4.

Endfuvirtide is a fusion inhibitor. It is taken by injections and it is used by patients which are not able to take any other ant-HIV drug. It is binds to the gp41 and it does not allow the gp41 to changce its structure in order to fuse with the host cell.